Pfizer-BioNTech COVID-19 vaccines

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Extended version of the vaccine

Pfizer-BioNTech COVID-19 vaccines

Authorization

Pfizer-BioNTech COVID-19 vaccine (original strain)

World Health Organization Emergency Use Listing Procedure

Listed for emergency use on 31 December 2020 [WHO, 2020 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 5 years of age and older [WHO, 2022 ].
SAGE/WHO Recommendation: Recommended for individuals 6 months of age and older [WHO, 2022 ].

European Commission (based upon the recommendation of the European Medicines Agency)

Authorized for emergency use (Conditional Marketing Authorization).
21 December 2020: For individuals 16 years of age and older [EMA, 2020 ].
28 May 2021: For individuals from 12 to 15 years of age [EMA, 2021 ].
07 December 2021: For individuals 5 years of age and older [EMA, 2022 ].

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Authorized for emergency use on 22 December 2020 [ADMINISTRACIÓN NACIONAL DE MEDICAMENTOS, 2020 ].

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Authorized for emergency use on 23 February 2021 [ANVISA, 2021 ].
11 June 2021: Authorized for emergency use in individuals 12 to 16 years of age [Agencia Nacional de Vigilancia Sanitaria, 2021 ].

Health Canada [Government of Canada, 2022 ].
Authorized for emergency use on 9 December 2020.
5 May 2021: Authorized for emergency use in individuals 12 to 17 years of age.
1 June 2022: Authorized for emergency use in individuals 5 years of age and older

Public Health Institute (ISP, Chile) [Instituto de Salud Pública de Chile, 2022 ].
Authorized for emergency use on 16 December 2020.
31 May 2021: Authorized for emergency use in individuals 12 to 16 years of age.
January 2022: Authorized for emergency use in individuals 5 years of age and older.
23 August 2022: Authorized for emergency use in individuals 6 months of age and older [Instituo de Salud Pública, 2022 ].

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use on 5 January 2021 [Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA), 2021 ].


Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized.

U.S. Food and Drug Administration
Authorized for emergency use.
11 December 2020: Emergency Use Authorization (EUA) for individuals 16 years of age and older [FDA, 2020 ].
10 May 2021: Emergency Use Authorization (EUA) for individuals 12 to 15 years of age [FDA, 2021 ].
29 October 2021: Emergency Use Authorization (EUA) for individuals from 6-11 years of age [FDA, 2021 ].
17 June 2022: Emergency Use Authorization (EUA) for individuals from 6 months to 5 years of age [FDA, 2021 ].

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use on 26 November 2021 [Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIF) Mexico, 2020 ].

Authorization in jurisdictions in Latin America and the Caribbean
Antigua and Barbuda
Aruba
Bahamas
Barbados
Belize
Bermuda
Bolivia
Cayman Islands
Costa Rica
Curaçao
Dominican Republic
Ecuador
El Salvador
Guadeloupe
Guatemala
Guyana
Maldives
Honduras
Jamaica
Martinique
Nicaragua
Panama
Paraguay
Peru
Puerto Rico
Saint Kitts and Nevis
Saint Vincent and the Grenadines
San Martin
Trinidad and Tobago
Turks and Caicos Islands
Uruguay

Authorization in other jurisdictions
Albania
Andorra
Angola
Armenia
Australia
Austria
Azerbaijan
Bahrain
Bangladesh
Belgium
Benin
Bhutan
Bonaire
Bosnia and Herzegovina
Botswana
Brunei
Bulgaria
Burkina Faso
Cabo Verde
Canada
Cameroon
Côte d’Ivoire
Croatia
Cyprus
Czechia
Democratic Republic of the Congo
Denmark
Egypt
Eswatini
Ethiopia
Estonia
European Union
Faroe Islands
Finland
France
Gabon
Georgia
Germany
Ghana
Greece
Greenland
Guinea
Guyana
Hong Kong
Hungary
Iceland
Indonesia
Iraq
Ireland
Israel
Italy
Japan
Jordan
Kazakhstan
Kenya
Kosovo
Kuwait
Kyrgyzstan
Lao People's Democratic Republic
Latvia
Lebanon
Libya
Liechtenstein
Lithuania
Luxembourg
Malawi
Malaysia
Maldives
Malta
Micronesia
Mauritius
Moldova
Monaco
Mongolia
Montenegro
Morocco
Namibia
Nepal
Netherlands
New Zealand
Nigeria
Niue
North Macedonia
Norway
Oman
Pakistan
Papua New Guinea
Philippines
Poland
Portugal
Qatar
Republic of Korea
Republic of Moldova
Romania
Rwanda
Saint Lucia
Saudi Arabia
Serbia
Singapore
Slovakia
Slovenia
South Africa
South Korea
Spain
Sri Lanka
Sudan
Sweden
Switzerland
Taiwan
Tanzania
Thailand
Timor-Leste
Togo
Tonga
Tunisia
Turkey
Ukraine
United Arab Emirates
United Kingdom
United States of America
Vatican
Viet Nam
West Bank
Zambia

Adapted Pfizer-BioNTech COVID-19 vaccines

Comirnaty bivalent (original + omicron BA.1)

World Health Organization Emergency Use Listing Procedure
Listed for emergency use on 19 October 2022.
EUL/WHO Authorization: Authorized for emergency use in individuals 12 years of age and older [WHO, 2022 ].
SAGE/WHO Recommendation: Recommended for booster doses in individuals 12 years of age and older according to its regulatory approval status [WHO, 2022 ].

European Commission (based upon the recommendation of the European Medicines Agency)
Authorized for emergency use (Conditional Marketing Authorization).
01 September 2022: For individuals 12 years of age and older [EMA, 2022 ].

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Not authorized.

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Not authorized.

Health Canada
Not authorized.

Public Health Institute (ISP, Chile)
29 September 2022: Authorized for emergency use in individuals 12 years of age and older [ISP, 2022 ].

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Not authorized.

Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized.

U.S. Food and Drug Administration
Not authorized.

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Not authorized.

Authorization in jurisdictions in Latin America and the Caribbean
Chile

Authorization in other jurisdictions
Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Japan
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom

Comirnaty bivalent (original + omicron BA.4/BA.5)

World Health Organization Emergency Use Listing Procedure
Listed for emergency use on 11 November 2022.
EUL/WHO Authorization: Authorized for emergency use in individuals 12 years of age and older [WHO, 2022 ].
SAGE/WHO Recommendation: Recommended for booster doses in individuals 12 years of age and older according to its regulatory approval status [WHO, 2022 ].

European Commission (based upon the recommendation of the European Medicines Agency)
Authorized for emergency use (Conditional Marketing Authorization).
12 September 2022: For individuals 12 years of age and older [EMA, 2022 ].

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Not authorized.

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Not authorized.

Health Canada
Not authorized.

Public Health Institute (ISP, Chile)
Not authorized.

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Not authorized.

Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized.

U.S. Food and Drug Administration
Authorized for emergency use [FDA, 2022 ].
31 August 2022: Emergency Use Authorization (EUA) for individuals 12 years of age and older.
12 October 2022: Emergency Use Authorization (EUA) for individuals 5 years of age and older.

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Not authorized.

Authorization in jurisdictions in Latin America and the Caribbean
Not authorized.

Authorization in other jurisdictions
Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Japan
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United States of America

The Emergency Use Authorization does not constitute marketing authorization in the country.

Manufacturing

Pfizer-BioNTech COVID-19 vaccine (original strain)

Manufacturer

Drug substance [WHO, 2022 ]
BioNTech Manufacturing GmbH. Mainz, Germany.
BioNTech Manufacturing Marburg. Marburg, Germany.
Rentschler Biopharma SE. Laupheim, Germany.
Pfizer Andover ACMF, Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC, USA.


Other manufacturers

Drug product [WHO, 2022 ]
Main manufacturer of the drug product:
Baxter Oncology GmbH. Westfalen, Germany.
BioNTech Manufacturing GmbH. Mainz, Germany.
Pfizer Manufacturing Belgium NV, Belgium.
Novartis. Stein, Switzerland.
Mibe GmbH Arzneimittel. Brehna, Germany.
Delpharm Saint-Remy. Saint-Remy sur Avre, France.
Sanofi-Aventis Deutschland GmbH, Germany.
Siegfried Hameln GmbH, Germany.
Patheon Italia S.p.A., Italy.
Pharmacia & Upjohn Company LLC, United States.
Hospira Inc., a Pfizer company, United States.
Exelead, Inc., United States.
Exela Pharma Sciences, United States.

Filling and packaging
Pfizer Inc., USA: Process of molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. For all markets, this stage is conducted in the United States.
Pfizer Manufacturing Belgium: The Pfizer plant in Puurs is responsible for all vials for destinations outside the United States.

Diluent Suppliers
Pfizer Perth, Australia.
Fresenius Kabi, USA.
Pfizer Manufacturing, Belgium.
Kwang Myung Pharm Co, Ltd, South Korea.

Adapted Pfizer-BioNTech COVID-19 vaccines

Comirnaty bivalent (original + omicron BA.1)


Manufacturers [WHO, 2022 ]
Pfizer Manufacturing Belgium NV. Puurs, Belgium
Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany

Comirnaty bivalent (original + omicron BA.4/BA.5)

Manufacturers [WHO, 2022 ]
Drug product
Pfizer Manufacturing Belgium NV. Puurs, Belgium
Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany
mibe GmbH Arzneimittel, Brehna, Germany

General characteristics

The Pfizer-BioNTech COVID-19 vaccine is an RNA vaccine composed of nucleoside-modified mRNA (modRNA). It is a single-stranded, 5'-capped messenger RNA that has been generated through cell-free in vitro transcription from a DNA template encoding the viral spike protein of SARS-CoV-2 [WHO, 2020 ].

The mRNA sequence encoding the protein was synthesized using an optimized T7 RNA polymerase-mediated transcription reaction with complete replacement of uridine by N1-methyl-pseudouridine [Deva Priya SA, 2021 ]. The reaction included a DNA template containing the immunogen open reading frame flanked by 5′untranslated region (UTR) and 3′UTR sequences and was terminated by an encoded polyA tail [Deva Priya SA, 2021 ].

The mRNA is encapsulated in lipid nanoparticles through a modified ethanol-drop nanoprecipitation process [Hassett KJ, 2019 ].After injection, body cells take up the lipid nanoparticle, delivering the mRNA sequence into cells for translation into viral protein and then initiating the immune response against COVID-19 [Hassett KJ, 2019 ].

The expressed membrane-bound spike protein of SARS-CoV-2 is then recognized by immune cells as a foreign antigen. This elicits both T-cell and B-cell responses to generate neutralizing antibodies, which may contribute to protection against COVID-19.

It is important for the immune system to respond to the virus at the prefusion stage because it would probably be too late for the immune system to intervene at the postfusion stage when the virus is entering into the cell [Xia X, 2021 ]. Proline substitution is one of the main techniques reported to stabilize the SARS-CoV-2 spike at prefusion conformation. Spike protein variants can exhibit different levels of expression in comparison to the parental construct, and improved ability to withstand heat stress, storage temperature and resistance to freeze-thaw cycles [Hsieh CL, 2020 ].

The modification of the lipid nanoparticles improves the immune response and improves tolerability [Hassett KJ, 2019 ].

 

Ingredients
The vaccine contains the following ingredients:

Active ingredient
One dose (0.3 mL) contains 30 mg nucleoside-modified messenger RNA encoding the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion configuration, embedded in lipid nanoparticles or LNP.

Excipients

((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315)

2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159)
1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC)
Cholesterol
Potassium chloride
Potassium dihydrogen phosphate
Sodium chloride
Disodium phosphate dihydrate
Sucrose
Water for injections

 

Risk considerations

The Pfizer-BioNTech COVID‑19 Vaccine is a non-replicating and non-integrating platform. This means the delivered mRNA does not interact with the genome and does not carry a risk for infection [GAVI,2020 ].

Lipid nanoparticle (LNP)-formulated mRNA vaccine technology allows the delivery of precise genetic information together with an adjuvant effect to antigen-presenting cells. It is molecularly well defined, in principle, free of materials of animal origin [WHO, 2020 ].

Dosing and schedule

Pfizer-BioNTech COVID-19 vaccine (original strain)

The recommended schedule for the Pfizer-BioNTech COVID-19 vaccine is: [WHO, 2022 ]
For children aged 6 months to 4 years: a series of three doses (3μg, 0.2 ml each). The first two doses are administered 3 weeks apart followed by a third dose at least 8 weeks after, according to the manufacturer label.
For children aged 5 to 11 years: a series of two doses (10 μg, 0.2 ml each) 4 to 8 weeks apart.
For persons 12 years of age and older: a series of two doses (30 μg, 0.3 ml) 4 to 8 weeks apart.
WHO recommends extending the interval between the first and second dose up to 8 weeks.

The preferred site of injection is the deltoid muscle of the upper arm.


This vaccine is presented as: [WHO, 2022 ]
This vaccine is presented as: [WHO, 2022 ]
1. Concentrate for dispersion for intramuscular injection provided in a multidose vial (6 doses of 0.3 mL per vial, after diluting with 0.9% Sodium Chloride) indicated for persons aged 12 and older (purple cap vial, dilution required).
2. Ready to use dispersion for injection provided in a multidose vial. One dose (0.3 mL) contains 30 micrograms of Pfizer COVID-19 vaccine indicated for persons aged 12 and older (grey cap vial).
3. Pediatric formulation: concentrate for dispersion for intramuscular injection provided in a multidose vial (10 doses of 0.2 mL per vial, after diluting with 0.9% Sodium Chloride) indicated for persons aged 5 to 11 years (orange cap vial, dilution required).
4. Pediatric formulation (6 months to 4 years): concentrate for dispersion for intramuscular injection provided in a multidose vial (10 doses of 0.2 mL per vial, after diluting with 0.9% Sodium Chloride) indicated for persons aged 6 months to 4 years (maroon cap vial, dilution required) [FDA, 2022 ].

Booster dose [WHO, 2022 ]
A booster dose is recommended for the highest priority-use groups (e.g. older adults and health workers) 4-6 months after the completion of the primary series. If more than 6 months have elapsed since the completion of the primary series, the booster dose should be given at the earliest opportunity.
Once high booster dose coverage has been achieved in the highest priority-use group, countries may also consider a booster for other lower priority-use groups.

WHO has not yet determined the need for and timing of booster doses for persons below 12 years of age, except for immunocompromised children.
EMA recommends a booster dose of Comirnaty 10 micrograms for children 5 to 11 years of age at least after 6 months after the primary schedule [EMA, 2022 ].

Second booster dose:
WHO recommends considering a second booster dose 4-6 months after the first booster dose for all older persons (age-specific cutoff defined by countries), all persons with moderate and severe immunocompromising conditions -regardless of age-, adults with comorbidities that put them at higher risk of severe disease, pregnant women, and health workers [WHO, 2022 ].

FDA recommends a second booster dose for persons 50 years of age and older and immunocompromised individuals from 12 years of age, provided at least after 4 months of the first booster dose [FDA, 2022 ].
EMA recommends second booster dose for persons 60 years of age and older and medically vulnerable individuals provided at least after 4 months of the first booster dose [EMA, 2022 ].


Heterologous schedule [WHO, 2022 ]
WHO supports a flexible approach to use different COVID-19 vaccine platforms for different doses (heterologous schedule) and considers two doses of any EUL COVID-19 vaccine to constitute a complete primary series.

For persons aged 12 and older, a 30 μg dose of the Pfizer-BioNTech COVID-19 vaccine may be used as a booster dose following a completed primary series using any other EUL COVID-19 vaccine platform.

A heterologous booster (i.e. using COVID-19 vaccines from other platforms than mRNA) and variant-adapted vaccines (once they have received regulatory approval) can be used for first and second boosters.

With heterologous schedules, the order of the vaccines administered can affect the levels of the immune response. A boost with the Pfizer COVID-19 vaccine after a primary series with another platform often led to higher neutralizing antibody titers. More information about clinical trials on vaccine efficacy for heterologous schedules is available in the "efficacy and effectiveness" section of this dashboard.
Heterologous vaccination should only be implemented with careful consideration of current vaccine supply, vaccine supply projections, and other access considerations, along with the potential benefits and risks of the specific products being used.


Vaccination schedule for immunocompromised persons [WHO, 2022 ]
WHO recommends an extended primary series including an additional (third) dose of 30 μg for immunocompromised persons aged 12 years and older, and 10 μg for immunocompromised persons aged 5 to 11 years.

An additional (third) dose should be given 1-3 months after the second dose in the standard primary series. If more than 3 months have elapsed since the second dose in the primary series, the additional (third) dose should be given at the earliest opportunity.

A first and second booster dose (fourth and fifth doses) given 4-6 months after the previous dose is recommended for all immunocompromised persons.

Adapted Pfizer-BioNTech COVID-19 vaccines

Comirnaty bivalent (original + omicron BA.1)

Comirnaty bivalent (original + omicron BA.1) is administered as a single booster dose (0.3 mL) for persons aged 12 years and older after three months of the primary series or monovalent booster [EMA, 2022 ].

The pharmaceutical form is a dispersion for intramuscular injection provided in a multidose vial (each 0.3 mL dose containing 15 μg of tozinameran and 15 μg of riltozinameran) [WHO, 2022 ].
The preferred site of injection is the deltoid muscle of the upper arm.

Comirnaty bivalent (original + omicron BA.4/BA.5)

Comirnaty bivalent (original + omicron BA.4/BA.5) is administered as a single booster dose (0.3 mL) for persons aged 12 years and older after three months of the primary series or monovalent booster [WHO, 2022 ].
FDA recommends to administer Comirnaty bivalent (original + omicron BA.4/BA.5) as a single booster dose (0.2 mL for persons aged 5-11 years, and 0.3 mL for persons aged ≥12 years) after two months of the primary series or monovalent booster [FDA, 2022 ].

The pharmaceutical form is a dispersion for intramuscular injection provided in a multidose vial (each 0.3 mL dose containing 15 μg of tozinameran and 15 μg of famtozinameran)
The preferred site of injection is the deltoid muscle of the upper arm.

Indications and contraindications

Pfizer-BioNTech COVID-19 vaccine (original strain)

Indications

Pfizer - BNT162b2 COVID-19 vaccine is indicated for individuals 6 months of age and older [WHO, 2022 ].

For prioritization by age and other considerations, refer to the WHO Prioritization Roadmap [WHO, 2022 ]

WHO recommends the use of Pfizer COVID-19 vaccine in pregnant persons.
WHO does not recommend pregnancy testing before vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2022 ].


Contraindications

Pfizer-BioNTech COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the vaccine [WHO, 2022 ]. (See the list of ingredients under 'General characteristics' in the extended version).
The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis after the first dose of the Pfizer-BioNTech COVID-19 vaccine [WHO, 2022 ].

Adapted Pfizer-BioNTech COVID-19 vaccines

Comirnaty bivalent (original + omicron BA.1)

Indications
Comirnaty bivalent (original + omicron BA.1) is indicated as a booster dose for individuals 12 years of age and older [WHO, 2022 ].

Contraindications

Comirnaty bivalent (original + omicron BA.1) is contraindicated in individuals with a known history of a severe allergic reaction to any component of the vaccine [EMA, 2022 ]. (See the list of ingredients under 'General characteristics' in the extended version).

Comirnaty bivalent (original + omicron BA.4/BA.5)

Indications
Comirnaty bivalent (original + omicron BA.4/BA.5) is indicated as a booster dose (0.3 mL) for persons aged 12 years and older [WHO, 2022 ].
FDA recommends to administer Comirnaty bivalent (original + omicron BA.4/BA.5) as a booster dose for individuals 5 years of age and older [FDA, 2022 ].

Contraindications

Comirnaty bivalent (original + omicron BA.4/BA.5) is contraindicated in individuals with a known history of a severe allergic reaction to any component of the vaccine [EMA, 2022 ], [FDA, 2022 ]. (See the list of ingredients under 'General characteristics' in the extended version).

Close observation for at least 30 minutes is recommended following vaccination.

Precautions

Pfizer-BioNTech COVID-19 vaccine (original strain)

Allergic reactions [WHO, 2022 ].
A history of anaphylaxis to any other vaccine or injectable therapy (i.e. intramuscular, intravenous, or subcutaneous vaccines or therapies), is not a contraindication to vaccination. For such persons, a risk assessment should be conducted by a health professional. Such persons should be observed for 30 minutes after vaccination.

Individuals with an immediate non-anaphylactic allergic reaction to the first dose (such as urticaria, angioedema, or respiratory symptoms) that occur within 4 hours of administration should not receive additional doses unless recommended after review by a health professional. However, subject to individual risk-benefit assessment, the Pfizer-BioNTech COVID-19 vaccine could be provided under close medical supervision if it is the only available vaccine for persons at high risk of severe disease.

As a small number of anaphylactic reactions have also been reported in vaccines without a history of anaphylaxis, it is recommended that Pfizer-BioNTech COVID-19 vaccine should be administered only in settings where anaphylaxis can be treated. Until more data are available with regard to anaphylaxis after vaccination, all vaccinees should be observed for at least 15 minutes after vaccination.

Food, insect venom and contact allergies and allergic rhinitis, eczema and asthma are not considered a contraindication to vaccination. The vial stoppers are not made with natural rubber latex, and there is no contraindication or precaution to vaccination for persons with a latex allergy. In addition, as BNT162b2 does not contain eggs or gelatine, there is no contraindication or precaution to vaccination for persons with allergies to any food substances.

Myocarditis [WHO, 2022 ].
Myocarditis is a very rare adverse event that has been reported after receipt of mRNA COVID-19 vaccines. The observed risk is highest in males aged 12–29 years, and higher after the second dose. Available data suggest that the immediate course of myocarditis and pericarditis following vaccination is generally mild and responds to treatment. Vaccinated individuals should be instructed to seek immediate medical attention if they develop symptoms indicative of myocarditis or pericarditis (e.g. persisting chest pain, shortness of breath, or palpitations following vaccination). Other potential causes of myocarditis and pericarditis should also be ruled out.

Pregnancy [WHO, 2022 ]
WHO recommends the use of Pfizer COVID-19 vaccine in pregnant persons.
WHO does not recommend pregnancy testing before vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination.

Breastfeeding [WHO, 2022 ].
Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults. As the Pfizer-BioNTech COVIV-19 vaccine is not a live virus vaccine and the mRNA does not enter the cell nucleus and is rapidly degraded, it is biologically and clinically unlikely to pose a risk to the nursing infant. Based on these considerations, WHO recommends its use in breastfeeding women.
WHO does not recommend stopping breastfeeding due to vaccination.

Children and adolescents [WHO, 2022 ].
The priority remains to prevent deaths by achieving high vaccine coverage (primary series and boosters) in the highest and high priority-use groups. It is of utmost importance for children to continue to receive the recommended childhood vaccines for other infectious diseases.

Older persons [WHO, 2022 ].
Vaccination is recommended for older persons without an upper age limit

Immunocompromised persons [WHO, 2022 ].
Information and, where possible, advice on the safety and efficacy of the vaccine in immunocompromised persons should be provided to inform individual risk-benefit assessment.

Persons living with HIV [WHO, 2022 ].
Persons living with HIV who are stable on antiretroviral therapy should be vaccinated. It is not necessary to test for HIV infection before administration of the vaccine.

Persons with previous SARS-CoV-2 infection [WHO, 2022 ].
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection.
The optimal minimum interval between a natural infection and vaccination is not yet known, but an interval of 3-6 months could be considered.

Persons with current acute COVID-19 [WHO, 2022 ].
Persons with acute PCR-confirmed COVID-19, including between doses, should not be vaccinated until after they have recovered from acute illness and the criteria for discontinuation of isolation have been met.

Persons who previously received passive antibody therapy for COVID-19[WHO, 2022 ]
Although some reduction in vaccine-induced antibody titers has been observed in this group, the balance of benefits versus risks favors vaccination.

Other precautions
Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5 °C) or acute infection [WHO, 2022 ].
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [WHO, 2020 ].

Co-administration with other vaccines
For adults, based on several co-administration studies, COVID-19 vaccines may be administered concomitantly or at any time before or after other adult vaccines, including: live attenuated vaccines, inactivated, adjuvanted, or non-adjuvanted vaccines.
When administered concomitantly, the vaccines should be injected at separate sites, preferably different extremities [WHO, 2022 ].

Inactivated influenza vaccine
WHO recommends that countries consider co-administration of COVID-19 vaccines with seasonal influenza vaccines, whenever feasible, dependent on seasonality [WHO, 2022 ].

Adapted Pfizer-BioNTech COVID-19 vaccines

Comirnaty bivalent (original + omicron BA.1)

Allergic reactions [EMA, 2022 ].
Events of anaphylactic reactions have been reported. Appropriate medical treatment and supervision should be available in case of an anaphylactic reaction following the administration of Comirnaty bivalent (original + omicron BA.1).
Close observation for at least 15 minutes is recommended following vaccination

Myocarditis and pericarditis [EMA, 2022 ].
The risk of myocarditis after a booster dose of Comirnaty bivalent (original + omicron BA.1) has not yet been characterized.
There is an increased risk of myocarditis and pericarditis after vaccination with Comirnaty, observed more often after the second dose, and in younger males.

Pregnancy [EMA, 2022 ]
There are no available data regarding the use of Comirnaty bivalent (original + omicron BA.1) during pregnancy.
However, a large amount of observational data from vaccination with Comirnaty during the second and third trimesters have not shown an increase in adverse pregnancy outcomes.

Breastfeeding [EMA, 2022 ].
There are no available data regarding the use of Comirnaty bivalent (original + omicron BA.1) during breastfeeding.
However, observational data from vaccination with Comirnaty from breastfeeding women have not shown an increase in adverse effects in breastfed infants.

Immunocompromised persons [EMA, 2022 ].
The efficacy and safety of this vaccine have not been assessed in immunocompromised persons. The efficacy of Comirnaty bivalent (original + omicron BA.1) may be lower in these individuals.

Other precautions
Vaccination should be postponed in individuals with an acute febrile illness or acute infection [EMA, 2022 ].
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [EMA, 2022 ].
Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions may occur in association with the vaccination process itself [EMA, 2022 ].

Comirnaty bivalent (original + omicron BA.4/BA.5)

Allergic reactions [EMA, 2022 ].
Events of anaphylactic reactions have been reported. Appropriate medical treatment and supervision should be available in case of an anaphylactic reaction following the administration of Comirnaty bivalent (original + omicron BA.4/BA.5).
Close observation for at least 15 minutes is recommended following vaccination

Myocarditis and pericarditis [EMA, 2022 ].
There is an increased risk of myocarditis and pericarditis after vaccination with Comirnaty, observed more often after the second dose, and in younger males.

Pregnancy [EMA, 2022 ]
There are no available data regarding the use of Comirnaty bivalent (original + omicron BA.4/BA.5) during pregnancy.
However, a large amount of observational data from vaccination with Comirnaty during the second and third trimesters have not shown an increase in adverse pregnancy outcomes.

Breastfeeding [EMA, 2022 ].
There are no available data regarding the use of Comirnaty bivalent (original + omicron BA.4/BA.5) during breastfeeding.
However, observational data from vaccination with Comirnaty from breastfeeding women have not shown an increase in adverse effects in breastfed infants.

Immunocompromised persons [EMA, 2022 ].
The efficacy and safety of this vaccine have not been assessed in immunocompromised persons. The efficacy of Comirnaty bivalent (original + omicron BA.4/BA.5) may be lower in these individuals.

Other precautions
Vaccination should be postponed in individuals with an acute febrile illness or acute infection [EMA, 2022 ].
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [EMA, 2022 ].
Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions may occur in association with the vaccination process itself [EMA, 2022 ].

Storage and logistics

Pfizer-BioNTech COVID-19 vaccine (original strain)

Storage [WHO, 2022 ].
The Pfizer-BioNTech vaccine is presented as: 1. Concentrated formulation (purple cap vial): concentrated frozen dispersion for injection 2. Ready to use formulation (grey cap vial): frozen dispersion for injection 3. Pediatric formulation (orange cap vial): concentrated frozen dispersion for injection
All presentations are provided frozen and stored at -75°C/-103°F (between -90°C to -60°C [-130°F to -76°F])

Ultra-low temperatures:
• at -80°C to -60°C (-112°F to -76°F) in freezer, or
• at -90°C to -60°C (-130°F to -76°F) in thermal shipper as temporary storage for up to 30 days from delivery (should be re-iced every 5 days if opened up to 2 times a day, less than 3 minutes at a time)
Diluent storage: Room temperature (up to 30 °C [86°F]).

Shelf life at different temperatures: [WHO, 2022 ].
Concentrated formulation (purple cap vial)
Undiluted vaccine at storage temperature -90°C to -60°C (-130°F to -76°F): 12 months.
Undiluted vaccine at storage temperature -25°C to -15°C (-13°F to -5°F): 2 weeks within the 12 months of shelf life.
Unopened thawed vial at 2−8 °C (36°F to 46°F): 1 month (31 days)

Ready to use formulation (grey cap vial)
Vaccine at storage temperature -90°C to -60°C (-130°F to -76°F): 12 months.
No not store at freezer temperature (-25ºC to -15ºC).
Unopened thawed vial at 2−8 °C (36°F to 46°F): 10 weeks.

Pediatric formulation (orange cap vial)
Undiluted vaccine at storage temperature -90°C to -60°C (-130°F to -76°F): 12 months.
No not store at freezer temperature (-25ºC to -15ºC).
Unopened thawed vial at 2−8 °C (36°F to 46°F): 10 weeks.

For all presentations
Do not refreeze thawed vials.
Do not freeze diluted vaccine (for concentrated and pediatric formulations).
Minimize exposure to room light.
Avoid exposure to direct sunlight and ultraviolet light.
Conditions before use: At room temperature (up to 30°C [86°F]) before dilution (if applicable) and administration.


Administration logistics
Concentrated formulation (purple cap vial) and pediatric formulation (orange cap vial)

Thaw before dilution: [WHO, 2022 ]
Verify that the vial corresponds to the targeted vaccination group.
Before dilution, vials must reach room temperature and be diluted within 2 hours
Concentrated formulation (purple cap vial) may take up to 3 hours to thaw at 2-8ºC (36-46ºF) or 30 minutes at 25°C (77°F) before dilution.
Concentrated pediatric formulation (orange cap vial) may take up to 4 hours to thaw at 2-8ºC or 30 minutes at 25°C (77°F) before dilution.

Dilute before use: [WHO, 2022 ]
1. Before dilution, invert vaccine vial gently 10 times, do not shake.
2. Draw into the mixing syringe 1.8 mL of diluent for concentrated formulation (purple cap vial, for individuals ≥12 years) or 1.3 mL for pediatric formulation (orange cap vial, for individuals 5-11 years).
3. Add the diluent into the vaccine vial and level/equalize the pressure in the vial before removing the needle by withdrawing 1.8 mL (for concentrated formulation) or 1.3 mL (for pediatric formulation) of air into the empty diluent syringe.
4. Discard diluent syringe in safety box (do not reuse) and discard diluent vial.
5. Gently invert the vial with diluted vaccine 10 times to mix. Do not shake.
6. Inspect to make sure that the vaccine is an off-white uniform dispersion. Do not use if discoloured or if containing particles.
7. Record date and time of dilution on the vaccine vial label.
8. Draw up the vaccine dose at the time of administration, pre-loading vaccine into syringes is not recommended. Use all vaccine within 6 hours after dilution.

Ready to use formulation (grey cap vial)
Thaw the vaccine for up to 6 hours at 2º-8ºC (36°F to 46°F) before use.


Administration
1.Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 mL reuse prevention syringe (RUP) or a 5 mL RUP syringe, and a 23G × 1 ”(0.60 × 25 mm) intramuscular injection needle.
To extract 6 or 10 doses from the same vial (according to the formulation), syringes and/or needles with a low dead volume (35 microliters maximum) should be used.
If conventional syringes and needles are used, there may not be enough volume to draw the last dose from the same vial.
3. If the amount of vaccine remaining in the vial cannot provide a full dose, discard the vial and the excess volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.


Storage after first puncture
Record the date and time the vial should be discarded.
After taking the first dose from the multidose vial, the vial should be used within a maximum of 6 hours (stored at 2°C to 8°C [36°F to 46°F]) or discarded at the end of the immunization session, whichever comes first [WHO, 2022 ].
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded [WHO, 2020 ].


Disposal
Due to the high risk that discarded vials of COVID-19 vaccines can be recovered, it is essential that they are guaranteed to be safely disposed at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Adapted Pfizer-BioNTech COVID-19 vaccines

Comirnaty bivalent (original + omicron BA.1)

Storage: [WHO, 2022 ]
Comirnaty Original + omicron BA.1 is provided as a frozen dispersion stored at -90 ºC to -60 ºC (-130°F to -76°F) for up to 12 months.

Unopened thawed vials may stored at 2−8 °C (36°F to 46°F) for up to 10 weeks.
No not store at freezer temperature (-25ºC to -15ºC).
Do not refreeze once thawed.
Store in the original package to protect from light.

Administration logistics [EMA, 2022 ]
Verify that the vial has a grey cap and grey border around the label and the product name is Comirnaty Original/Omicron BA.4-5.
Thaw the vaccine for up to 6 hours at 2º-8ºC (36°F to 46°F) before use.
Do not dilute the vaccine.
Do not shake the vaccine. Swirl the vial gently 10 times prior to use.

Administration [EMA, 2022 ]
1.Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Withdraw 0.3 mL of Comirnaty Original/Omicron BA.1
To extract 6 doses from the same vial, syringes and/or needles with a low dead volume (35 microliters maximum) should be used.
If conventional syringes and needles are used, there may not be enough volume to draw the last dose from the same vial.
3. If the amount of vaccine remaining in the vial cannot provide a full dose, discard the vial and the excess volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Storage after first puncture [WHO, 2022 ]
Record the date and time the vial should be discarded.
After taking the first dose from the multidose vial, the vial should be used within a maximum of 6 hours (stored at 2°C to 8°C [36°F to 46°F]) or discarded at the end of the immunization session, whichever comes first.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Disposal
Due to the high risk that discarded vials of COVID-19 vaccines can be recovered, it is essential that they are guaranteed to be safely disposed at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Comirnaty bivalent (original + omicron BA.4/BA.5)

1. Comirnaty Original + Omicron BA.4/BA.5 (15/15 micrograms, grey cap vial)

Storage: [EMA, 2022 ]
This vaccine is presented as a frozen dispersion for injection stored at -90°C to -60°C (-130°F to -76°F) for up to 12 months.

Unopened thawed vials may stored at 2−8 °C (36°F to 46°F) for up to 10 weeks.
No not store at freezer temperature (-25ºC to -15ºC).
Do not refreeze once thawed.
Store in the original package to protect from light.

Administration logistics [EMA, 2022 ]
Verify that the vial has a grey cap and grey border around the label and the product name is Comirnaty Original/Omicron BA.4-5.
Thaw the vaccine for up to 6 hours at 2º-8ºC (36°F to 46°F) before use.
Do not dilute the vaccine.
Do not shake the vaccine. Swirl the vial gently 10 times prior to use.

Administration [EMA, 2022 ]
1.Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Withdraw 0.3 mL of Comirnaty Original/Omicron BA.4/BA.5.
To extract 6 doses from the same vial, syringes and/or needles with a low dead volume (35 microliters maximum) should be used.
If conventional syringes and needles are used, there may not be enough volume to draw the last dose from the same vial.
3. If the amount of vaccine remaining in the vial cannot provide a full dose, discard the vial and the excess volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Storage after first puncture [EMA, 2022 ]
Record the date and time the vial should be discarded.
After taking the first dose from the multidose vial, the vial should be used within a maximum of 12 hours (stored at 2°C to 8°C [36°F to 46°F]).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Disposal
Due to the high risk that discarded vials of COVID-19 vaccines can be recovered, it is essential that they are guaranteed to be safely disposed at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

2. Comirnaty Original + Omicron BA.4/BA.5 (5/5 micrograms, orange cap vial):

Storage: [FDA, 2022 ]
This vaccine is presented as a concentrated frozen dispersion for injection stored at -90°C to -60°C (-130°F to -76°F) for up to 12 months.

Unopened thawed vials may stored at 2−8 °C (36°F to 46°F) for up to 10 weeks.
No not store at freezer temperature (-25ºC to -15ºC).
Do not refreeze once thawed.
Store in the original package to protect from light.

Administration logistics [FDA, 2022 ]
Verify that the vial has a orange cap and orange border around the label and the product name is Comirnaty Original/Omicron BA.4-5 "age 5 to <12 years".

Thawing prior to dilution: [FDA, 2022 ]
Thaw the vaccine for up to 4 hours at 2º-8ºC (36°F to 46°F) before use.
Do not shake the vaccine. Swirl the vial gently 10 times prior to use.

Dilution before administration: [FDA, 2022 ]
1. Gently invert the vial 10 times prior to dilution. Do not shake.
2. This vaccine must be diluted in its original vial with 1.3 mL sodium chloride 0.9%. Before removing the needle from the vial stopper, equalize vial pressure by withdrawing 1.3 mL air into the empty diluent syringe.
3. Gently invert the diluted dispersion 10 times to mix. Do not shake.
4. Inspect to make sure that the vaccine is an off-white uniform dispersion; do not use if discolored or if containing particles.
5. Record date and time of dilution on the vaccine vial label.

Administration [EMA, 2022 ]
1.Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Withdraw 0.2 mL of Comirnaty Original/Omicron BA.4/BA.5.
To extract 10 doses from the same vial, syringes and/or needles with a low dead volume (35 microliters maximum) should be used.
If conventional syringes and needles are used, there may not be enough volume to draw the last dose from the same vial.
3. If the amount of vaccine remaining in the vial cannot provide a full dose, discard the vial and the excess volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Storage after first puncture [EMA, 2022 ]
Record the date and time the vial should be discarded.
After taking the first dose from the multidose vial, the vial should be used within a maximum of 12 hours (stored at 2°C to 8°C [36°F to 46°F]).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Disposal
Due to the high risk that discarded vials of COVID-19 vaccines can be recovered, it is essential that they are guaranteed to be safely disposed at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Clinical studies - general characteristics

The following randomized clinical trials have reported vaccine efficacy and/or safety data:

Phase 1:
The BNT162-03 trial (NCT04523571, [BioNTech RNA Pharmaceuticals GmbH, 2020 ]), conducted in China, initiated in August 2020, included 144 healthy adults aged ≥18 and ≤55 years and adults ≥65 and ≤85 years. Participants were randomized in a 1:1:1 ratio to receive either low-dose BNT126b1 or high-dose BNT126b1 or placebo. The intervention was administered as the main dose and a booster dose of BNT162b1 vaccine candidate at 10 μg in 0.5 ml or 30 μg in 0.5 ml, or 0.5 ml placebo, 21 days apart. [Zhu F, 2021 ], [Li J, 2021 ].

Phase 1/2:
The trial conducted by Chuang CH et al (NCT05132855, [Chang Gung Memorial Hospital, 2021 ]) in Taiwan, started in November 2021, included 340 health workers who had received two doses of AstraZeneca. Participants, 90 days after the second dose, received one of four vaccines: Pfizer, Moderna half-dose, Moderna, or MVC-COV1901 [Chih-Hsien Chuang, 2022 ].

Phase 1/2/3:
The C4591001 trial (NCT04368728, [Biontech SE, 2020 ]), conducted in the United States, started in May 2020. During phase 1 the groups of participants aged 18 to 55 years and 65 to 85 years received doses of 10 μg, 20 μg or 30 μg of BNT162b1 or BNT162b2 or placebo, in a two-dose schedule; a group of participants aged 18 to 55 years was assigned to receive 100 μg doses of BNT162b1 or placebo. All participants were assigned to receive two 0.5 mL injections of the active vaccine (BNT162b1 or BNT162b2) or placebo, given 21 days apart. Phase 2/3 included 37,706 adults aged 16 years and older who were healthy or had stable chronic medical conditions. Participants were randomly assigned in a 1:1 ratio to receive the vaccine (30 μg, 0.3 mL volume per dose) or placebo [Thomas SJ, 2021 ], [Frenck RW, 2021 ], [Thomas SJ, 2021 ], [Walsh EE, 2020 ], [Mulligan MJ, 2020 ], [Mulligan MJ, 2020 ], [Polack, Fernando P., 2020 ].

Phase 2:
The trial by Bonelli M et al (2021-002348-57 [Medical University of Vienna, 2021 ]), conducted in Vienna, started in May 2021, included 60 adults with chronic inflammatory rheumatic or neurological diseases under current treatment with rituximab randomized in a 1:1 ratio based on in the presence or absence of peripheral B lymphocytes to receive a third dose of an mRNA vaccine (Pfizer or Moderna, according to their initial vaccination compound) or a third vaccination with a vector COVID-19 vaccine (AstraZeneca) [Michael Bonelli, 2021 ], [Bonelli M, 2022 ].

The TVTN001 trial (NCT05049226 [Mahidol University, 2021 ]) conducted in Thailand, initiated in September 2021, included 1,320 participants in 2 arms (660 each) who received a third full or half-dose of AstraZeneca or Pfizer. Each group was stratified into 3 subgroups (1:1:1) of intervals in terms of days to receive the booster dose, after the second dose of Sinovac, at 60 and less than 90 days, 90 to less than 120 days, and 120 to 180 days [Suvimol Niyomnaitham, 2022 ].

The trial conducted by Niyomnaitham et al. (TCTR20210720007, [Faculty of Medicine Siriraj Hospital, 2021 ]) in Thailand, started in July 2021, including 210 individuals who were randomly assigned 1:1:1:1:1:1:1 to one of seven main booster groups: CoronaVac-AstraZeneca, CoronaVac-Pfizer, AstraZeneca-CoronaVac, AstraZeneca-Pfizer, Pfizer-CoronaVac, Pfizer-AstraZeneca, or Pfizer counterpart. [Niyomnaitham S, 2022 ]

The CombiVacS trial (NCT05378191 [Spanish Clinical Research Network - SCReN, 2021 ]), conducted in Spain, started in April 2021, included 676 adult individuals. The participants were vaccinated with a single dose of AstraZeneca. Between 8 and 12 weeks after vaccination, they were randomly assigned (2:1) to receive the Pfizer vaccine (intervention group) or continue observation (control group). [Nora V. Butta, 2022 ], [García-Pérez J, 2022 ], [Borobia AM, 2021 ], [José Alcamí Pertejo, 2022 ].

The COV-BOOST trial (ISRCTN73765130, [University Hospital Southampton NHS Foundation Trust, 2021 ]), conducted in the UK since June 2021 included 2,878 participants who were randomized 1:1:1:1 into Group A, 1:1:1:1:1 in group B and 1:1:1:1 in group C to receive an experimental or control vaccine as booster dose after a primary schedule of the AstraZeneca or Pfizer-BioNTech COVID-19 vaccine. The intervention was administered as follows: group A received Novavax, half-dose Novavax, AstraZeneca, or control quadrivalent meningococcal conjugate vaccine (MenACWY); group B received Pfizer, Valneva, half-dose Valneva, Janssen, or MenACWY; group C received Moderna, CureVac, half-dose Pfizer, or MenACWY. [Munro, Alasdair P S, 2021 ], [Munro APS, 2022 ], [Liu X, 2022 ].

The Com-COV trial (ISRCTN69254139, [University of Oxford, 2021 ]), conducted in the United Kingdom, initiated in February 2021, included 830 participants who were randomly assigned (1:1:1:1:1:1:1:1) to receive AstraZeneca/AstraZeneca, AstraZeneca/Pfizer, Pfizer/Pfizer, or Pfizer/AstraZeneca, given at 28-day or 84-day booster intervals [Shaw RH, 2022 ], [Liu X, 2021 ], [Shaw RH, 2021 ].

The HeVacc trial (NCT04907331 [Medical University Innsbruck, 2021 ]) conducted in Austria since May 2021 included 254 individuals aged 18 through 65, with a first dose of AstraZeneca (AZ) or Pfizer (BNT) COVID-19 vaccine to receive an AZ or BNT second dose. The homologous AstraZeneca and AZ/BNT heterologous arms were randomized 1:1 (AZ/AZ n=109, AZ/BNZ n=115), and the homologous Pfizer arm was observational (BNT/BNT n=30) [Bánki Z, 2022 ].

The trial conducted by Nantanee et al (TCTR20211027002 [Puthanakit T, 2021 ]) in Thailand, initiated in November 2021, included 100 adults grouped into two cohorts of 18 to 59 years and 60 to 69 years who had received 2 doses of the AstraZeneca COVID-19 vaccine more than 60 days before, with an interval of at least 8 weeks apart. Participants were vaccinated with the Pfizer COVID-19 vaccine 0.15 ml (15 µg, half dose), or 0.3 mL (30 µg, standard dose) [Nantanee R, 2022 ].

Phase 2/3:
The trial conducted by Shinkai et al. (RCT2031210470) in Japan, started in December 2021 including 206 participants 20 years of age and older, who had received two doses of the Pfizer COVID-19 vaccine at least 6 months ago. Participants were randomized 1:1 to receive an intramuscular injection of 0.5 mL of S-268019-b or 0.3 mL of Pfizer [Shinkai M, 2022 ].

Phase 3:
The PRIBIVAC trial (NCT05142319, [Tan Tock Seng Hospital, 2021 ]) conducted in Singapur, initiated in December 2021, included 600 adults receiving four different COVID-19 booster schedules. Participants who received a BNT162b2 (Pfizer COVID-19 vaccine) primary schedule (n=100) were randomized 1:1 to either homologous BNT162b2 booster or heterologous mRNA-1273 (Moderna) booster [Poh XY, 2022 ], [Poh X, 2022 ], [Poh XY, 2022 ].

The CVIM 4 trial (TCTR20211102003), conducted in Thailand, initiated in November 2021, included 85 adult kidney transplant recipients, randomized using a stratified block approach (by previous vaccination regimen) to receive an mRNA vaccine (Pfizer-BioNTech or Moderna; group M) or the AstraZeneca vaccine (group V) [Bruminhent J, 2022 ].

The C4591031 trial (NCT04955626, [BioNTech SE, 2021 ]), conducted in the United States, Brazil, and South Africa, started in July 2021, included 10,136 participants, of which 5,081 corresponded to the intervention group with a third dose of Pfizer and 5,044 to the placebo group. The participants received two 30-μg doses of the Pfizer vaccine at least 6 months ago [Moreira ED, 2022 ].

The COVIBOOST trial (NCT05124171 [Assistance Publique - Hôpitaux de Paris, 2021 ]), conducted in France, initiated in November 2021, included 247 participants 18 years of age and older, randomized in a 1:1:1 ratio to receive the Pfizer vaccine, CoV2 preS dTM adjuvanted vaccine (D614) or CoV2 preS dTM adjuvanted vaccine (Beta) vaccine as third doses [Odile LAUNAY, 2022 ].

Phase 4:
The Cobovax study (NCT05057169 [The University of Hong Kong, 2021 ]) conducted in China, initiated in November 2021, included 219 adults who had received two doses of an inactivated vaccine (CoronaVac) or an mRNA vaccine (Pfizer) 6 or more months previously, were randomized in a proportion 1:1 ratio to receive a third dose of either vaccine [Nancy H. L. Leung, 2022 ].

The RHH-001 trial (RBR-9nn3scw, [Instituto D'Or de Pesquisa e Ensino, 2021 ]) conducted in Brazil and El Salvador since in August 2021, enrolled 1240 participants randomly assigned to receive a booster dose of Janssen (n= 306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), or Sinovac (n=290) COVID-19 vaccines at least 6 months after the second dose [Costa Clemens SA, 2022 ], [Sue Ann Costa Clemens, 2021 ].

The REDU-VAC trial (NCT04852861, [Sciensano, 2021 ]), conducted in Belgium, started in April 2021, included 144 adults between 18 and 55 years of age, without uncontrolled comorbidities. Participants were randomly assigned to receive Pfizer 20 µg/20 µg (split dose) or 30 µg/30 µg (full dose), administered intramuscularly three weeks apart. [Pieter Pannus, 2022 ]

The mBoost trial (NCT05057182, [The University of Hong Kong, 2021 ]) conducted in China, started in October 2021, included 315 adults over 30 years of age. Participants had received two doses of inactivated COVID-19 vaccines at least 3 months before, receiving a third dose of the Pfizer vaccine [Leung, N. H. L., 2022 ], [Nancy H. L. Leung, 2022 ].

Other trials reporting data:
The SWITCH trial (NCT04614948, [Erasmus Medical Center, 2021 ]) conducted in the Netherlands, initiated June 2021 and September 2022, included 461 participants over the age of 18, who were randomized 1:1:1:1 to not receiving a booster, receiving a Janssen booster, receiving a Moderna booster, or receiving a Pfizer–BioNTech booster [Sablerolles RSG, 2022 ].

The ARNCOMBI trial (NCT04900467, [Assistance Publique - Hôpitaux de Paris, 2021 ]) conducted in France, started in May 2021, included 414 participants who were randomly assigned in a 1:1 ratio to receive a second dose of Pfizer or Moderna, within each group split to receive the vaccine 28 to 49 days after the first dose [Janssen C, 2022 ].

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

The capacity to induce protective immune responses against an infectious pathogen by a directly injected, non-replicating mRNA had been previously demonstrated for other pathogens [Petsch B, 2012]. [Petsch B, 2012 ]

Direct preclinical evidence of immune response induced by Pfizer-BioNtech COVID-19 Vaccine came from one study in nonhuman primates that received 10 or 100 μg of the vaccine or no vaccine [Corbett KS, 2020 ]. Antibody and T-cell responses were assessed before upper and lower airway exposure to SARS-CoV-2, active viral replication and viral genomes in bronchoalveolar-lavage fluid and nasal swab specimens were assessed by polymerase chain reaction. Histopathological analysis and viral quantification were performed on lung-tissue specimens. The vaccination induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung.

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

In the phase 1 component of the C4591001 trial [Walsh EE, 2020 ], the vaccine elicited dose-dependent SARS-CoV-2-neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. The results were similar in younger and older adults.

In the phase 2 portion of the trial, 360 participants were enrolled and randomized 1:1 to the vaccine or placebo. Immunogenicity results 1 month after second dose 2 vaccination, showed the vaccine elicited robust SARS-CoV-2 immune responses, defined by SARS-CoV-2 50% neutralizing titers. Titers were higher in younger participants (18 to 55 years of age) than in older ones (56 to 85 years of age) [FDA, 2020 ]

Key messages

Pfizer-BioNTech COVID-19 vaccine reduces the risk of contracting COVID-19

Pfizer-BioNTech COVID-19 vaccine probably reduces the risk of contracting severe COVID-19


Main efficacy outcomes of Pfizer-BioNTech COVID-19 vaccine

Contracting COVID-19 (measured at least 7 days after the second injection)

The relative risk of contracting COVID-19 in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.05 (95% CI 0.02 to 0.1). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 in 95%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 850 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21096 presented this outcome (403 per 10000) versus 77 out of 20998 in the group that did receive it (37 per 10000). In other words, 366 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 91%, or that the intervention reduced the risk of contracting COVID-19 by 91 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 27. Which means that 27 people need to receive the vaccine for one of them to not contracting COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence, imprecision or publication bias.


Contracting severe COVID-19 (measured at least 7 days after the second injection)

The relative risk of contracting severe COVID-19 in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.25 (95% CI 0.03 to 2.23). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting severe COVID-19 in 75%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting severe COVID-19. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 23 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 23037 presented this outcome (10 per 10000) versus 1 out of 23040 in the group that did receive it (0 per 10000). In other words, 10 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 96%, or that the intervention reduced the risk of contracting severe COVID-19 by 96 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 10000. Which means that 10000 people need to receive the vaccine for one of them to not contracting severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The reason for downgrading the certainty of the evidence is imprecision because of the low number of events and wide confidence interval. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence or publication bias.

Mortality

The existing evidence does not allow to assess the impact of Pfizer-BioNTech COVID‑19 Vaccine on the risk of mortality. The information provided by randomized trials was not adequately powered to estimate a difference in this outcome. Deaths can occur in the intervention and control group for reasons unrelated to COVID-19 or the vaccine. Establishing that there is a reduction (or increase) in the risk of death attributable to COVID-19 would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (>65y) (measured at least 7 days after the second injection)

The relative risk of contracting COVID-19 (>65y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.06 (95% CI 0.03 to 0.12). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 (>65y) by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (>65y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 124 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21096 presented this outcome (59 per 10000) versus 7 out of 20998 in the group that did receive it (3 per 10000). In other words, 56 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 94%, or that the intervention reduced the risk of contracting COVID-19 (>65y) by 94 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 179. Which means that 179 people need to receive the vaccine for one of them to not contracting COVID-19 (>65y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Contracting COVID-19 (5-15 y) (measured at least 7 days after the second injection, with a median follow-up of < 4 month after 2nd dose )

The relative risk of contracting COVID-19 (5-15 y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.08 (95% CI 0.02 to 0.23). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 (5-15 y) by 92%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (5-15 y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 34 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 1861 presented this outcome (183 per 10000) versus 3 out of 2636 in the group that did receive it (14 per 10000). In other words, 169 less people per did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 92%, or that the intervention reduced the risk of contracting COVID-19 (5-15 y) by 92 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 59. Which means that 59 people need to receive the vaccine for one of them to not contracting COVID-19 (5-15 y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Summary of findings table (iSoF)

Efficacy and effectiveness of the vaccine in subgroups

Age 
Randomized trials
The proportion of patients >55 years of age in the C4591001 trial was 42.2% (15921 out of 37706 participants) [Polack, Fernando P., 2020 ].
Vaccine efficacy in the different age groups was consistent with that observed in the overall population. Efficacy was 95.6% (89.4 to 98.6) in the group 16 to 55 years, 93.7% (80.6 to 98.8) in >55 years, 94.7% (66.7 to 99.9) in ≥65 years and 100.0% (−13.1 to 100.0) in ≥75 years [Polack, Fernando P., 2020 ].

The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants)  [Frenck RW, 2021 ]. 
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants)  [Frenck RW, 2021 ].
In the group that included 1983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3 to 100). In the group that included all 2229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95%, 78,1 a 100) [Frenck RW, 2021 ].

The phase 3, randomized, double-blind trial B7471026 is currently evaluating the efficacy/safety of the vaccine in vaccinated adults 65 years of age and older [Pfizer, 2021 ].

The proportion of participants 65-85 years in the BNT162-03 was 50% (72 out of 144 participants) [Li J, 2021 ].

The older participants generally had a lower peak neutralizing antibody response than the younger participants. The vaccine-induced highest neutralizing titers were observed on day 43 (21 days after the BNT162b1 boost dose) for the older adults in the BNT162b1 group. Moreover, geometric mean neutralizing titers reached 1.3-fold in the older adults group versus a panel of COVID-19 convalescent human sera obtained at least 14 d after positive SARS-CoV-2 polymerase chain reaction test [Li J, 2021 ].

Puthanakit T et al was a phase 2 randomized clinicla trial conducted in Thailand. The study included 80 participants  aged 12 to < 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac (SV) 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Immunogenicity was determined using IgG antibody against spike-receptorbinding domain of wild type(anti-S-RBD IgG) and surrogate virus neutralization test(sVNT) against Delta variant at 14 days and 5 months after the 2nd dose. Neutralization tests(sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean(GM) of anti-S-RBD IgG in SV3w/PZ30lg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in SV6w/PZ30lg. The GMs of sVNT against Delta variants at day 14 among participants in SV3w/PZ30lg and SV6wk/PZ30lg arm were 95.3 % and 99.7 %inhibition, respectively. [Puthanakit T, 2022 ]

Other comparative studies
The interventional, randomized study">non-randomized study COGEVAX-BIO is currently evaluating the effectiveness/safety of the vaccine in people over age 75 institutionalized in the long-term care units [Gérond'if, 2021 ].

The randomized study">non-randomized study Covid-19-Abs is currently evaluating the effectiveness/safety of the vaccine in residents and staff associated with nursing homes, extended care facilities, and over 55 communities [Dr. Sidney J. Stohs, 2021 ].

The VIVALDI study included 1317 samples from 402 residents and 632 staff fully vaccinated  (AstraZeneca=593; Pfizer=534). Data were collected 21 days after the second dose. The study showed that two-dose of AstraZeneca or Pfizer COVID-19 vaccine elicits robust and stable antibody responses in older Long-Term Care Facility residents, consistent with overall levels of vaccine-induced immunity [Oliver Stirrup, 2022 ].

The cohort study using Senior Shield data, included 43,596 residents of long term facilities,  39,482 received one dose, 37,656 received two doses, with a follow-up period of 5 months. This study shows that the Pfizer-BioNTech mRNA COVID-19 vaccine effectively prevents SARS-CoV-2 infection, COVID-19-related death, and all-cause mortality in LTCF residents [Goldin S, 2022 ].

The test-negative case-control study using COVID-19 Shared Data Resource from the Veterans Health Administration (VA), included 971,750 veterans who received the Pfizer-BioNTech vaccine. In people aged 65 and over the study showed a vaccine effectiveness against symptomatic infection of 66.3% (95 CI 55.7 to 74.4) 1 month after receiving the vaccine, and –23.3% (95 CI –40.5 to –8.2) 7 months after. The efectiveness against hospitalization was 61% (95 CI 41.3 to 74.2) 1 month after receiving the vaccine and 1.7% (95 CI –22.0 to 20.8) 7 months after receiving the vaccine. [Mayr FB, 2022 ]

Wang L et al was a retrospective cohort study of 262,847 vaccinated older adults (age 73.8 ± 6.81 years old) between December 2020 and August 2021, 2764 of whom had a diagnosis of Alzheimer disease, 1244 had a diagnosis of VD, 259 had a diagnosis of Lewy body dementia (LBD), 229 had a diagnosis of frontotemporal dementia (FTD), and 4385 had a diagnosis of mild cognitive impairment (MCI). the overall risk of breakthrough infections beginning 14 days following vaccination in older adults without dementia was 5.6%. The risks of breakthrough infections were significantly higher in patients with various types of dementias: 10.3% for AD, 12.5% for VD, 14.3 for LBD, 11.8% for FTD, and 11.6% for MCI. The overall risk for hospitalization after breakthrough infections in patients with dementia was 39.5% for AD, 46.2% for VD, and 30.4% for MCI. [Wang L, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of CoronaVac and BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Vaccine effectiveness against severe complications after two doses of BNT162b2 awas 82.1% (74.6-87.3) in those aged ≥65, 83.0% (69.6-90.5) in those aged 50-64, 78.3% (60.8-88.0) in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, 90.8% (83.4-94.9) for BNT162b2 against severe complications. The findings show that BNT162b2 vaccination were effective against COVID-19-related severe complications against the Omicron BA.2 pandemic, and risks decreased further with the third dose. [Yan VKC, 2022 ]

Fleming-Dutra et al was a test-negative case-control study conducted in the United States, based on data from the Increasing Community Access to Testing (ICATT) platform, including 121,952 tests during the Omicron variant predominance period between December 2021 and February 2022, in participants between 5 and 15 years old who received the Pfizer-BioNTech vaccine. The effectiveness 2 months after the second dose for symptomatic infection was 28.9% (95% CI, 24.5% to 33.1%) for the 5-11 years old group and 16.6% (95% CI, 8.1% to 24.3%) for the 12-15 years old group. [Fleming-Dutra KE, 2022 ]

Sex
Randomized trials
The proportion of females in the C4591001 trial was 49.4% (18631 out of 37706 participants) [Polack, Fernando P., 2020 ].
Vaccine efficacy was consistent in the different sex groups. Efficacy was 96.4% (88.9 to 99.3) in males and 93.7% (84.7 to 98.0) in females.

Other comparative studies
In Bjork et al [Jonas Bjork, 2021 ], no difference in vaccine effectiveness was observed between females and males.
The phase 4, randomized study">non-randomized study Shieldvacc2 is currently evaluating the effectiveness/safety of the vaccine in women of child-bearing potential using contraception, 12 years of age and older, vaccinated with two-doses of Comirnaty [Medizinische Universität Innsbruck, Institut für Virologie, 2021 ].
    
Children and adolescents
Randomized trials
The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants)  [Frenck RW, 2021 ]. 
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants)  [Frenck RW, 2021 ].
In the group that included 1983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3 to 100). In the group that included all 2229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95%, 78,1 a 100) [Frenck RW, 2021 ].

Other comparative studies
C4591007 is an ongoing randomized study">non-randomized study evaluating the efficacy of the vaccine in children and adolescents [BioNTech SE, 2021 ].

The randomized study">non-randomized study COVA is currently evaluating the effectiveness/safety of the vaccine in healthy or clinically stable participants aged 11 years and older [The University of Hong Kong, 2021 ].

Levy M et al  is comparative study conducted in France. The study included pediatric patients diagnosed with multisystem inflammatory syndrome admitted to 1 of the 41 French pediatric intensive care units (PICUs) between September 1, 2021, and October 31, 2021. The HR for multisystem inflammatory syndrome in children was 0.09 (95% CI, 0.04-0.211) after the first vaccine dose compared with unvaccinated adolescents. Sensitivity analyses showed similar result. The authors suggest that COVID-19 mRNA vaccination was associated with a lower incidence of multisystem inflammatory syndrome in adolescents.

Oliveira CR et al.  is a case-control conducted in the United States. The study included adolescents (aged 12-18 years old): 186 SARs-CoV-2 PCR+ cases and 356 matched controls. Vaccine effectiveness against any infection was estimated to be 91% (95% CI, 80 to 96); against asymptomatic infection, 85% (95% CI, 57 to 95). Effectiveness after a single dose was estimated to be 74% (95% CI, 18 to 92).[Oliveira CR, 2022 ]

Florentino et al. conducted a test-negative case-control study, to estimate vaccine effectiveness (VE) against COVID-19 in adolescents aged 12-17 years in Scotland and Brazil after two doses of the Pfizer-BioNTech vaccine. They analyzed 503,776 eligible SARS-CoV-2 tests (RT-PCR or antigen) of adolescents in Brazil and 127,168 eligible tests of adolescents in Scotland. During the delta-dominant period, VE for symptomatic infection after two doses peaked at 14-27 days (80.7% [95% CI 77.8–83.3] in Brazil; 92.8% [95% CI 85.7–96.4] in Scotland). Protection started to decline reducing to 26.6% (4.1–43.9) in Brasil and 86.5% (72.2–93.4) in Scotland, at 56–69 days. Vaccines were less effective against the omicron variant than the delta variant at all intervals after two-dose vaccination in both countries: between 14-27 days was 64.7% (95% CI 63.0–66.3) in Brazil, and 82.6% (95% CI 80.6–84.5) in Scotland; and reducing to 5.9% (95% CI 2.2–9.4) in Brazil and 50.6% (42.7–57.4) at 98 days and longer [Florentino PTV, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records of participants aged 12 to 17 years with an emergency department (ED) or urgent care (UC) encounter from November 1, 2021, through March 18, 2022. The main outcome was vaccine effectiveness (VE) associated with BNT162b2 against the emergency department and urgent care encounters related to Delta or Omicron variant SARS-CoV-2 infection. The study included data from 3168 adolescents, including 1004 with ED visits and 2164 with UC visits. VE for 2 doses of BNT162b2 was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Ziv et al was a case-control study conducted in Israel that evaluated the effectiveness of PfizerBioNTech vaccination among 1639 adolescents with juvenile-onset inflammatory rheumatic diseases the control group comprised 524,471 adolescents without juvenile-onset inflammatory rheumatic diseases, the estimated vaccine effectiveness for adolescents with IRD was 76.3% after the first dose, 94.8% after the second and 99.2% after the third dose [Ziv A, 2022 ].

Cohen-Stavi CJ was a comparative cohort study conducted in Israel. The study included 15,289 children aged 5 to 11 years. Vaccine effectiveness (VE) against documented severe SARS-CoV-2 infection and symptomatic Covid-19 was estimated after the first and second vaccine doses during the Omicron wave. VE against documented infection was 17% (95% CI, 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. VE against symptomatic Covid-19 was 18% (95% CI, −2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose. [Cohen-Stavi CJ, 2022 ].

Sacco C et al was a retrospective study conducted in Italy. The study included data from 2,965,918 children aged 5–11 years: 1,063,035 with two doses of the Pfizer vaccine, 134,386 with one dose of the Pfizer vaccine, and 1,768,497 unvaccinated. The aim of this study was to estimate the effectiveness of the paediatric BNT162b2 vaccine in preventing SARS-CoV-2 infections and severe COVID-19 (hospitalization or death) in children using routinely collected data in Italy. Adjusted vaccine effectiveness against infection in partly vaccinated group was 27.4% (95% CI 26.4-28.4) and 29.4% (95% CI 28.5-30.2) in fully vaccinated group. Adjusted vaccine effectiveness against severe disease in partly vaccinated group was 38.1% (95% CI 20.9-51.5) and 41.1 (95% CI 22.2-55.4) for fully vaccinated group [Sacco C, 2022 ].

Molteni et al was a prospective cohort study conducted in the United Kingdom. The study included 115,775 children and adolescents aged 12-17 years, among which, 25,971 received one dose of Pfizer-BioNTech. Based on data from the Covid Symptom Study between august 2021 and February 2022. Infection risk reduction was -80.4% (95%CI -82 to -78) 14-30 days after the primary dose of Pfizer-BioNTech in the august-november (Delta) period. Infection risk reduction 14-30 days after primary vaccination was -53.7% (95%CI -62 to -43) during the december-february (Omicron) period [Molteni E, 2022 ].

González S et al was a retrospective cohort study conducted in Argentina including 1,536,435 participants: 689,552 in the BIBP vaccine group and 846,883 in the mRNA vaccine group (539,093 with Pfizer/Pfizer schedule, 15,552 with Pfizer/Moderna schedule and 44,862 with Moderna/Pfizer schedule). mRNA-1273 and BNT162b2 vaccines were administered to 12−17- year subjects; and BBIBP-CorV to 3−11-year subjects. Vaccine effectiveness for the mRNA vaccine group was 80.0% (95% CI 64.3 to 88.0) for the 12−17 age (mRNA vaccines) subgroup [González S, 2022 ].

Tan SHX et al was a retrospective cohort study conducted in Singapore based on data from the National Ministry of Health registry, including 255,936 children between 5 and 11 years of age. The Pfizer-BioNTech vaccine effectiveness during the Omicron variant predominance period in partially vaccinated children was 13.6% (95% CI, 11.7% to 15.5%) against all SARS-CoV-2 infections, 24.3% (95% CI, 19.5% to 28.9%) against PCR-confirmed infections and 42.3% (95% CI, 24.9% to 55.7%) against hospitalization. In fully vaccinated children the effectiveness was 36.8% (95% CI, 35.3% to 38.2%), 65.3% (95% CI, 62.0% to 68.3%), and 82.7% (95% CI, 74.8% to 88.2%), respectively. [Tan SHX, 2022 ]

Kim J et al was a retrospective cohort study conducted in South Korea, including 3,203,985 adolescents aged 12 to 17 years. The estimated effectiveness of the Pfizer-BioNTech vaccine was 80.4% (95% CI, 77.8% to 82.7%) among those aged 16-17 years, and 79.2% (95% CI, 77.4% to 80.1%) among those aged 12 to 15 years. [Kim J, 2022 ]

Chemaitelly H et al was a retrospective cohort study conducted in Qatar, including 37,456 participants aged 5-11 years, 18,728 vaccinated with 10-μg of BNT162b2 and 18,728 unvaccinated matched participants. The overall effectiveness against Omicron was 25.7% (95% CI, 10% to 38.6%). The overall effectiveness was 46.3% (95% CI, 21.5% to 63.3%) among children 5-7 years of age and 16.6% (95% CI, −4.2% to 33.2%) among children 8-11 years of age. In the pre-Omicron period, effectiveness was 35.6% (95% CI, 31.2% to 39.6%) among adolescents 12 to 14 years of age and 20.9% (95% CI, 13.8% to 27.4%) among participants between 15-17 years of age. [Chemaitelly H, 2022 ]

Puthanakit T et al was a randomized trial conducted in Thailand, that assessed the immunogenicity of fractional doses and booster doses of Pfizer-BioNTech SARS-CoV-2 vaccine among healthy adolescents.  The GMR of Anti-S-RBD IgG post second dose compared to the 3wPZ30/30 group was 0.80 (95% CI, 0.67–0.97) for the 3wPZ30/20 group, 1.00 (95% CI, 0.83–1.20) for the 3wPZ20/20 group, 1.37 (95% CI, 1.13–1.65) for the  6wPZ30/30 group, 1.24 (95% CI, 1.02–1.50) for the 6wPZ30/20 group and 1.36 (95% CI, 1.13–1.64) for the 6wPZ20/20 group. [Puthanakit T, 2022 ]

Buchan SA et al was a case-control study with a test-negative design conducted in Canada that included participants between 12-17 years old, 9,902 Omicron cases with 19,953 controls, and 502 Delta cases with 17,930 controls. Vaccine Effectiveness (VE) against symptomatic infection with Omicron was 51% (95% CI, 38% to 61%) after two doses and 62% (95% CI, 49% to 72%) after the third dose. VE against severe outcomes with Omicron was 85% (95% CI, 74% to 91%) after two doses. VE against symptomatic infection with Delta was 97% (95% CI, 94% to 99%). [Buchan SA, 2022 ]
 

Pregnancy
Randomized trials
Pregnant females of 18 years of age and older were excluded from the C4591001 trial, so no data are available for this subgroup [Polack, Fernando P., 2020 ].

C4591015 is an ongoing phase 2/3, randomized trial evaluating the efficacy in this subgroup [BioNTech SE, 2021 ].

Breastfeeding
Randomized trials
Breastfeeding females were excluded from the C4591001 trial, so no data are available for this subgroup [Polack, Fernando P., 2020 ].

Other comparative studies
Golan et al. was a prospective cohort study that enrolled 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM increased significantly in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation [Golan Y et al., 2021 ].

The cohort O'Connor DL et al is currently evaluating the effectiveness/safety of the vaccine in lactating mothers [Deborah O'Connor, 2021 ].
    
Esteve-Palau E et al was a prospective cohort study conducted in Spain. This study included 33 breastfeeding women volunteers. The primary endpoint was to determine SARS-CoV-2 vaccine-induced antibody levels in the breast milk of lactating women 4 weeks after Pfizer-BioNTech COVID-19 complete vaccination (2 doses in 21 days). Median (IQR) SARS-CoV-2 immunoglobulin G (IgG) spike protein subunit S1 (S1) vaccine-induced levels at different timepoints for serum–milk pairs were 519 (234–937) to 1 (0–2.9) arbitrary units (AU)/mL at 2 weeks after the first dose and 18 644 (9923–29 264) to 78 (33.7–128), 12 478 (6870–20 801) to 50.4 (24.3–104), 4094 (2413–8480) to 19.9 (10.8–51.9), 1350 (831–2298) to 8.9 (7.8– 31.5) AU/mL at 2, 4, 12 and 24 weeks after the second dose, respectively [Esteve-Palau E, 2022 ].

Guedalia J et al was a cohort study conducted in Israel that included 82,803 women who had a documented delivery between August 1st 2021 and March 22nd 2022. During the Delta predominance period the vaccine effectiveness (VE) of second dose against hospitalization was 61% (95% CI, 51% to 69%), 97% (95% CI, 92% to 99%) for significant disease and 96% (95% CI, 86% to 99%) for severe disease. In the same period, VE of the booster dose was 97% (95% CI, 95% to 99%) against hospitalization, 99% (95% CI, 93% to 100%) for significant disease and 99% (95% CI, 89% to 100%) for severe disease. During the Omicron predominance period, VE of second dose against hospitalization was −12% (95% CI, −36% to 8%), 51% (95% CI, −47% to 84%) against significant disease and 83% (95% CI, −47% to 98%) against severe disease. In the same period, VE of booster dose was 43% (95% CI, 31% to 53%) against hospitalization, 97% (95% CI, 72% to 100%) against significant disease and 94% (95% CI, 43% to 99%) against severe disease. [Guedalia J, 2022 ]

Immunocompromised persons
Randomized trials
Immunocompromised participants were excluded from the C4591001 trial, therefore no data are available for this subgroup [Polack, Fernando P., 2020 ].

The phase 4, a single-center, open-label, investigator-initiated randomized controlled, superiority trial BECAME is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [dafna yahav, 2021 ].

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].

The phase 2, randomized, single-blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].

Other comparative studies
The study COVIVAC-ID [Assistance Publique - Hôpitaux de Paris, 2021 ] plans to enroll 485 vaccinated immunocompromised people (autoimmune or auto-inflammatory disease, HIV infection, multiple sclerosis, solid cancer, organ transplantation) to determine the humoral and cellular response to vaccination and efficacy against SARS-CoV-2 variants.
                     
The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna and Astra-Zeneca vaccines [University Hospital, Strasbourg, France, 2021 ].

The randomized study">non-randomized study COVAC-IC is currently evaluating the effectiveness/safety of the vaccine in immunocompromised and immunocompetent haematology patients aged 18 years and older [University Hospitals of North Midlands NHS Trust, 2021 ].

The monocentric observational study ANTICOV is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older, to evaluate the effectiveness of BNT162b2 or mRNA-1273 vaccine [Azienda Socio Sanitaria Territoriale di Cremona, 2021 ].

The randomized study">non-randomized study UNICO is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older [Ente Ospedaliero Ospedali Galliera, 2021 ].

The randomized study">non-randomized study COViNEPH-1 is currently evaluating the effectiveness/safety of the vaccine in patients on chronic dialysis vaccinated with BNT162b2 [Medical University of Gdansk, 2021 ].

The prospective, cohort, non-interventional, single-center clinical study ImmunoHaema-COVID-VAX-21 is currently evaluating the effectiveness/safety of the vaccine in patients with haematological malignancies 18 years of age and older [Ospedale di Circolo - Fondazione Macchi, 2021 ].

The phase 2, randomized study">non-randomized study C4591024 is currently evaluating the effectiveness/safety of the vaccine in immunocompromised participants ≥2 Years Of Age [BioNTech SE, 2021 ].

The randomized study">non-randomized study IROC is currently evaluating the effectiveness/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].

The randomized study">non-randomized study LymphVAX is currently evaluating the effectiveness/safety of the vaccine in women with a history of breast cancer [Massachusetts General Hospital, 2021 ].

The randomized study">non-randomized study VIOLA is currently evaluating the effectiveness/safety of the vaccine in COVID-negative Multiple Sclerosis patients treated with ocrelizumab [NYU Langone Health, 2021 ].

The phase 4, randomized study">non-randomized study Covid Vaccin Allo is currently evaluating the effectiveness/safety of the vaccine in patients allo-hematopoietic cell transplantation recipients [University of Liege, 2021 ].

The randomized study">non-randomized study VAX4FRAIL is currently evaluating the effectiveness/safety of the vaccine in frail subjects with impaired immuno-competence, due to their underlying diseases or ongoing therapies that received SARS-CoV-2 with Pfizer-BioNTech or Moderna vaccines [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].

The phase 4, randomized study">non-randomized study EREVA is currently evaluating the effectiveness/safety of the vaccine in adults immunocompromised or non-immunocompromised volunteers [Centre Hospitalier Régional d'Orléans, 2021 ].

The phase 1 and 2, interventional, randomized study">non-randomized study PACIFIC is currently evaluating the effectiveness/safety of the vaccine in children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old) [Assistance Publique - Hôpitaux de Paris, 2021 ].

The randomized study">non-randomized study CPAT is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

The phase 4, randomized study">non-randomized study HHCTC_COVID-19_VACCINE_Ab is currently evaluating the effectiveness/safety of the vaccine in adults with chronic liver disease or Underlying CLD, aged 18 years and older [Humanity & Health Medical Group Limited, 2021 ].

Huang HJ et al. included 241 transplant candidates and 1,163 transplant recipients (Pfizer=858; Moderna=546). Data were collected 2 weeks to 3 months after the second dose. The study showed that transplant candidates exhibited a response to the anti-SARS-CoV-2 Total Ig of 93.5% after two doses. Anti-spike ELISA assay demonstrated that  91.9%  of transplant candidates increased in titer from <1:50 (negative) to ≥1:50 (positive) after two doses. For transplant recipients,  30.7% exhibited a response (anti-SARS-CoV-2 IgG assay)after the second dose. Results for the anti-spike titer in recipients became positive in 30.1% after two doses
[Huang HJ, 2022 ].

Spensley K et al. included 1121 patients on haemodialysis. All patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between December 1, 2021 and January 16, 2022. The study showed that partial vaccination did not provide protection against infection. Vaccine effectiveness against Omicron infection in patients who had received a booster vaccine was 58%. Analysing vaccine effectiveness in the 747 patients who had been boosted, significant effectiveness was seen in both patients who received AstraZeneca COVID-19 vaccine (47%)and Pfizer COVID-19 vaccine (66%).

Tenforde MW et al. included 2,952 adults (1,385 COVID-19  case-patients  and  1,567  COVID-19–negative  controls) hospitalized at 21 hospitals between August - December 2021. Among them, 1,077 adults with immunocompromising conditions (twos-dose of Pfizer= 332; two-dose Moderna=238; three dose Pfizer =120, Three-dose Moderna= 57, Both vaccines= 4). The study showed results combined for Pfizer and Moderna COVID-19 vaccine. Among patients with immunocompromising conditions, those who received 2-dose were more likely to be enrolled as a case-patient (34%) than those received 3-dose (20%).  Vaccine Effectiveness  against  COVID-19  hospitalization  among  adults  without  immunocompromising  conditions  was  82%  (95% CI 77% to 86%)  for  2  doses  and  97%  (95% CI 95% to 99%) for 3 doses . Vaccine effectiveness against COVID-19 hospitalization among adults with immunocompromising conditions was 69% (95% CI 57% to 78%) for  2  doses  and  88%  (95%  CI  81% to 93%)  for  3  doses [Tenforde MW, 2022 ].

Bassi et al was a comparative study conducted in Switzerland that evaluated the immune response elicited by mRNA COVID-19 vaccines (Pfizer-BioNTech or Moderna) in dialysis patients 143 dialysis patients (n=143, 130 on hemodiafiltration and 13 on peritoneal dialysis) compared to healthy healthcare workers (n=48). Results from plasma samples collected 2 to 3 weeks after the first and second dose show 94.4% of dialysis patients seroconverted versus 100% of healthcare workers. Importantly, 35% of dialysis patients had low or undetectable levels of antibodies while all the healthcare workers had high levels. Compared to healthcare workers, 49% of dialysis patients had no or low neutralizing activity against the Wuhan wild-type virus. Neutralizing activity against the Delta variant was low or undetectable in 76.9% of dialysis patients. Almost all participants, including healthcare workers, showed a greater than 2-fold reduction in neutralizing activity against the Delta variant. Neutralizing activity against other variants was lower compared to Delta, 7.3 lower for Beta, 1.8 for Alpha and 3.3 for Lambda. The study found that dialysis patients do not develop sufficient levels of neutralizing antibodies against SARS-CoV-2 variants after two doses of mRNA vaccines [Bassi J, 2022 ].
   
The phase 4, randomized study">non-randomized study HHCTC_COVID-19_VACCINE_Ab is currently evaluating the effectiveness/safety of the vaccine in adults with chronic liver disease or Underlying CLD, aged 18 years and older [Humanity & Health Medical Group Limited, 2021 ].

Schiavetti et al. is a retrospective study conducted in Italy which analyzed data from Multiple Sclerosis centers on patients with Multiple Sclerosis undergoing the SARS-CoV-2 vaccination [Irene Schiavetti, 2022 ]. This study estimated the rate of breakthrough infections and of infection requiring hospitalization per disease-modifying therapy. The rate of breakthrough infections was significantly higher in patients treated with ocrelizumab (RR=3.55, 95% CI: 2.74-4.58) and fingolimod (RR=2.65, 95% CI: 1.75-4.00) compared to patients treated with all the other disease-modifying therapies. In the ocrelizumab group, the hospitalization rate was 16.7% vs 19.4% in pre-vaccination rates and 3.9% in all the other disease-modifying therapy groups vs 11.9% in pre-vaccination rates. The authors suggest that the risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod. The rate of severe infections was significantly reduced in all the disease-modifying therapies excluding ocrelizumab [Irene Schiavetti, 2022 ].

Kennedy NA et al was a comparative cohort study conducted in United Kingdom. The aim of the study was to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with inflammatory bowel disease. 7224 patients were recruited to the CLARITY study from 92 UK hospitals. Anti-S RBD antibody concentrations were lower in infliximabtreated than vedolizumab-treated patients following a fourth dose with an mRNA-based vaccine (3353 U/mL (3.9) vs 18152 U/mL (2.6), p<0.0001), irrespective of whether they had received two doses of ChAdOx1 nCoV 19 (3257 U/mL (4.3) vs 17535 U/mL (2.6), p<0.0001) or BNT162b2 (3489 U/mL (3.4) vs 19183 U/mL (2.6), p<0.0001) vaccines first . There was no difference between geometric mean (SD) anti-S RBD peak antibody concentrations following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. [Kennedy NA, 2022 ]

Torres R et al was a comparative cohort study conducted in Chile. A total of 12,301 patients were evaluated; 10,615 (86.3%) received a complete vaccination (2 doses), 490 (4.0%) received incomplete vaccination, and 1196 (9.7%) were not vaccinated. The clinical effectiveness of anti-SARS-CoV-2 vaccination in end-stage renal disease patients on chronic hemodialysis from February to August 2021. Patients vaccinated with BNT162b2 compared to those vaccinated with CoronaVac had a lower infection incidence (BNT162b2: 0.4211000 person-days, CoronaVac: 0.5501000 person-days), hospitalization (BNT162b2: 0.0831000 person-days, CoronaVac: 0.1161000 person-days), and death associated with COVID-19 (BNT162b2: 0.0081000 person-days, CoronaVac: 0.0311000 person-days). Vaccine effectiveness against COVID-19 diagnosis for BNT162b2 complete schedule was 42.6% (95% CI 32.1% to 51.3%). Against hospitalization, vaccine effectiveness for the BNT162b2 vaccine was 68.6% (95% CI 57.6%–76.6%) [Torres R, 2022 ].

Harboe ZB et al was a prospective cohort study conducted in Denmark. The study included 626 patients diagnosed with chronic pulmonary disease who received the Pfizer-BioNTech COVID-19 vaccine. Antibody concentrations as geometric means with 95% CI of receptor binding domain (RBD)-IgG and neutralizing antibody index of inhibition of ACE-2/RBD interaction (%) were reported. A low responder was defined as a neutralizing index in the lowest quartile (primary outcome) or RBD-IgG <225 AU/mL plus neutralizing index <25% (secondary outcome), measured at 2 months. For the primary outcome, 34.7% of patients (n=157/453) and 12.9% of controls (n=46/359) were low responders (p<0.0001). For the secondary outcome, 8.6% of patients (n=39/453) and 1.4% of controls (n=5/359) were low responders (p<0.001) [Harboe ZB, 2022 ].

Wing Tak Cheng et al. conducted a retrospective cohort study in Honk Kong. In individuals with chronic kidney disease, of whom 28,374 had received no vaccine, 27,129 had received two doses of Pfizer and 47,640 two doses of CoronaVac. Vaccine efficacy was estimated to be 38% (95% CI: 34%–41%) for BNT162b2 and 4% (95% CI: 0%–8%) for CoronaVac compared to the unvaccinated group. [Tak Cheng FW, 2022 ].

Coburn SB et al was a cohort study conducted in United States. The study included 113,994 patients (33,029 people with HIV and 80,965 people without HIV). The aim of the study was to determine whether HIV status was associated with increased rate or risk of COVID-19 breakthrough infection among fully vaccinated patients in the United States by vaccination type and, among PWH, by immune and viral suppression status. The incidence rate of breakthrough infections was higher in people with HIV (55 [95% CI, 52-58] cases per 1000 person-years) vs people without HIV (43 [95% CI, 42-45] cases per 1000 person-years). The breakthrough rate was highest with the Janssen vaccine (70 [95% CI, 63-78] cases per 1000 person-years), followed by Pfizer (54 [95% CI, 52-56] cases per 1000 person-years), and Moderna (34 [95% CI, 32-36] cases per 1000 person-years) [Coburn SB, 2022 ].

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine health-care system, the Michigan State Registry and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA based COVID-19 vaccines during the Omicron dominant period December 2021 to March 2022. The effectiveness of the Pfizer-BioNTech vaccine during the Omicron period in immunocompromised participants the effectiveness was 13% (95%CI –19 to 39) for two doses and 50% (95% CI 31 to 64) for three doses [Risk M, 2022 ].

Embi P et al. conducted a case-control study with a test-negative design among eight VISION Network sites in the United States during the Delta variant predominance period. Persons aged 18 years and older with ≥1 immunocompromising conditions were included and compared with non-immunocompromised individuals. It included 8,848 emergency department/urgent care (ED/UC) events and 18,843 hospitalizations among immunocompromised (IC) patients; and 200,071 ED/UC events and 70,882 hospitalizations among non-IC patients. In the IC population, adjusted vaccine effectiveness (VE) for the Pfizer vaccine was 61% (95% CI, 54% to 67%) for ED/UC events, and 66% (95% CI, 61% to 70%) for hospitalization, measured 14 days after the second dose. After a third dose, VE was 74% (CI 95%, 62% to 82%), and 76% (CI 95%, 69% to 82%) for ED/UC encounters and hospitalization, respectively. Preprint. [Peter J. Embi, 2022 ]

Furer V et al was a prospective cohort study conducted in Israel including 729 participants with autoimmune inflammatory rheumatic diseases and 122 controls. The study assessed long-term immunogenicity of the BNT162b2 mRNA vaccine in adult patients with AIIRD. Seropositivity rates 2-to-6 weeks after the second dose were 100% for controls and 84.72% for AIIRD patients, at 6 months, 96.55% versus 74.36%, respectively. After the third vaccine dose, 100% of the controls and 82.26% of patients had detectable positive S1/S2 IgG titers. [Furer V, 2022 ]

Wagner A et al was an open-label phase 4 randomized trial conducted in Austria, including 263 patients: 63 with solid tumors, 70 with multiple myeloma, 130 with inflammatory bowel disease and 66 controls. The seronegativity rate 6 months after the primary schedule was 12.1% in the SOT group and 18.9% in the MM group. [Furer V, 2022 ]

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324 ,033 participants that received Moderna or Pfizer COVID-19 vaccine. Based on data from a test negative design study among patients who had symptoms consistent with covid-19 between 14 December 2020 and 19 April 2021. Results showed vaccine effectiveness of 91% (95% CI 88 to 93)[Chung H, 2021 ].

Dagan N et al. was a cohort study conducted in Israel. The study enrolled 1,193,236 general population participants that received Pfizer-BioNTech COVID-19 vaccine. Based on data from Israel’s largest health care organization (Clalit Health Services) during the period from December 20, 2020, to February 1, 2021. Results showed vaccine effectiveness against documented infection was 92% (95% CI 88 to 95) and symptomatic infection was 94% (95% CI 87 to 98) [Dagan N, 2021 ] .

Muhsen K et al. was a comparative cohort study conducted in Israel. The study enrolled 9,162 participants: 6,960 Vaccine group; 2,202 Control group. Based on data from Health care workers from a tertiary care facility adhering to routine testing since July 2020. Outcome measured at ≥ 14 days after the second dose. Results showed vaccine effectiveness of 89% (95% CI 83 to 93)
[Khitam Muhsen, 2021 ].

Cabezas C et al. was a comparative cohort study conducted in Spain. The study enrolled 116,783 participants: 98,494 Vaccine group; 18,289 Control group. Based on data from three cohorts from Catalonia from December 27 2020 to March 5, 2021. Outcomes were measured at ≥ 12 days after vaccination. Results showed vaccine effectiveness in nursing home residents was 92% (95% CI 91 to 93); nursing home staff was 88% (95% CI 85 to 90), and healthcare workers was 95% (95% CI 93 to 96) [Carmen Cabezas, 2021 ].

Haas EJ et al. was a comparative cohort study conducted in Israel. The study enrolled 6,538,911 participants: 4,714,932 Vaccine group; 1,823,979 Control group. Based on national surveillance data from the first 4 months of the nationwide vaccination campaign in people aged ≥ 16 years from Jan 24 to April 3, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against asymptomatic infection of 91.5% (95% CI 90.7 to 92.2), symptomatic infection of 97.0% (95% CI 96.7 to 97.2), and documented infection (asymptomatic and symptomatic) of 95.3% (95%CI 94.9 to 95.7) [Haas EJ, 2021 ].

Saciuk Y et al. was a comparative cohort study conducted in Israel. The study enrolled 1,650,885 participants: 575,259 in the vaccine group and 302,909 in the control group. Based on retrospective surveillance data from the nationwide vaccination program in people aged ≥ 16 years in Maccabi HealthCare Services, Israel, between January 18th to April 25th 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness was 93.0% (95% CI, 92.6% to 93.4%) [Saciuk Y, 2021 ].

Emborget HD et al. was a comparative cohort study conducted in Denmark. The study enrolled 864,096 participants: 850,799 Vaccine group; 13,297 Control group. Based on data from The Danish Civil Registration System from five cohorts of priority groups for vaccination (long-term care facility residents, individuals 65 years and older living at home but requiring practical help and personal care, individuals ≥85 years of age health-care workers and individuals with comorbidities) between December 27, 2020, and April 11, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness of 82% (95% CI 79 to 84) [Hanne-Dorthe Emborg, 2021 ].

Bjork J et al. was a comparative cohort study conducted in Sweden. The study enrolled 805,741 participants: 26,587 Vaccine group; 779,154 Control group. Based on data from the working population from registers kept for administrative purposes at the Skåne county council, Sweden between 27 December 2020 until 28 February 2021.Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness of 86% (95% CI 72 to 94) [Jonas Bjork, 2021 ].

Moustsen-Helms I et al. was a comparative cohort study conducted in Denmark. The study enrolled 370,079 participants: 114,406 Vaccine group; 255,673 Control group. Based on retrospective data from population-based registries from all Long Term Care Facilities residents and all Health Care Workers, between December 27, 2020, and February 18, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness in long term care facility residents was 64% (95% CI 14 to 84) and health care workers was 90% (95% CI 82 to 95)[Ida Rask Moustsen-Helms, 2021 ].

Pilishvili T et al. was a case-control study conducted in United States. The study enrolled 4,931 participants: 1,482 Vaccine group; 3,449 Control group. Based on a test-negative  case–control study involving  health  care  personnel  across 25 U.S. states, between December 28, 2020 and May 19, 2021. Outcome was measured starting at ≥ 14 days after vaccination. Results showed a vaccine effectiveness of 88.8% (95%CI 84.6 to 91.8) [Pilishvili T, 2021 ]

Trunfio M et al. was a Case-control study conducted in Italy. The study enrolled 6,910 participants: 6,800 vaccine group; 110 Control group. Based on data from all the health care workers of the entire health district ASL Città di Torino, between 27 December 2020 and 1 April 2021. Outcome measured starting at ≥ 8 days after second dose. Results showed an Incident relative risk of 0.06 (95%CI 0.05 to 0.07) [Trunfio M, 2021 ].

Chico-Sánchez P et al. was a case-control study conducted in Spain. The study enrolled 624 participants: 518 vaccine group, 106 control group. Based on electronic health records and interviews to health care personnel from the Alicante-Hospital-General health department between January 25 and June 6, 2021. Results showed a vaccine effectiveness of 96.3% (95%CI 82.5̶ to 99.2) for preventing COVID infection with the complete vaccination regimen. The results also showed a vaccine effectiveness of 68.0% (95%CI 30.0̶ to 85.4) with the incomplete vaccine regimen [Chico-Sánchez P, 2021 ].  

Amanda Zheutlin et al. was a case-control study conducted in the United States. The study included data from 168,857,729 participants with 7,926,846 receiving Pfizer vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing incident breakthrough infection, hospitalization or ICU admission in months two through six following full vaccination were estimated relative to the first month after full vaccination. The study results showed evidence of waning protection against infections starting in month 2 from vaccination for both BNT162b2 and mRNA-1273 and in month 4 for Ad26.COV2.S. Evidence of waning protection against hospitalization started in month 2 for BNT162b2 and in month 3 for mRNA-1273. There was no evidence of waning protection against hospitalization for Ad26.COV2.S.  No waning of protection was observed at any time for ICU admissions for all three vaccines [Amanda Zheutlin, 2022 ].

Bedston S et al was a comparative cohort study in United Kingdom. The study included 82,959 health care workers. Based on data from a national cohort of health care workers to describe uptake of COVID-19 vaccines, effectiveness, and waning of the Pfizer vaccine effectiveness against PCR-confirmed infection following first and second doses up to 26 weeks post-vaccination, between from 7 December 2020 to 30 September 2021. The study results showed that the effectiveness of the Pfizer vaccine was found to be strong and consistent across the characteristics considered; 52% three to six weeks after first dose, 86% from two weeks after second dose, though this declined to 53% from 22 weeks after the second dose [Bedston S, 2022 ].

Haruka Maeda et al. was a case-control study conducted in Japan. The study enrolled 1,936 participants: 396 vaccine group; 1,540 control group.  Based on data from patients aged16 years or older visiting hospitals or clinics with signs or symptoms consistent with COVID-19 from July 1 to September 30, 2021, when the Delta variant was dominant and responsable of more than 90% of severe SARS-CoV-2 infections nationwide in Japan, the study results showed a vaccine effectiveness against symptomatic infection of  86.7% (95% CI 73.5 to 93.3) in patients 16-64 years and of 85.8% (95% CI 59.4 to 95.0) in participants aged ≥ 65 years 3 to 6 months after vaccination [Haruka Maeda, 2022 ].

Chadeau-Hyam M et al. was a cohort study conducted in United Kingdom. The study enrolled 172,862 participants: 76,291 vaccine group; 96,571 control group. Based on data from a  series of random cross-sectional surveys in the general population of England aged 5 years and older, between May 2020 and September 2021, the study results showed a vaccine effectiveness of 71.3% (95%CI 56.6 to 81.0) against infection in vaccinated individuals [Chadeau-Hyam M, 2022 ].

Chin ET et al. was a retrospective cohort study conducted in the United States. The study enrolled 60,707 participants from the California state prisons: 29,947 vaccine group; 30,760 control group. Based on data from the California Department of Corrections and Rehabilitation from December 22, 2020 through March 1, 2021, including daily data for all prison residents related to demographic, clinical, and carceral characteristics, as well as COVID-19 testing, vaccination, and outcomes, measuring outcome 14 days after second dose, the study results showed an agregated vaccine effectiveness of 97% (95% CI, 88-99%) in vaccinated individuals (Pfizer and Moderna) [Chin ET, 2022 ].

Johnson AG et al. included 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Data were collected between April 4, 2021, to December 25, 2021. Combined results showed that age-standardized case incidence rate ratios among unvaccinated persons compared with fully vaccinated persons with a booster dose declined from 13.9 during October–November to 4.9 during December, representing potential decreases in crude vaccine effectiveness for infection from 93% to 80%, respectively. Comparing unvaccinated persons with fully vaccinated persons without a booster dose, age-standardized case incidence rate ratios during October–November, and December were 4.0 and 2.8 respectively, representing decreases in vaccine effectiveness from 75% to 64% [Johnson AG, 2022 ].

The VISION Network study included 222,772 encounters from 383 emergency departments (ED) and urgent care (UC), and 87,904 hospitalizations from 259 hospitals. Data were collected during periods of Delta and Omicron variant predominance between august 2021to January 2022. Based on all results combined, during the Delta-predominant period, vaccine effectiveness against Lab-confirmed COVID-19 was significantly lower among patients who received the second dose ≥180 days earlier (76%; 95% CI 75 to 77) than among those who received the third dose (94%; 95% CI 93 to 94). In the omicron-predominant period, vaccine effectiveness against the same outcome was significantly lower among those who received the second dose ≥180 days earlier (38%; 95% CI 32 to 43) than those who received the third dose (82%; 95% CI 79 to 84)[Thompson MG, 2022 ].

Butt AA et al was a cohort study conducted in the United States. The study enrolled 6,076 participants: 2,700 vaccine group; 3,376 control group. Based on the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify all Veterans with chronic hemodialysis who were tested for SARS-CoV-2 between January 26, 2021 and August 31, 2021, the study results showed a vaccine effectiveness against documented infection of 68.9% (95% CI.:61.9,74.7)( Outcome measured 14 days after second dose) [Butt AA, 2022 ].

Molani S et al. was a cohort study conducted in the United States. The study included 7,620,084 records of 2,627,914 vaccinated participants with either Pfizer-BioNTech, Moderna or Janssen, and  191,722 non-vaccinated individuals with history of COVID-19 infection. The study was based on data from Providence-St. Joseph Health electronic health records. The vaccine-induced cohort period data was collected from December 12, 2020, the infection-induced cohort data was collected from the beginning of the pandemic, data collection finished in to May 11, 2021. Survival against breakthrough for Pfizer-BioNTech was 99.7% in 180 days. [Sevda Molani, 2022 ]

Goldin S et al was a cohort study conducted in Israel. The study enrolled 43,596 participants: 39,482 received one dose; 37,656 received two doses. Based on data from the Senior Shield task force. Residents began receiving Pfizer-BioNTech vaccines in December 2020. The study follow-up period ended in May 2021 (a total of 5 months). The study results showed a vaccine effectiveness against documented infection of  61.8% (95% CI: 58.2 to 65.1) after one dose(Outcome measured 10 days after vaccination) and 81.2% (95% CI: 78.6 to 83.5) after two doses (Outcome measured 7 days after second dose) [Goldin S, 2022 ]

Oster Y et al was a comparative cohort study conducted in Israel. The study enrolled 5,371 healthcare workers: 398 received two doses, 4,973 received three doses. Based on data from healthcare workers at the Hadassah tertiary care medical center in Jerusalem, who had received two vaccine doses (Pfizer-BioNTech) in early 2021 and were not infected until August 2021. The follow-up period lasted 120 days after the last dose for each group. The vaccine effectiveness against breakthrough infection was  97% ( 95% CI, 95% to 99%).  [Oster Y, 2022 ]

Draws PE et al. It was a case-control study conducted in the United States. The study included 4,547,945 participants: 1,732,112 were fully vaccinated with Pfizer and 1,066,645 were fully vaccinated with Moderna. A Pfizer booster was given to 609,153 people and a Moderna booster to 395,634 people. The study is based on statewide COVID-19 vaccination data from the Minnesota Immunization Information Connection (MIIC), linked through a privacy-preserving record-linking process with electronic medical record data. (EHR) of the 11 largest health systems in Minnesota. The main results showed that the effectiveness of the vaccine after 26 weeks of the second dose was 45% (95% CI 44 to 47) for the Pfizer-BioNTech vaccine [Drawz PE, 2022 ].

Mallow C et al. was a case-control study conducted in the United States. The study analyzed data from 13,203 adult presentations (age ≥ 18) to the emergency department: 3,134 were fully vaccinated and negative to COVID-19, 108 were fully vaccinated and positivo to COVID-19, 8,817 not  vaccinated and COVID-19 negative, and 1,144 were not vaccinated and positive to COVID-19. The aim of the study was to assess the effectiveness of messenger RNA vaccines against SARS-COV-2 in the emergency department.  Data was collected from January 1 through August 25, 2021, from subjects with SARS-COV-2 PCR testing and symptoms of acute respiratory infection. The main results showed that Pfizer vaccine effectiveness was 73.9% (95 CI 66.3 to 79.8) [Mallow C, 2022 ].

Roberts E et al. was a case control study conducted in the United States. The study analyzed data from 170,487 positive for COVID-19 adult patients: 74,060 fully vaccinated, 18,425 partially vaccinated and 7187 fully vaccinated and had received at least 1 booster dose. The aim was to investigate the COVID-19 vaccine effectiveness against test positivity and severe COVID-19 outcomes across 2021, and to examine  vaccine effectiveness stratified by the two most common vaccines Pfizer-BioNTech and Moderna, and by sociodemographic and clinical characteristics that are associated with COVID-19 outcomes. Results reported a vaccine effectiveness for contracting COVID-19 of 82.9% (95% CI 80.7 to 84.9) [Emily Roberts, 2022 ].

Fano V et al was a comparative cohort study conducted in Italy. The study included 371,423 participants: 221,000 received Pfizer vaccine and 150,423 received AstraZeneca vaccine. The study estimated the effectiveness of Pfizer and AstraZeneca vaccines since 27/12/2020, and followed until diagnosis of SARS-CoV-2 infection or 25/4/2021, whichever came first. Adjusted hazard ratios of SARS-CoV-2 infection at weekly intervals since the first dose were estimated through a Cox regression model using 0-13 days as reference time-interval. Adjusted Pfizer vaccine effectiveness between 35 and 41 days was 81.1% ( 95%CI 71.1 to 87.7) [Fano V, 2022 ].

Winkelman TNA et al  was a comparative cohort study conducted in the USA. The study included 4,431,190 individuals: 3,013,704 fully vaccinated and 1,417,486 not vaccinated. It used data from the Minnesota Immunization Information Connection from October 25, 2020, through October 30, 2021 that were linked with electronic health record (EHR) data from health systems collaborating as part of the Minnesota EHR Consortium (MNEHRC). Vaccine Effectiveness for Medically Attended SARS-CoV-2 Infections was 53% (95% CI 52 to 54) and 38% (95% CI 35 to 41) for adults ≥ 65 years. [Winkelman TNA, 2022 ]

Goldberg Y et al was a comparative cohort study conducted in Israel. The study included 4,606,250 PCR tests. The study analyzed an updated individual-level database of the entire population of Israel to assess the protection of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Outcome data were collected from December 20, 2020 up to March 20, 2021.Vaccine effectiveness was 94.5% (95% CI 94.3 to 94.7). [Goldberg Y, 2022 ]

Berec L was a case-control study conducted in Czechia. The study used Czech national health data from the beginning of the Covid-19 pandemic till November 2021 to estimate risks of reinfection, breakthrough infection, hospitalization, and death among fully vaccinated individuals at two time points (0-2 months and 7-8 months after the second dose) and after a booster dose. The study analyzed 5,011,115 individuals vaccinated with the Pfizer-BioNTech vaccine. The vaccine effectiveness against any PCR-confirmed SARS-CoV-2 infection declined for from 87% (95% CI 86–87) 0–2 months after the second dose to 53% (95% CI 52–54) at 7–8 months; against hospitalizations, VE declined from 90% (95% CI 89–91) at 0–2 months to 75% (95% CI 73–76) at 7–8 months [Berec L, 2022 ].

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against infections at 14 -83 days after the second dose was 44.1% (95% CI -140.0 to 72.6) for residents (>65 years old) and 66.8% (95% CI 53.1 to 76.6) for staff (>18 years old) [Shrotri M, 2022 ].

Paternina-Caicedo A et al was a retrospective cohort study conducted in Colombia. The study included 719,735 participants over 40 years old: 539,010 unvaccinated, 76,729 with two-dose CoronaVac, and 56,140 with two-dose Pfizer vaccine. This study estimated the vaccine effectiveness (VE) against COVID-19 symptomatic cases, hospitalization, critical care admission, and deaths in a cohort of insured subjects older than 40 years in northern Colombia, a setting with a high SARS-CoV-2 transmission. VE for two doses of BNT162b2 against laboratory-confirmed symptomatic Covid-19 was 29.6% (95% CI 21.1 to 37.2) [Paternina-Caicedo A, 2022 ].

Oren Miron et al was a secondary analysis of a phase 3 randomized clinical trial conduct in 166 different locations. The study reunited data from 43,448 participants aged 16 to 91 years that were enrolled to receive two doses of Pfizer-BioNTech vaccine on days 0 and 21 (n= 21,720) and placebo group (n= 21,728). Vaccine effectiveness (VE) was defined by the ratio between the COVID-19 cumulative rate in vaccinated participants and in the placebo group participants. The study results showed that  the cumulative incidence of COVID-19 increased by 0.09% from day 0 to 7, by 0.06% from day 7 to 14, and by 0.01% from day 14 to 21. From day 21 to 111, the incidence increased on average by 0.01% per week and reached 0.29%, as oppose to controls that reached 2.22% at day 111. The BNT162b2 effectiveness at days 7, 14, and 21 was 12%, 80%, and 94% respectively, followed by a mean of 94% effectiveness until day 112 [Oren Miron, 2021 ].

Horne E et al was a cohort study conducted in England, including 7,594,195 participants, amongst which 1,951,866 were Pfizer-BioNTech recipients, 3,219,349 AstraZeneca recipients and 2,422,980 remained unvaccinated. Rates of COVID-19 related hospital admission and death were substantially lower among vaccinated than unvaccinated adults up to 26 weeks after the second dose, with estimated vaccine effectiveness ≥80% for BNT162b2. By weeks 23-26, rates of positive SARS-CoV-2 test in vaccinated people were similar to or higher than unvaccinated people (adjusted hazard ratios up to 1.72 (1.11 to 2.68) for BNT162b2. COVID-19 related hospitalizations: Estimated adjusted hazard ratios comparing BNT162b2 with unvaccinated people in the ≥65 subgroup were 0.08 (95% confidence interval 0.05 to 0.13) during weeks three to six after the second dose, waning to 0.20 (0.17 to 0.25) during weeks 23-26. [Horne EMF, 2022 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of 2 doses of Pfizer against infection was 74.5% (95% CI 74 to 75) and 47.4% (95% CI 46.6 to 48.2), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ]

Chung et al. conducted a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11th and November 21th 2021 in Ontario, Canada. They included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for ChAdOx1/mRNA-1273 7-59 days after second dose was 91% (95% CI, 89% to 93%) against any infection, 96% (95% CI, 93% to 97%) against symptomatic infection and 99% (95% CI, 95% to 100%) against severe outcomes. VE for BNT162b2/BNT162b2 7-59 days after second dose was 89% (95% CI, 88% to 89%) against any infection and 93% (95% CI, 93% to 94%) against symptomatic infection. VE BNT162B2/BNT162B2 >240 days after second dose was 74% (95% CI, 71% to 77%) against any infection and 87% (95% CI, 84% to 89%) against symptomatic infection. [Chung H, 2022 ]

Contracting severe COVID-19
Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324 ,033 participants that received Moderna or Pfizer COVID-19 vaccine. Based on data from a test negative design study among patients who had symptoms consistent with covid-19 between 14 December 2020 and 19 April 2021. Results showed vaccine effectiveness of 96% (95%CI 82 to 99)
[Chung H, 2021 ].

Dagan N et al. was a cohort study conducted in Israel. The study enrolled 1,193,236 general population participants that received Pfizer-BioNTech COVID-19 vaccine. Based on data from Israel’s largest health care organization (Clalit Health Services) during the period from December 20, 2020, to February 1, 2021. Results showed vaccine effectiveness against severe infection 92% (95% CI 75 to 100) and hospitalizations was 87% (95% CI 55 to 100) [Dagan N, 2021 ].

Cabezas C et al. was a comparative cohort study conducted in Spain. The study enrolled 116,783 participants: 98,494 Vaccine group; 18,289 Control group. Based on data from three cohorts from Catalonia from December 27 2020 to March 5, 2021. Outcomes were measured at ≥ 12 days after vaccination. Results showed vaccine effectiveness in nursing home residents was 97% (95%CI 95 to 98) and nursing home staff was 98% (95%CI 97 to 99)[Carmen Cabezas, 2021 ].

Haas EJ et al. was a comparative cohort study conducted in Israel. The study enrolled 6,538,911 participants: 4,714,932 Vaccine group; 1,823,979 Control group. Based on national surveillance data from the first 4 months of the nationwide vaccination campaign in people aged ≥ 16 years from Jan 24 to April 3, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against hospitalisation of 97.5% (95%CI 97.1 to 97.8) and deaths of 96.7% (95%CI 96.0 to 97.3) [Haas EJ, 2021 ].

Saciuk Y et al. was a comparative cohort study conducted in Israel. The study enrolled 1,650,885 participants: 575,259 in the vaccine group and 302,909 in the control group. Based on retrospective surveillance data from the nationwide vaccination program in people aged ≥ 16 years in Maccabi HealthCare Services, Israel, between January 18th and April 25th 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against hospitalization was 93.4% (95% CI, 91.9% to 94.7%) and deaths of 91.1% (95% CI, 86.5% to 94.1%) [Saciuk Y, 2021 ].

Emborget HD et al. was a comparative cohort study conducted in Denmark. The study enrolled 864,096 participants: 850,799 Vaccine group; 13,297 Control group. Based on data from The Danish Civil Registration System from five cohorts of priority groups for vaccination (long-term care facility residents, individuals 65 years and older living at home but requiring practical help and personal care, individuals ≥85 years of age health-care workers and individuals with comorbidities) between December 27, 2020, and April 11, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against of hospitalisation of 93% (95% CI 89 to 96) and deaths of 94% (95% CI 90 to 96) [Hanne-Dorthe Emborg, 2021 ].

Sheikh A 2021, was a cohort study conducted in Scotland. This study used data from a national surveillance database to estimate vaccine effectiveness against death from delta variant infection between April 1 and August 16, 2021, among adult participants who were followed up to September 27, 2021. Mortality analysis was based on 114,706 adults who tested positive for SARS-CoV-2 and a total of 201 deaths were reported. Among participants between 40 and 59 years of age, vaccine effectiveness against death from COVID-19 was 88% (95% CI, 76 to 93) for ChAdOx1 nCoV-19 and 95% (95% CI, 79 to 99) for BNT162b2. Among participants aged 60 years or older vaccine effectiveness was 90% (95% CI, 84 to 94) and 87% (95% CI, 77 to 93), respectively. Overall, vaccine effectiveness against death from the delta variant 14 or more days after the second vaccine dose was 90% (95% CI, 83 to 94) for BNT162b2 and 91% (95% CI, 86 to 94) for ChAdOx1 nCoV-19 [Sheikh A, 2021 ].

Suah JL et al. was a Cohort study conducted in Malaysia. The study enrolled 1,239,445 participants: 489,921 Vaccine group; 749,524 Control group. This study used data from four secondary data sets constructed from national COVID-19 surveillance: (1) the COVID-19 casesline listing, (2) the ICU admissions register, (3) the COVID-19 deaths line listing, and (4)the COVID-19 vaccine recipients line listing, linked deterministically with the case and personal identification numbers, between 1 April 2021 and 15 September 2021. Outcome was measured starting 14 days after the second dose.  Results showed a Vaccine effectiveness of 90.3% (95%CI 88.8 to 91.6) for ICU admission and  92.7% (95%CI 91.7 to 93.6) for death [Suah JL, 2021 ].

Zeina Farah et al. was a case-control study conducted in Libanon. The study enrolled 1,159 participants aged 75 years or older. Based on randomly selected data from the COVID-19 database of the Epidemiological Surveillance Unit(ESU) at the Ministry of Public Health(MOPH) between April and May 2021, the study results showed a vaccine effectiveness of 82% (95%CI = 69%-90%) against COVID-19 associated hospitalization for those fully vaccinated and 53% (95%CI = 23%-71%) for those partially vaccinated (≥14 days of first or within 14 days of second dose), after adjusting for month of admission and gender [Zeina Farah, 2022 ].

Lytras T et al. included a total of 14,676,605 vaccine administered doses ( Pfizer= 11,427,784; Moderna= 1,161,905; AstraZeneca=1,505,334; Janssen= 581,582). Data were collected between 11 January 2020 and 8 December 2021. The study showed that two doses of Pfizer, Moderna, or AstraZeneca COVID-19 vaccines offered vaccine effectiveness >90% against both intubation and death across all age groups. The effectiveness of the Janssen COVID-19 vaccine ranged between 61-81%. There was some waning over time but vaccine effectiveness remained >80% at six months, and three doses increased vaccine effectiveness again to near 100%. Vaccination prevented an estimated 19,691 COVID-19 deaths (95% CI 18,890 to 20,788) over the study period [Theodore Lytras, 2022 ].

Wright BJ et al. was a case-control study conducted in the United States. It included data from 9,667 admissions for severe COVID-19 and 38,668 controls. Based on hospital admission registries from a large health-care system (Providence). to analyze vaccine effectiveness against severe COVID-19 over time. Between April 1, 2021, and Oct 26, 2021. The effectiveness of the vaccine was 94.9% (95% CI 93.2 to 96.2) between 50 to 100 days after the 2nd dose and it wanted to 74.1% (95% CI 69.6 to 77.9) between 200-250 days after the 2nd dose [Wright BJ, 2022 ].

Arregocés-Castillo et al was a retrospective cohort study conducted in Colombia. The study included 2,828,294 participants: 1,414,147 fully vaccinated (any vaccine) and 1,414,147 unvaccinated. The study evaluated the effectiveness of vaccines against COVID-19-related hospitalization and death in people aged 60 years and older. Participant follow-up was done between March 11, 2021, and Oct 26, 2021. It was estimated the overall effectiveness of being fully vaccinated, as well as the effectiveness of each vaccine. The aim results showed that vaccine effectiveness against hospitalization without death was 83% (95% CI 78.4 to 86.6) in adults > 60 years. Effectiveness against death after hospitalization was 94.8% (95% CI 93.3 to 96) and against death without hospitalization was 88.3% (95% CI 84.1 to 91.4) in adults > 60 years [Arregocés-Castillo L, 2022 ].

Winkelman TNA et al  was a comparative cohort study conducted in the USA. The study included 4,431,190 individuals: 3,013,704 fully vaccinated and 1,417,486 not vaccinated. It used data from the Minnesota Immunization Information Connection from October 25, 2020, through October 30, 2021 that were linked with electronic health record (EHR) data from health systems collaborating as part of the Minnesota EHR Consortium (MNEHRC). Vaccine Effectiveness for SARS-CoV-2–Related Hospitalizations: was 81% (95% CI 79 to 82) and 55% (95% CI 50 to 59) [Winkelman TNA, 2022 ].

Goldberg Y et al was a comparative cohort study conducted in Israel. The study included 4,606,250 PCR tests. The study analyzed an updated individual-level database of the entire population of Israel to assess the protection of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Outcome data were collected from December 20, 2020 up to March 20, 2021.Vaccine effectiveness against hospitalization 95.8% (95% CI 95.2 to 96.2) [Goldberg Y, 2022 ].
Elsie MF Horne et al. was a comparative cohort study conducted in England. The study included data from the OpenSAFELY-TPP database. The study included 1,773,970 individuals with BNT162b2 vaccine, 2,961,011 individuals with ChAdOx1 vaccine and 2,433,988 unvaccinated individuals. The study compared individuals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated individuals during six 4-week comparison periods, separately by age subgroups. The Hazard Ratio versus unvaccinated for COVID-19 hospitalization ranged from (≥ 65 years) 1.23 (95% CI 1.15 to 1.32) to 1.27 (95% IC 1.20 to 1.34) for the BNT162b2 vaccine. Rates of COVID-19 hospitalization and COVID-19 death at week 26 showed HRs <0.20 (>80% vaccine effectiveness) for the BNT162b vaccine.

Pálinkás A et al was a retrospective cohort study conducted in Hungary including 4,026,849 fully vaccinated participants (1,604,250 with the Pfizer vaccine) and 2,377,853 unvaccinated. This study aimed to describe all-cause mortality rates by COVID-19 vaccination groups in Hungary between an epidemic period (1 April to 20 June 2021) and a nonepidemic period (21 June to 15 August 2021) and to determine the vaccines’ effectiveness in preventing all-cause mortality utilizing non-epidemic effectiveness measures. Hazard ratio (HR) reduction in epidemic period corrected with nonepidemic period’s HR with 95% confidence interval for each vaccine was used to describe the vaccine effectiveness (VE). The hazard ratio for the Pfizer vaccine was 0.384 (95% CI 0.370 to 0.399). The difference in hazard ratio was 0.513 (95% CI 0.487 to 0.539). The effectiveness in preventing all-cause mortality was 0.487 (95% CI 0.461 to 0.513) [Pálinkás A, 2022 ].

Berec L was a case-control study conducted in Czechia. The study used Czech national health data from the beginning of the Covid-19 pandemic till November 2021 to estimate risks of reinfection, breakthrough infection, hospitalization, and death among fully vaccinated individuals at two time points (0-2 months and 7-8 months after the second dose) and after a booster dose. The study analyzed 5,011,115 individuals vaccinated with the Pfizer-BioNTech vaccine. The vaccine effectiveness against any PCR-confirmed SARS-CoV-2 infection declined for from 87% (95% CI 86–87) 0–2 months after the second dose to 53% (95% CI 52–54) at 7–8 months; against hospitalizations, VE declined from 90% (95% CI 89–91) at 0–2 months to 75% (95% CI 73–76) at 7–8 months [Berec L, 2022 ].

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against hospitalization at 14 - 83 days after the second dose was 91.8% (95% CI 39.8 to 98.9) for residents (>65 years old) and 92.1% (95% CI 69.3 to 97.9) for staff (>18 years old) [Shrotri M, 2022 ].

Paternina-Caicedo A et al was a retrospective cohort study conducted in Colombia. The study included 719,735 participants over 40 years old: 539,010 unvaccinated, 76,729 with two-dose CoronaVac, and 56,140 with two-dose Pfizer vaccine. This study aimed to estimate vaccine effectiveness (VE) to prevent COVID-19 symptomatic cases, hospitalization, critical care admission, and deaths in a cohort of insured subjects older than 40 years in northern Colombia, a setting with a high SARS-CoV-2 transmission. Effectiveness of two-dose vaccination with BNT162b2 (with laboratory-confirmed Covid-19) against hospitalization, critical care admission and death were 54.2% (95% CI 34.6 to 67.9), 82.1% (95% CI 56.5 to 92.6) and 93.5% (95% CI 73.9 to 98.4) respectively [Paternina-Caicedo A, 2022 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of two doses of Pfizer against hospitalization was 77.2% (95% CI, 74-79.9) and 70.9% (95% CI, 65.3-75.6), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ].

Grasselli G et al was a cohort study conducted in Italy that included 10,107,674 residents, among which 7,863,417 were vaccinated. The study was based on data from the Italian National Health Service, from August 2021 to August 2022. The study included participants vaccinated with Pfizer, Moderna, AstraZeneca and Janssen. The effectiveness of mRNA vaccines against ICU Admission was IRR 0.10 (95 CI%, 0.08-0.12). [Lin DY, 2022 ]

Chung et al. conducted a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11th and November 21st 2021 in Ontario, Canada. It included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for BNT162b2/BNT162b2 7-59 days after second dose was 98% (95% CI, 97% to 98%) against severe outcomes (hospitalization/death). VE for BNT162B2/BNT162B2 >240 days after second dose was 98% (95% CI, 95% to 99%) against severe outcomes (hospitalization/death). [Chung H, 2022 ]

Transmission
Abu-Raddad LJ et al. was a retrospective cohort study conducted in Qatar. The study enrolled 384,246 participants: 192,123 received Moderna vaccine; 192,123 received Pfizer vaccine. Based on data from national Covid-19 electronic health databases of the two matched cohort of participants between December 21, 2020, and October 20, 2021 and measuring the outcome 1 to 6 months after the second dose, the study results showed that vaccination with COVID-19 vaccines was associated with a lower incidence of SARS-CoV-2 breakthrough infection, with an adjusted Hazard Ratio (HR) for breakthrough infection of 0.82 (95%CI 0.60 to 1.12)[Abu-Raddad LJ, 2022 ]. 

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7)
Tarke A et al. was a comparative cohort study conducted in the United States. The study enrolled 80 healthy adults (14 received Pfizer, 13 received Moderna, 28 COVID-19 group, 23 unexposed group). This study evaluated T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccines for their capacity to recognize peptides derived from the ancestral reference sequence and the alpha variant. Comparison of the variant to the ancestral sequence showed no significant differences for CD4+ and CD8+ T cell reactivity in the activation-induced marker assay for B.1.1.7. CD4 + T cells (p = 0.41) and CD8 + T cells (p = 0.10) [Tarke A, 2021 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) on day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Alpha variant (BBB group: 98.0% (95% CI 96.3 to 98.6); BBM group: 98.4% (95% CI 98.0 to 98.7). There was statistical difference of neutralizing activity against the Gamma variant between the homologous and the heterologous booster dose groups (p= 0.0184) [Poh XY, 2022 ].

Beta (B.1.351)
Tarke A et al. was a comparative cohort study conducted in the United States. The study enrolled 80 healthy adults (14 received Pfizer, 13 received Moderna, 28 COVID-19 groups, 23 unexposed groups). This study evaluated the T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccines for their capacity to recognize peptides derived from the ancestral reference sequence and the beta variant. Comparison of the variant to the ancestral sequence showed significant differences for CD4+ and CD8+ T cell reactivity in the activation-induced marker assay for B.1351. Decreases of 14% and 22%, respectively, were observed with the B.1.351 pools for CD4+ and CD8+ T cells (B.1.351: p < 0.01 for both comparisons) [Tarke A, 2021 ].

Angkasekwinai N et al. was a cohort study conducted in Thailand. Data was collected from a single-tertiary care hospital between July to September 2021. Results showed that for both Sinovac and AstraZeneca prime-vaccination groups, the PRNT50 GMT against the Delta and Beta variant was significantly higher among those participants who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistically significant difference in the PRNT50 between boosting with 30µg or 15µg of Pfizer vaccine, regardless of the primary vaccination series and the type of variant evaluated. The study showed that the PRNT50 against the Beta variant was 1.5-fold lower compared to Delta variant for CoronaVac and AstraZeneca prime-vaccination groups. The GMTs of the PRNT50 observed between post-boost, and post-primary vaccination series were highest among participants who received Pfizer boosting in both Sinovac and AstraZeneca groups [ ].

Lu et al. was a prospective cohort study that recruited 135 COVID-19 recovered individuals scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the vaccinated individuals' Beta, Delta, and Omicron variants to the unvaccinated ones. The study found that one dose of the Pfizer vaccine greatly increased the neutralizing titers against all three variants and seropositivity rate. Neutralizing titers against the Delta and Beta variants were not significantly different than against the ancestral lineage [Lu Lu, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose. Levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as the second dose had significantly higher neutralizing titers against Delta and Beta than those that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and was 28- to 229-fold lower than Delta. Neutralization against the Delta and Omicron variants was significantly lower among groups who received Sinovac as a second dose than the other groups. Seropositivity rate for the Omicron variant was of 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) on day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Beta variant (BBB group: 95.0% (95% CI 92.0 to 96.3); BBM group: 96.0% (95% CI 93.7 to 97.1). There was statistical difference of neutralizing activity against the Gamma variant between the homologous and the heterologous booster dose groups (p= 0.0293) [Poh XY, 2022 ].

Odile Launay et al was a randomized clinical trial conducted in France. The study included 247 participants who had received two doses of BNT162b2 of whom 85 received a Sanofi/GSK MV(D614) vaccine booster, 80 Sanofi/GSK MV(Beta) vaccine booster, and 82 BNT162b2 vaccine booster. The study evaluated the immunogenicity and safety of a homologous booster dose of BNT162b2 or recombinant vaccine with adjuvant (Sanofi/GSK MV(D614) formulation or MV B.1.351 (Beta) formulation) in recipients primed with two doses of BNT162b2 between 3 and 7 months earlier. The proportion of participants with at least a 10-fold increase of neutralizing antibody titers between day 0 and day 15 for the Wuhan (D614) SARS-CoV-2 strain (Pfizer BNT162b2) was 63.2% (95% CI 51.3 to 73.9) and for the B.1.351 (Beta) viral strain was 51.3% (95% CI 39.6 to 63.0). The geometric mean titer of anti-S1 increased from 253.6 at day 0 to 2405.4 BAU/mL at day 15 [Odile LAUNAY, 2022 ].

Gamma (P.1)
Tarke A et al. was a comparative cohort study conducted in the United States. The study enrolled 80 healthy adults (14 received Pfizer, 13 received Moderna, 28 COVID-19 groups, and 23 unexposed groups). This study evaluated the T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccines for their capacity to recognize peptides derived from the ancestral reference sequence and the gamma variant. Comparison of the variant to the ancestral sequence showed no significant differences for CD4+ and CD8+ T cell reactivity in the activation-induced marker assay for P.1 (CD4+ T cells: p = 0.29) (CD8+ T cells: p = 0.09) [Tarke A, 2021 ].
Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 Vaccine groups (15 participants received Pfizer vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained [Roanne Keeton, 2021 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Gamma variant (BBB group: 96.0% (95% CI 92.9 to 97.2); BBM group: 97.1% (95% CI 94.9 to 97.9). There was statistical difference of neutralizing activity against the Gamma variant between the homologous and the heterologous booster dose groups (p= 0.0254) [Poh XY, 2022 ].

Delta (B.1.617.2)
Angkasekwinai N et al. was a cohort study conducted in Thailand. Data was collected from a single-tertiary care hospital between July to September 2021. Results showed that for both Sinovac and AstraZeneca prime-vaccination groups, the PRNT50 GMT against the Delta and Beta variant was significantly higher among those participants who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistically significant difference in the PRNT50 between boosting with 30µg or 15µg of Pfizer vaccine, regardless of the primary vaccination series and the type of variant evaluated. The study showed that the PRNT50 against the Beta variant was 1.5-fold lower compared to Delta variant for CoronaVac and AstraZeneca prime-vaccination groups. The GMTs of the PRNT50 observed between post-boost, and post-primary vaccination series were highest among participants who received Pfizer boosting in both Sinovac and AstraZeneca groups [ ].

Perez-Then et al. was a cohort study conducted in the Dominican Republic. The study compared the neutralizing capabilities of plasma from 101 non-hospitalized adults who received two doses of CoronaVac plus a Pfizer vaccine booster dose to a cohort of healthcare workers immunized with two doses of an mRNA vaccine (Pfizer or Moderna). The results showed increased neutralizing activity against the Omicron variant of the boosted cohort (1.4 fold increase) compared to the mRNA and CoronaVac-only regimens. Neutralization against the Delta variant was similar in the boosted and mRNA groups but lower in the CoronaVac-only group [Pérez-Then E, 2022 ].

Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 Vaccine groups (15 participants received Pfizer vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained [Roanne Keeton, 2021 ].

Alidjinou et al. was a cohort study conducted in France. The study assessed the immune response generated by a booster dose of the Pfizer vaccine against the Omicron and Delta variants. The study included 106 adults older than 65 who received the Pfizer COVID-19 vaccine booster dose. The study assessed the antibody response generated against the Delta and Omicron variants on COVID-19 naive and recovered individuals after vaccination. Results showed COVID-19 recovered individuals had higher neutralizing titers overall. A booster vaccination increased the number of participants who had neutralizing antibodies for the Delta and Omicron variants. The response against the Omicron variant was ~35 fold lower than for the Delta variant [Enagnon Kazali Alidjinou, 2022 ].

Lu et al. was a prospective cohort study that recruited 135 COVID-19 recovered individuals scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the vaccinated individuals' Beta, Delta, and Omicron variants to the unvaccinated ones. The study found that one dose of the Pfizer vaccine greatly increased the neutralizing titers against all three variants and seropositivity rate. Neutralizing titers against the Delta and Beta variants were not significantly different than against the ancestral lineage [Lu Lu, 2022 ].

Kanokudom et al. recruited 222 adults with a complete CoronaVac schedule who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), and 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54), or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants unaffected by dosage. On day 28, the GMT of neutralizing antibodies against the Delta variant were 1 505 and 2 088 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups [Kanokudom S, 2022 ].

Niyomnaitham et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 1243 participants with CoronaVac primary schedule: 312 in the AstraZeneca booster (half dose) group, 307 in the AstraZeneca booster (full dose) group, 316 in the Pfizer booster (half dose) group and 308 in the Pfizer booster (half dose) group. Vaccination-induced immunogenicity to Ancestral, Delta and Omicron BA.1 strains were evaluated by assessing anti-spike (‘anti-S’), anti-nucleocapsid antibodies, pseudovirus neutralization (‘PVNT’), micro-neutralization titers, and T-cells assays. Within platforms and irrespective of dose or platform, seroconversions were greater than 97%, and greater than 90% for neutralising antibodies against pseudovirus, but similar against SARS-CoV-2 strains. Anti Spike RBD IgG Geometric means concentration (U/mL) at day 28 were 8237.0 (95% CI, 7679.3-8835.2) for the AstraZeneca half dose group, 8973.6 (95% CI, 8328.1-9669.2) for the AstraZeneca full dose group, 14073.9 (95% CI, 13236.4-14964.4) for the Pfizer half dose group and 15920.7 (95% CI, 15135.7-16746.4) for the Pfizer full dose group. Pseudovirus Neutralizing Antibody Titer (PVNT50) against Omicron (GMT) were 118.9 (95% CI, 97.3-145.2) for the AstraZeneca full dose group and 255.9 (95% CI, 222.9-293.7) for the Pfizer full dose group. Immunogenicity according to Pseudovirus Neutralizing Antibody Titer (PVNT50) against delta variant at day 28 were 468.3 (95% CI, 409.8-535.2) for AstraZeneca half dose group, 530.6 (95% CI, 470.4-598.5) for AstraZeneca full dose group, 801.5 (95% CI, 715.4-897.8) for Pfizer half dose group and 856.1 (95% CI, 777.8-942.1) for Pfizer full dose group. [Suvimol Niyomnaitham, 2022 ]

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Delta variant (BBB group: 98.1% (95% CI 96.6 to 98.7); BBM group: 98.52% (95% CI 97.7 to 99.0). There was no statistical difference of neutralizing activity against the Delta variant between the homologous and the heterologous booster dose groups (p= 0.0617) [Poh XY, 2022 ].

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. This study investigated neutralizing activities against Omicron and Delta variants in each schedule. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628). [Choi JY, 2022 ]

Nantanee R et al was a randomized clinical trial conducted in Thailand. The study included 100 adults with a median age of 59.3 years (IQR 33.4–65.5) with two-dose AZD1222: 50 received half-Dose BNT162b2 Booster (15 µg/Dose) and 50 received a standard-Dose BNT162b2 Booster (30 µg/Dose). The participants were randomized to receive the BNT162b2 vaccine intramuscularly half (15 µg) vs. the standard dose (30 µg). The immunogenicity was evaluated by a surrogate virus neutralization test (sVNT) against Omicron variants and anti-spike-receptor-bindin-domain IgG (anti-S-RBD IgG). At day 14, both groups had sVNT against delta variant GMs of 100.0% inhibition [Nantanee R, 2022 ].

García-Pérez J was a randomized clinical trial conducted in Spain. The study included 676 adults primed with ChAdOx1-S. 441 participants were randomized to the intervention group and received Pfizer as a second dose. 223 participants were randomized to the control group and did not receive a second vaccine. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralization assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-g and IL-2 immunoassays, were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180. NT50 against Delta variant on day 28 after second dose was 717.13 (95%CI 587.27−876.13) in the interventional group and 837.14 (95%CI 609.7−1149.41) in the control group [García-Pérez J, 2022 ].

Renia L et al was a cohort study that included 312 participants vaccinated with the Pfizer COVID-19 vaccine.  This study compared the kinetics of specific antibodies, B and T cell memory responses in a cohort of BNT162b2-vaccinated healthcare workers and elderly individuals in Singapore up to 6 months postimmunization and for a subset of elderly low responders after a third dose. After the second dose, all but one of the participants developed anti-Spike protein antibodies by day 90. Immunoglobulin isotyping showed that the proportion of vaccinees with detectable IgM (above both cohort and individual baseline) was >85% at day 21 but dropped to 12% by day 90 (12%) and was negligible by day 180. After the second dose, all individuals seroconverted by day 90. However, 36.5% of individuals mounted a poor anti-RBD IgG response. More than 79.1% of the plasma had neutralizing antibodies above individual baseline after the first dose, 99% after the second dose and 93% at day 180. The antibody response against the Delta variant was lower than the Wildtype ancestral strain and extremely low or non-existent against the Omicron variant. The third dose strongly boosted the antibody responses against the total Spike protein or its RBD. The boosting injection also induced a strong antibody response against the spike protein of the Delta and Omicron variants [Renia L, 2022 ].

Omicron (B.1.1.529.1)
Roanne Keeton et al. was a non-comparative study conducted in South Africa. The study enrolled 138 participants: 40 Vaccine group (15 participants received Pfizer vaccine) and was based on data from peripheral blood mononuclear cells samples of vaccinated individuals and unvaccinated convalescent individuals. The study results showed that CD4 T cell frequencies to Omicron spike were consistently and significantly lower than ancestral spike, with a median decrease of 14-30% of the CD4 response to Omicron and a  median reduction of 17-25% of the CD8 response to Omicron compared to the ancestral virus. 70-80% of the CD4 and CD8 T cell response to spike was maintained [Roanne Keeton, 2021 ]. 
     
Gao Y et al . was a non-comparative study conducted in Sweden. The study enrolled 40 healthy individual volunteers (Pfizer recipients) and was based on data from peripheral blood mononuclear cells samples of vaccinated individuals and unvaccinated convalescent individuals. The study results showed that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells cross-recognized B.1.1.529 less comprehensively in convalescent versus Pfizer-vaccinated individuals, suggesting that booster immunization may provide benefits that extend beyond the induction of broadly neutralizing antibodies to enhance natural protection against recurrent episodes of COVID-19 [Gao Y, 2022 ].

Angkasekwinai N et al. was a cohort study conducted Thailand. Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that for both the Sinovac-prime and AstraZeneca-prime groups, the PRNT50 GMT against the Delta and Beta variant were significantly higher among those who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistical difference in PRNT50 between boosting with 30µg and 15µg- Pfizer regardless of the primary series vaccine and the type of variants. However, the PRNT50 against the Beta variant was in general around 1.5-fold lower than the Delta variants for both CoronaVac-prime and ChAdOx1-prime groups. The GMRs of the PRNT50 between post-boost and post-primary series were highest among the participants who received Pfizer boosting vaccination in bothSinovac-prime and AstraZeneca-prime groups. The SARS-CoV-2 RBD IgG levels and the neutralizing titers against Delta variant or Beta variant were strongly correlated.[ ].

XiaH et al. was a noncomparative study conducted in the United States. The study included serum panels containing 22 samples collected on the day of the third dose of Pfizer 30 µg administered between 7.9 and 8.8 months after the second dose and 1 and 4 months after the third dose. The results of the study showed that three doses of Pfizer elicited substantial neutralizing activity against Omicron-spike SARS-CoV-2, while two doses showed a significant reduction [Hongjie Xia, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as the second dose had significantly higher neutralizing titers against Delta and Beta than those that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and was 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against the Delta and Omicron variants was significantly lower among groups who received Sinovac as a second dose than the other groups. Seropositivity rate for the Omicron variant was : 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and: Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].
 

Lu et al. was a prospective cohort study that recruited 135 COVID-19 recovered individuals scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the vaccinated individuals' Beta, Delta, and Omicron variants to the unvaccinated ones. The study found that one dose of the Pfizer vaccine greatly increased the neutralizing titers against all three variants and seropositivity rate. Neutralizing titers against the Delta and Beta variants were not significantly different than against the ancestral lineage [Lu Lu, 2022 ].
 

Kanokudom et al. recruited 222 adults with a complete CoronaVac schedule who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), and 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54), or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants unaffected by dosage. On day 28, the GMT of neutralizing antibodies against the Omicron variant increased to 343.3 and 541.2 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups [Kanokudom S, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901 (control). The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. Compared with pre-boost, all study vaccines elicited significantly higher anti-spike IgG at 28 days post-boost (P < 0.0001). Surrogate neutralizing antibodies by ELISA GMT after boost were 524 (481-573) IU/mL, with a fold change of 32.27 (27.38-38.04). Live virus neutralizing antibody (omicron), NT50 were 146 (119-179) IU/mL with fold change of Fold change 8.38 (6.82-10.29) [Chih-Hsien Chuang, 2022 ].

Suntronwong N et al was a cohort study conducted in Thailand. 167 participants primed with heterologous CoronaVac/Oxford-AstraZeneca vaccination were enrolled to receive a booster dose of Oxford-AstraZeneca (n= 60), Pfizer-BioNTech (n= 55) of Moderna (n= 52) vaccines. This study assessed the capability of the booster vaccination to induce an increase in neutralizing antibodies and T-cell responses against SARS-CoV-2, Omicron (BA.1 and BA.2), and Delta variants. Individuals boosted with mRNA vaccines demonstrated a higher level of neutralizing activity than those boosted with Oxford-AstraZeneca. Median neutralizing activity to Omicron (day 28) were 10,1% for AstraZeneca, 55,6 for Pfizer and 78,2% for Moderna. NAb titers at day 28 for Omicron BA.a variant were 40.3 (3.16-fold increase) for AstraZeneca, 171.0 (9.91-fold increase) for Pfizer, and 271.6 (24.78-fold increase) for Moderna. NAb titers at day 28 for Omicron BA.2 were 59.3 (2.43-fold increase) for AstraZeneca, 130.7 (4.63 fold-increase) for Pfizer, and 235.3 (19.67 fold-increase) for Moderna. [Suntronwong N, 2022 ]

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results of the study showed that both vaccine schedules induced increases in the level of neutralizing antibodies against the Omicron variant (BBB group: 82.5% (95% CI 68.5 to 90.3); BBM group: 84.2% (95% CI 78.2 to 91.0). There was no statistical difference of neutralizing activity against the Omicron variant between the homologous and the heterologous booster dose groups (p= 0.110) [Poh XY, 2022 ].

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild-type (WT) SARS-CoV-2, Delta variant, and Omicron variant. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628)[Choi JY, 2022 ].

Nantanee R et al was a randomized clinical trial conducted in Thailand. The study included 100 adults with a median age of 59.3 years with two-dose AZD1222: 50 received a half-Dose BNT162b2 Booster (15 µg/Dose) and 50 received a standard-Dose BNT162b2 Booster (30 µg/Dose). The immunogenicity was evaluated by a surrogate virus neutralization test (sVNT) against Omicron variants and anti-spike-receptor-bindin-domain IgG (anti-S-RBD IgG). At day 14, the geometric means of sVNT against the omicron variant were 74.4% (95% CI 68.8–80.5)  inhibition post-half-dose BNT162b2 boosters and 67.3% inhibition (95% CI 57.9 to 78.1) post-standard-dose boosters. At day 14, anti-S-RBD IgGs were comparably boosted with GMs of 2329.8 BAU/mL (95% CI 2109.3–2573.4) post-half-dose BNT162b2 boosters and 2574.7 BAU/mL (2262.5–2929.9) post-standard-dose boosters. At 14 days after boosters, the T cell responses were significantly enhanced to 406 SFU/106 PBMCs (IQR 206–718, p < 0.001) in the half-dose and 402 SFU/106 PBMCs (148–678, p < 0.001) in the full-dose groups, without a difference between the dosage groups (p 0.80) [Nantanee R, 2022 ].

García-Pérez J was a randomized clinical trial conducted in Spain. The study included 676 adults primed with ChAdOx1-S. 441 participants were randomized to the intervention group and received Pfizer as a second dose and 223 participants were randomized to the control group and did not receive a second vaccine. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralization assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-g and IL-2 immunoassays, were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180. By SARS-CoV-2 variants, the poorest neutralization capability at day 28 post-vaccination was found with the Omicron variant in both interventional and control groups (GMT 144.84 [95%CI 116.65−179.85] and 204.84 [95%CI 151.99−276.06]). A decrease in NT50 was also observed for the Beta variant in both interventional and control groups (GMT 293.21 [95%CI 234.8−366.15] and 483.89 [95%CI 352.53−664.2]) [García-Pérez J, 2022 ].

Renia L et al was a cohort study that included 312 participants vaccinated with the Pfizer COVID-19 vaccine. This study compared the kinetics of specific antibodies, B and T cell memory responses in a cohort of BNT162b2-vaccinated healthcare workers and elderly individuals in Singapore up to 6 months postimmunization and for a subset of elderly low responders after a third dose. After the second dose, all but one of the participants developed anti-Spike protein antibodies by day 90. Immunoglobulin isotyping showed that the proportion of vaccinees with detectable IgM (above both cohort and individual baseline) was >85% at day 21 but dropped to 12% by day 90 (12%) and was negligible by day 180. After the second dose, all individuals seroconverted by day 90. However, 36.5% of individuals mounted a poor anti-RBD IgG response. More than 79.1% of the plasma had neutralizing antibodies above the individual baseline after the first dose, 99% after the second dose, and 93% at day 180. The antibody response against the Delta variant was lower than the Wildtype ancestral strain and extremely low or non-existent against the Omicron variant. The third dose strongly boosted the antibody responses against the total Spike protein or its RBD. The boosting injection also induced a strong antibody response against the spike protein of the Delta and Omicron variants. [Renia L, 2022 ].

Niyomnaitham et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 1243 participants with CoronaVac primary schedule: 312 in the AstraZeneca booster (half dose) group, 307 in the AstraZeneca booster (full dose) group, 316 in the Pfizer booster (half dose) group and 308 in the Pfizer booster (half dose) group. Vaccination-induced immunogenicity to Ancestral, Delta and Omicron BA.1 strains were evaluated by assessing anti-spike (‘anti-S’), anti-nucleocapsid antibodies, pseudovirus neutralization (‘PVNT’), micro-neutralization titers, and T-cells assays. Within platforms and irrespective of dose or platform, seroconversions were greater than 97%, and greater than 90% for neutralising antibodies against pseudovirus, but similar against SARS-CoV-2 strains. Anti Spike RBD IgG Geometric means concentration (U/mL) at day 28 were 8237.0 (95% CI, 7679.3-8835.2) for the AstraZeneca half dose group, 8973.6 (95% CI, 8328.1-9669.2) for the AstraZeneca full dose group, 14073.9 (95% CI, 13236.4-14964.4) for the Pfizer half dose group and 15920.7 (95% CI, 15135.7-16746.4) for the Pfizer full dose group. Pseudovirus Neutralizing Antibody Titer (PVNT50) against Omicron (GMT) were 118.9 (95% CI, 97.3-145.2) for the AstraZeneca full dose group and 255.9 (95% CI, 222.9-293.7) for the Pfizer full dose group. Immunogenicity according to Pseudovirus Neutralizing Antibody Titer (PVNT50) against delta variant at day 28 were 468.3 (95% CI, 409.8-535.2) for AstraZeneca half dose group, 530.6 (95% CI, 470.4-598.5) for AstraZeneca full dose group, 801.5 (95% CI, 715.4-897.8) for Pfizer half dose group and 856.1 (95% CI, 777.8-942.1) for Pfizer full dose group. [Suvimol Niyomnaitham, 2022 ]

Gilboa M et al was a prospective cohort study conducted in Israel, including 3,972 healthcare workers who received 3 vaccine doses and 4,868 healthcare workers who received 2 doses. The study measured the neutralizing response against Omicron, 5 months after vaccination. The GMT of neutralizing antibodies with the booster dose was 4,315 (95% CI, 4,051-4,595) compared to 611 (95% CI, 557-671) after 2 doses, and the response waned to 132 (95% CI, 121-144) and 1,001 (95% CI, 895-1,119) with 3 and 2 doses respectively, after 140 days. [Gilboa M, 2022 ]

Efficacy outcomes
Beta (B.1.351)
C4591001 was a phase 1/2/3 randomized trial conducted in the United States. The study recruited 567 participants from South Africa (291 vaccine group and 276 placebo group), where the beta variant of SARS-CoV-2 predominated from 16 years of age. Efficacy was measured up to seven days after receiving the second dose among participants with no evidence of infection. In South Africa, where the worrying variant B.1.351 (or beta) of SARS-CoV-2 was predominant, a vaccine efficacy of 100% was observed (95% CI, 53.5 to 100 [0fcaf6c231ddef9a741a8aa51b61778088250d861].

Effectiveness outcomes
Alpha (B.1.1.7)
Nasreen S. et al was a case-control (test- negative) study conducted in Canada that included 44,688 symptomatic cases of Alpha variant positive test (159 received two doses of Pfizer) and 599,191 negative symptomatic controls of SARS-CoV-2 (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against Alpha variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed an effectiveness against symptomatic infection of 88% in patients <60 years (95% CI 85 to 90) and 91% in patients ≥60 years (95% CI 87 to 94). In addition, 99% VE against hospitalization or death was evidenced in patients <60 years (95% CI 94 to 100) and 95% in patients ≥60 years (95% CI 92 to 96) [Nasreen, S., 2021 ].

Arjun Puranik et al. conducted a comparative cohort study in the United States that included 47,054 participants (22,064 vaccinated group and 24,990 unvaccinated group). The study evaluated the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna and Pfizer/BioNTech in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. The results showed a COVID-19 vaccine efficacy of 83% (CI 95% 69 to 91.3) and a COVID-19 severe disease vaccine efficacy of 87% (CI 95% 57 to 97.5)  [Arjun Puranik, 2021 ].

Fabiani M et al conducted a comparative cohort study in Italy that included 33,250,344 individuals aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. The aim of the study was to estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different times after vaccination during predominant circulation of the delta variant. The results showed a vaccine effectiveness against infection during Alpha variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 79.0% (95% CI 76.8 to 80.9), >14 days after the second dose. Furthermore, Vaccine effectiveness against severe infection during Alpha variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 89.4% (95 CI 87.6 to 91.0), > 14 days after second dose [Fabiani M, 2022 ].

Bansal D et al. was a case-control study that included individuals with first infection (irrespective of vaccination status) with SARS-CoV-2 reported in the state of Qatar between 1 January 2021 and 20 February 2022 (BNT162b2 30μg: 33,599; BNT162b2 10μg: 104; mRNA-1273: 17,767; ChAdOx1: 120). This study assessed how much the risk of requiring intensive care is decreased if someone does get detected with infection (conditional vaccine effectiveness). The predominant circulating variants in the wave from March to April 2021 were the alpha and beta variants, while in December 2021 to January 2022 wave, omicron was predominant. From March to April 2021, the percentage of infections by month for alpha and delta variants increased by 30 and above, compared to 5 and under between December 2021 and January 2022 (Omicron Wave) [Bansal D, 2022 ].

Beta (B.1.351)
Nasreen S. et al was a case-control (negative test) study conducted in Canada that included 378 positive beta variant test symptomatic cases (≤5 received two doses of Pfizer) and 599,191 SARS-CoV- negative symptomatic controls. 2 (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against the beta variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed efficacy against symptomatic infection of 83% in patients <60 years (95% CI -22 to 98) and an estimated 100% in patients ≥60 years based on zero vaccinated cases with a positive test. In addition, 89% efficacy against hospitalization or death was evidenced in patients ≥60 years (95% CI 13 to 99) (results for this outcome were not reported in patients <60 years due to an extremely imprecise 95% CI) [Nasreen, S., 2021 ].

Bansal D et al. was a case-control study that included individuals with first infection (irrespective of vaccination status) with SARS-CoV-2 reported in the state of Qatar between 1 January 2021 and 20 February 2022 (BNT162b2 30μg: 33,599; BNT162b2 10μg: 104; mRNA-1273: 17,767; ChAdOx1: 120). This study assessed how much the risk of requiring intensive care is decreased if someone does get detected with infection (conditional vaccine effectiveness). The predominant circulating variants in the wave from March to April 2021 were the alpha and beta variants, while in December 2021 to January 2022 wave, omicron was predominant. From March to April 2021, the percentage of infections by month for alpha and delta variants increased by 30 and above, compared to 5 and under between December 2021 and January 2022 (Omicron Wave) [Bansal D, 2022 ].

Gamma (P.1)
Nasreen S. et al was a case-control (test negative) study conducted in Canada that included 1,969 Gamma variant positive test symptomatic cases (9 received two doses of Pfizer) and 599,191 SARS-CoV-2 negative symptomatic controls. (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against the gamma variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed efficacy against symptomatic infection of 93% in patients <60 years (95% CI: 78 to 98) and 58% in patients ≥60 years (95% CI: -26 to 86). In addition, an estimated efficacy against hospitalization or death of 100% in patients ≥60 years based on zero vaccinated cases with a positive test was evidenced and 87% in patients ≥60 years (95% CI: 45 to 97) [Nasreen, S., 2021 ].
 

Delta (B.1.617.2)
Nasreen S. et al was a case-control (negative test) study conducted in Canada that included 3,136 Gamma variant positive test symptomatic cases (121 received two doses of Pfizer) and 599,191 SARS-CoV-2 negative symptomatic controls. (36,328 received two doses of Pfizer). The study evaluated the vaccine effectiveness against the delta variant measured 7 days after two doses of vaccine between 14 December 2020 and 3 August 2021. The results showed effectiveness with symptomatic infection of 92% in patients <60 years (95% CI: 90 to 94) and 89% in patients ≥60 years (95% CI: 83 to 93). Furthermore, there was evidence of 99% effectiveness against hospitalization or death in patients <60 years (95% CI: 96 to 100) and 96% in patients ≥60 years (95% CI: 95 to 98) [Nasreen, S., 2021 ].

Arjun Puranik et al. conducted a comparative cohort study in the United States that included 47,054 participants (22,064 vaccinated group and 24,990 unvaccinated group). The study evaluated the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna and Pfizer/BioNTech in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. Results showed a COVID-19 vaccine efficacy of 75% (95% CI 24 to 93.9) and COVID-19 severe disease vaccine efficacy of 42% (95% CI : 13 to 62) [Arjun Puranik, 2021 ].

C4591014 was a case-control study (Test-negative) conducted in United States. The study included 14,137 admissions. Based on data from members of Kaiser Permanente Southern California (KPSC), which contains a large integrated health-care system (CA, USA), between December 1, 2021, through January 11, 2022. The study results showed that Pfizer 2-dose protection against delta waned: Emergency department admission: 80% (95% CI 69 to 87) at <3 months to 63% (95% CI 57 to 69) at ≥6 months; hospital admission: 88% (95% CI 71to 95) at <3 months to 74% ( 95% CI 65 to 80) at ≥6 months.  A third dose restored high vaccine effectiveness against delta, with 88% (95% CI 84 to 91) against Emergency department admission and 93% (95% CI 89 to 96) against hospital admission  [Sara Y. Tartof, 2022 ].

Accorsi EK et al included 23 391 cases and 46 764 controls (3 doses= 12 476; 2 doses=19839; Unvaccinated= 17 177). Data were collected ≥14 days after dose 3 and ≥6 months between doses 2 and 3. The study showed that receiving three doses of Pfizer COVID-19 vaccine compared to not receiving any and receiving only two doses, was associated with protection against both the Omicron and Delta. Comparison of 3 Doses vs Unvaccinated showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.38) and for Delta variant OR 0.077 (95% CI 0.070 to 0.086). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.37) and for Delta variant OR 0.17 (95% CI,0.16 to 0.19) [Accorsi EK, 2022 ].

Buchan SA et al. included 20,348 tests (Omicron-positive cases=16,087;  Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021.  The study showed that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for Delta and Omicron variants. Vaccine efficacy against Delta variant was 97% (95% CI 96 to 98) and 60% (95% CI 55 to 65)  for Omicron in symptomatic infection 7 days after a third dose [Buchan, S. A., 2022 ].

Johnson AG et al was a cohort study conducted in the United States. The study enrolled 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Based on data collected between April  4, 2021, to December  25,  2021. During periods of Delta and Omicron variant emergence. The protection against infection during the Delta predominant period (October-November) was higher among booster recipients, especially among persons over 50 years of age. The average weekly IRR  was 3.7 (95% CI 3.4 to 4.1)  for the group without a booster and IRR 12.9 (95% CI 11.4 to 14.5) for the booster group [Johnson AG, 2022 ].

Kislaya I et al. was a case-control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on data from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal from December 6 to 26, 2021. The effectiveness against the Delta variant was 62.5% (95% CI: 61 to 63.9) for the primary scheme, and 94% (95% CI: 93.4 to 94.6) for the booster [Irina Kislaya, 2022 ].

McKeigue PM et al. was a case-control study conducted in Scotland, the study registered 5,645 severe cases and 50,096 controls, based on data from a subset of patients  from   REACT-SCOTpresenting from Dec 1, 2020, to Sept 8, 2021, ensuring follow-up for at least 14 days after presentation date. Pooled effectiveness against developing severe COVID-19 during the Delta variant predominant period for mRNA vaccines was 32% (95%CI: 20 to 42) for one dose and 89% (95%CI: 86 to 91) for two doses [McKeigue PM, 2022 ].

Fabiani M et al conducted a comparative cohort study in Italy that included 33,250,344 individuals aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. The aim of the study was to estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different times after vaccination during predominant circulation of the delta variant. The results showed a vaccine effectiveness against infection during Delta variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 69% (95% CI 66.7 to 71.2), >14 days after the second dose. Furthermore,Vaccine effectiveness against severe infection during Delta variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 91.1% (95% CI 89.7 to 92.2), > 14 days after second dose ​​[Fabiani M, 2022 ].

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna, the study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Delta variant of the booster dose compared to the two dose regimen was 86.1% (95% CI 67.3 to 94.1) for symptomatic infection [Abu-Raddad LJ, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  Pfizer-BioNTech effectiveness against Delta variant for symptomatic infection was 72.3% (95% CI 69.4 to 74.9) 4 weeks after the first dose, 62.7% (95% CI 61.6 to 63.7) 25 weeks after the second dose, 89.9% (95% CI 89.2 to 90.5) 10 weeks after a Pfizer-BioNTech booster and 94.9% (95% CI 93.0 to 96.2)        10 weeks after a Moderna booster [Andrews N, 2022 ].

Florentino et al. conducted a test-negative case-control study, to estimate vaccine effectiveness (VE) against COVID-19 in adolescents aged 12-17 years in Scotland and Brazil after two doses of the Pfizer-BioNTech vaccine. They analyzed 503,776 eligible SARS-CoV-2 tests (RT-PCR or antigen) of adolescents in Brazil and 127,168 eligible tests of adolescents in Scotland. In Brazil, the estimated vaccine effectiveness against severe COVID-19 during the omicron-dominant period 14 days or longer after the first dose was 56.3% (95% CI 45.9–64.6). From 14 days to 27 days after the second dose, protection increased to 75.6% (58.1–85.8). More than 27 days after the second dose, vaccine effectiveness reached more than 80% and remained at a similar level of protection at 98 days and longer after the second dose (82.7% [68.8–90.4]) [Florentino PTV, 2022 ]

Young-Xu Y et al. was a case-control study with matched test-negative design conducted in the United States. The study used records and COVID-19 laboratory test data from the Veterans Health Administration (VHA), which includes 1,293 healthcare facilities that attend US veterans. Positive tests during November 2021 were presumed to be delta SARS-CoV-2 infections. Each case (positive test) was matched with up to four controls (negative tests). Vaccine effectiveness was estimated through the number of infections, hospitalizations, and death within 30 days of a positive test. The vaccine effectiveness (VE) against delta infection after two mRNA vaccine doses was 54% (95% CI 50 to 57) and increased to 90% (95% CI 88 to 92) after the booster mRNA dose. The VE against hospitalizations was 75% (95% CI 69 to 80) after two mRNA vaccine doses and increased to 94% (95% CI 90 to 96) after the booster mRNA dose. The VE against death after two mRNA vaccine doses was 95% (95% CI 85 to 97) and was similar after the booster mRNA dose (96%; 95% CI 87 to 99) [Young-Xu Y, 2022 ].

Vokó Z et al was a comparative cohort study conducted in Hungary. The study population included 8,087,988 individuals who were 18–100 years old at the beginning of the pandemic. This study examined vaccine effectiveness (VE) and durability of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection, Covid-19-related hospitalization, and mortality during the Delta wave, compared to an unvaccinated control population without prior SARS-CoV-2 infection. Adjusted VE against registered SARS-CoV-2 infection during the Delta wave was 70.3% (95% CI 69.2 to 71.3) for primary Pfizer vaccination at 14 to 120 days, and 82.2% (95% CI 81.5 to 82.8) for the homologous booster vaccination (Pfizer/Pfizer) during the Delta wave [Vokó Z, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records in the US. Participants included 3168 members ages 12 to 17 years with an ED or UC encounter from November 1, 2021, through March 18, 2022. The main outcome was VE associated with BNT162b2 against the emergency department and urgent care encounters related to Delta or Omicron variant SARS-CoV-2 infection.  Vaccine effectiveness (VE) associated with 2 doses of BNT162b2 was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Arashiro T et al was a multi-center test-negative design case-control study conducted in Japan. The study included 5795 participants: 2595 positive cases and 3200 controls from 16 healthcare facilities in Japan 8 during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic SARS-CoV-2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period, compared to unvaccinated individuals. VE during the Delta-dominant period was 65% (95% CI 54 to 74) for participants who received dose 1 only or were ≤13 days since dose 2, 88% (95% CI 82 to 93) for participants with 14 days to 3 months after dose 2 and 87% (95% CI: 38 to 97) for participants with 3 to 6 months after dose 2 (*Aggregated data for Pfizer vaccine (55.8%), Moderna (40.4%), and other mRNA vaccines) [Arashiro T, 2022 ].

Suphanchaimat R et al was a test-negative case-control study conducted in Thailand. The study included 1,460,458 participants: 482,372 cases and 978,086 controls aimed to explore the vaccine effectiveness (VE) of various schedules against the SARS-CoV2 Delta variant in Thailand during September–December 2021. VE against any infection according to vaccine regimens was: 62.4% (95% CI 59.4 to 65.1) for BNT162b2 + BNT162b2, 88.7% (95% CI 85.6 to 91.1) for ChAdOx1 + BNT162b2, 82.3% (95% CI 74.3–87.7) and 94.0% (95% CI 93.4 to 94.6) for CoronaVac + BNT162b2 [Suphanchaimat R, 2022 ].

Hatfield KM et al. was a comparative cohort that included 4,315 nursing home residents during December 14, 7 2020  to November 9, 2021 (BNT162b2:1861; mRNA-1273:833; Ad26.COV2.S: 52; Unknown vaccine:192). The study assessed the effectiveness of COVID-19 vaccination in preventing SARS-CoV-2 infections before and during predominance of the Delta variant. During the Delta period, vaccine effectiveness measured >150 days after the second dose was 33% (95% CI -2% to 56%) for Pfizer-BioNTech [Hatfield KM, 2022 ].

Rennert L was a observational study conducted in United States. The study included 21,261 university students undergoing repeated surveillance testing during which the delta was the dominant SARS-CoV-2 variant. Estimated BNt162B2 effectiveness against any SARS-CoV-2 infection was 65.7% (95% CI: 61.6 - 69.8). Between 0 to 6 months post-vaccination estimated protection decreased from 80.2% to 49.2%, with a significant increase in the risk of SARS-CoV-2 infection with each month since full vaccination (HR = 1.17, 95% CI: 1.09,1.26) [Rennert L, 2022 ].

Kerr S was a test-negative design and cohort study conducted in Scotland, which used the Scotland-wide Early Pandemic Evaluation and Enhanced Surveillance (EAVE-II) platform to estimate the vaccine effectiveness (VE) of the ChAdOx1, BNT162b2, and mRNA-1273 vaccines. The test-negative design (TND) was used to analyse the VE against symptomatic COVID-19 infection and the cohort design to analyse the VE against hospitalisation or death caused by the Delta variant. The study included 5.4 million individuals, with 269 719 cases of RT-PCR confirmed SARS-CoV-2 infections. In the TND anaysis, VE of those who had received a second dose of any vaccine >28 days before their positive test was 87.2% (95% CI 74.7 to 93.5) and was 78.7% (CI 95% 69.9 to 85) for participants  that had received the second dose of the   Pfizer BioNTech vaccine.The hazard ratio (HR) for COVID-19 emergency hospital admission or death 28 days after two doses of any vaccine was 0,13 (95% IC 0.06 to 0.25) and VE was 87.2% (CI 95% 74.7 to 93.5) [Kerr S, 2022 ].

Richterman A et al was a test-negative case-control study that analyzed data from 7098 tests during the Omicron period (2270 SARS-CoV-2 PCR Positive) and 7422 tests during the Delta period (506 SARS-CoV-2 PCR Positive). The aim of this study was to estimate BNT162b2 and mRNA1273 primary vaccination and booster effectiveness against SARS-CoV-2 infection and symptomatic coronavirus disease 2019 during an Omicron surge among employees of the University of Pennsylvania Health System. Vaccine effectiveness (VE) for 2 doses of Pfizer was 41% (95% CI −17% to 87%) during the Omicron period and 75% (95% CI 52% to 87%) during the Delta period. VE for 3 doses of Pfizer was 54% (95% CI 23% to 73%) during the Omicron period and 93% (95% CI 78% to 98%) during Delta period [Richterman A, 2022 ].

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario (Canada) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years), 4261 were Delta-positive cases, and 114 087 were test-negative controls. VE against Delta symptomatic Infection was 97% (95% CI, 96-98), and 99% (95% CI 98-99) against Delta-related severe disease [Buchan SA, 2022 ].

Rudan I et al was an observational study conducted in Scotland. The analysis of the vaccine uptake was based on information from the Turas Vaccination Management Tool, inclusive of Mar 1, 2022. Vaccine safety was evaluated using national data on hospital admissions and General Practice (GP) consultations, through a self-controlled case series (SCCS) design and Vaccine effectiveness (VE) against symptomatic COVID-19 disease for Delta and Omicron variants was estimated using a test-negative design (TND). Vaccine effectiveness against Delta variant for 16-17 year olds  was 96.7% (95% CI, 51.3-99.8) after at least 6 weeks from the second dose. Among 12-15 year olds for the Delta period, the first dose led to a 65.4% (95% CI, 61.5-68.8) reduction in the period 2-5 weeks after vaccination. No symptomatic cases were observed in the period 2-5 weeks after the second dose, suggesting a VE of 100%, which decreased to 92.9% (95% CI, 42.5-99.1) in the period 10-13 weeks after the second dose. Vaccine effectiveness against Omicron variant for 16-17 year olds  was 43.3% (95% CI, 26.9-56.2) after at least 6 weeks from the second dose. [Rudan I, 2022 ]

Chiew CJ et al was a national cohort study conducted in Singapore. This study assessed the incidence of confirmed SARS-CoV-2 infection and hospitalisation among adolescents aged 12–17 years vaccinated with BNT162b2 from Sept 1 to Dec 15, 2021, during the delta variant wave, and from Jan 21 to April 28, 2022, during the omicron variant wave. Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during delta variant wave was 0.66% (95% CI, 0.63-0.69). Vaccine effectiveness against hospitalisation during delta variant wave was 0.83 (95% CI, 0.74-0.89). Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during omicron variant wave was 0.25% (95% CI, 0.21-0.29) with 2 doses and 0.56 (95% CI 0.53-0.58) with homologous booster dose. Vaccine effectiveness against hospitalisation during omicron variant wave was 0.75 (95% CI, 0.56-0.86) and 0.94 (95% CI, 0.86-0.97) with homologous booster dose. [Chiew CJ, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Delta-predominant period for Pfizer vaccine was 95% (95% CI, 93-96) (less than two months after the second dose) and 95% (95% CI, 94-96) with the third booster dose. [Ferdinands JM, 2022 ]

Andrews et al conducted a test-negative case-control design to estimate vaccine effectiveness (VE) against symptomatic COVID-19 and related hospitalization and death in England. 6,056,673 SARS-CoV-2 PCR test with a sample within 10 days after symptom onset were successfully linked to the NIMS database for vaccination status. VE against symptomatic Covid-19 with the delta variant peaked in the early weeks after receipt of the second dose and then decreased by 20 weeks to 66.3% (95% CI 65.7 to 66.9) with the BNT162b2 vaccine. Waning of VE was greater in persons 65 years of age or older than in those 40 to 64 years of age. At 20 weeks or more after vaccination, VE decreased less against hospitalization to 91.7% (95% CI, 90.2 to 93.0) with the BNT162b2 vaccine, and death to 91.9% (95% CI, 88.5 to 94.3). Greater waning in VE against hospitalization was observed in persons 65 years of age or older in a clinically extremely vulnerable group and in persons 40 to 64 years of age with underlying medical conditions than in healthy adults. Results from the sensitivity analysis with the use of only hospitalizations that had been coded as respiratory admissions were similar to those of the primary analysis, showing VE of 93.5% (95% CI, 91.9 to 94.7) for the BNT162b2 vaccine against the delta variant at 20 weeks or more after vaccination. [Andrews N, 2022 ]
 

Omicron (B.1.1.529.1)
Collie S et al. conducted a Case-control study in South Africa that included 78,173 participants (32,325 fully vaccinated and 26,331 not vaccinated). The study was based on data from Discovery Health, a South  African managed care organization and estimated the vaccine effectiveness of two doses of the BNT162b2 vaccine (i.e., full vaccination) against hospitalization for Covid-19 caused by the omicron variant. The study resutls showed a vaccine effectiveness of 70% (95%CI 62 to 76) against hospitalization in the vaccinated individuals [Collie S, 2021 ].

C4591014 was a case-control study (Test-negative) conducted in United States. The study included 14,137 admissions. Based on data from members of Kaiser Permanente Southern California (KPSC), which contains a large integrated health-care system (CA, USA), between December 1, 2021, through January 11, 2022. The study results showed that protection against omicron-related emergency department admission appeared to wane after two doses, from 60% (95% CI 43 to 72) at <3 months to 41% (95% CI  32 to 50) at ≥6 months. Vaccine effectiveness of three doses against omicron-related emergency department admission also waned, from 78% (95% CI 73 to 82) <3 months to 48% (95% CI 14 to 69) at ≥3 months. Against hospital admission, two-dose vaccine effectiveness against omicron was 68% (95% CI 58 to 75), and three-dose effectiveness was 89% (95% CI 84 to 92). Waning two- or three-dose effectiveness against omicron-related hospitalization was not observed [Sara Y. Tartof, 2022 ].

Accorsi EK et al included 23,391 cases and 46,764 controls (3 doses= 12,476; 2 doses=19,839; Unvaccinated= 17,177). Data were collected ≥14 days after dose 3 and ≥6 months between doses 2 and 3. The study showed that receiving three doses of Pfizer COVID-19 vaccine compared to not receiving any and receiving only two doses, was associated with protection against both the Omicron and Delta. Comparison of 3 Doses vs Unvaccinated showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.38) and for Delta variant OR 0.077 (95% CI 0.070 to 0.086). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.37) and for Delta variant OR 0.17 (95% CI,0.16 to 0.19) [Accorsi EK, 2022 ].

Spensley K et al. included 1,121 patients on haemodialysis. All patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between December 1, 2021 and January 16, 2022. The study showed that partial vaccination did not provide protection against infection. Vaccine effectiveness against Omicron infection in patients who had received a booster vaccine was 58%. Analyzing vaccine effectiveness in the 747 patients who had been boosted, significant effectiveness was seen in both patients who received AstraZeneca COVID-19 vaccine (47%)and Pfizer COVID-19 vaccine (66%) [Katrina Spensley, 2022 ].

Buchan SA et al. included 20,348 tests (Omicron-positive cases=16,087; Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021. The study showed that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for Delta and Omicron variants. Vaccine efficacy against Delta variant was 97% (95% CI 96 to 98) and 60% (95% CI 55 to 65) for Omicron in symptomatic infection 7 days after a third dose [Buchan, S. A., 2022 ].

Johnson AG et al was a cohort study conducted in the United States. The study enrolled 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Based on data collected between April  4, 2021, to December  25,  2021. During periods of Delta and Omicron variant emergence. The protection against infection during the Omicron emergence period (December) was higher among booster recipients, especially among persons over 50 years of age. The average weekly IRR  was 2.6 (95% CI 1.4 to 4.7)  for the group without a booster and IRR 4.5 (95% CI 2.4 to 8.3) for the booster group [Johnson AG, 2022 ].

Kislaya I et al. was a case control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on data from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal from December 6 to 26, 2021. The effectiveness against Omicron variant was 28.1% (95% CI: 12.2 to 40.9) for the primary scheme, and  68.8% (95% CI: 46.4 to 81.7) for the booster [Irina Kislaya, 2022 ].
 

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna, the study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Omicron variant of the booster dose compared to the two dose regimen was 49.4% (95% CI 47.1 to 51.6)  for symptomatic infection and 76.5% (95% CI 55.9  to 87.5) for hospitalization and death [Abu-Raddad LJ, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  Pfizer-BioNTech effectiveness against Omicron variant for symptomatic infection was 31.5% (95% CI 29.9 to 33.1) 4 weeks after the first dose, 8.8% (95% CI 7.0 to 10.5) 25 weeks after the second dose, 45.7%  (95% CI 44.7 to 46.7) 10 weeks after a Pfizer-BioNTech booster and 64.4% (95% CI 62.6 to 66.1)10 weeks after a Moderna booster [Andrews N, 2022 ].
 

Hansen C et al was a comparative cohort study conducted in Denmark. The study included 202,896 unvaccinated individuals, 874,421  vaccinated with BNT162b2 (2 doses), 1,553,188 vaccinated with BNT162b2 (3 doses), 216,976 vaccinated with mRNA-1273 (2 doses) and 243,352 vaccinated with mRNA-1273 (3 doses). In this nationwide cohort analysis, from 28 December , 2021 to February 15, 2022 during which Omicron was the predominant variant, PCR testing data are combined with other national register data with near-complete information on all vaccinations, hospitalisations and comorbidities in the population. Vaccine effectiveness against infection after 2 doses was 37.0 (95% CI 35.6 to 38.3), against hospitalization after 2 doses was 50.5 (95% CI 33.9 to 63.0), against infection after 3 doses was 47.9 (95% CI 47.4 to 48.3) and against hospitalization after 3 doses was 88.8 (95% CI 87.3 to 90.1) [Hansen C, 2022 ].

Price AM was a case control study that assessed vaccine effectiveness against laboratory-confirmed Covid-19 leading to hospitalization and against critical Covid-19 (i.e., leading to receipt of life support or to death). From July 1, 2021, to February 17, 2022, we enrolled case patients with Covid-19 and controls without Covid-19 at 31 hospitals in 23 states. The study enrolled 1,185 case patients (1,043 [88%] of whom were unvaccinated, 291 [25%] of whom received life support, and 14 of whom died) and 1,627 controls.During the delta-predominant period, vaccine effectiveness against hospitalization for Covid-19 among adolescents 12 to 18 years of age was 93% (95% confidence interval [CI], 89 to 95) 2 to 22 weeks after vaccination and was 92% (95% CI, 80 to 97) at 23 to 44 weeks. Among adolescents 12 to 18 years of age (median interval since vaccination, 162 days) during the omicron-predominant period, vaccine effectiveness was 40% (95% CI, 9 to 60) against hospitalization for Covid-19, 79% (95% CI, 51 to 91) against critical Covid-19, and 20% (95% CI, −25 to 49) against noncritical Covid-19. During the omicron period, vaccine effectiveness against hospitalization among children 5 to 11 years of age was 68% (95% CI, 42 to 82; median interval since vaccination, 34 days) [Price AM, 2022 ].

Ranzani O et al was a case-control study (test negative design) conducted in Brazil including 1,386,544 positive antigen/PCR SARS-CoV-2 tests and matched controls. The study estimated the vaccine effectiveness (VE) for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac during the Omicron predominance period. VE against symptomatic COVID-19 for the homologous CoronaVac booster was 8.1% (95% CI, 4.6% to 11.4%) and 57.3% (95% CI, 56.8% to 57.9%) for the Pfizer heterologous booster, measured 8-59 days after the third dose. For hospitalization or death, VE was 86% (95% CI, 71.7% to 93.1%) and 92.1% (95% CI, 90.2% to 93.7%) after 8-59 days of the homologous and heterologous booster schedules, respectively [Ranzani OT, 2022 ].

Grewal R et al was a case-control study (test negative design) conducted in the United States. The aim of this study was to estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of mRNA covid-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the omicron variant. Vaccine effectiveness of three doses of Pfizer vaccine against omicron variant against any infection was 32% (95%CI 24 to 38), against symptomatic infection was 53% (95%CI 39 to 63) and against severe outcomes 77% (95% CI 67 to 83) [Grewal R, 2022 ].

Florentino et al. conducted a test-negative case-control study, to estimate vaccine effectiveness (VE) against COVID-19 in adolescents aged 12-17 years in Scotland and Brazil after two doses of the Pfizer-BioNTech vaccine. They analyzed 503,776 eligible SARS-CoV-2 tests (RT-PCR or antigen) of adolescents in Brazil and 127,168 eligible tests of adolescents in Scotland. During the omicron-dominant period, after the second BNT162b2 dose, vaccine effectiveness peaked between 14–27 days in Brazil (64.7% [95% CI 63.0–66.3]). Protection started to decline after 27 days (at 28–41 days protection was 53.0% [51.3–54.7]), reducing to 5.9% (95% CI 2.2–9.4) at 98 days and longer. In Scotland, vaccine effectiveness for symptomatic infection during the omicron-dominant period also peaked at 14–27 days after the second dose (82.6% [95% CI 80.6–84.5]), and after 98 days and more was 50.6% (42.7–57.4). In Brazil, the estimated vaccine effectiveness against severe COVID-19 during the omicron-dominant period 14 days or longer after the first dose was 56.3% (95% CI 45.9–64.6). From 14 days to 27 days after the second dose, protection increased to 75.6% (58.1–85.8). More than 27 days after the second dose, vaccine effectiveness reached more than 80% and remained at a similar level of protection at 98 days and longer after the second dose (82.7% [68.8–90.4]) [Florentino PTV, 2022 ].

Young-Xu Y et al. was a case-control study with matched test-negative design conducted in the United States. The study used records and COVID-19 laboratory test data from the Veterans Health Administration (VHA), which includes 1,293 healthcare facilities that attend US veterans. Positive tests during January 2022 were presumed to be Omicron SARS-CoV-2 infections. Each case (positive test) was matched with up to four controls (negative tests). Vaccine effectiveness was estimated through the number of infections, hospitalizations, and death within 30 days of a positive test. The vaccine effectiveness (VE) against omicron infection after two mRNA vaccine doses was 12% (95% CI 10 to 15) and increased to 64% (95% CI 63 to 65) after the booster mRNA dose. The VE against hospitalizations was 63% (95% CI 58 to 67) after two mRNA vaccine doses and increased to 89% (95% CI 88 to 91) after the booster mRNA dose. The VE against death after two mRNA vaccine doses was 77% (95% CI 67 to 83) and after the booster mRNA dose increased to 94% (95% CI 90 to 96) [Young-Xu Y, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records in the US. Participants included 3168 members ages 12 to 17 years with an ED or UC encounter from November 1, 2021, through March 18, 2022. The main outcome was VE associated with BNT162b2 against the emergency department and urgent care encounters related to Delta or Omicron variant SARS-CoV-2 infection.  Vaccine effectiveness (VE) associated with 2 doses of BNT162b2 was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Arashiro T et al was a multi-center test-negative design case-control study conducted in Japan. The study included 5795 participants: 2595 positive cases and 3200 controls from 16 healthcare facilities in Japan 8 during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic SARS-CoV-2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period, compared to unvaccinated individuals. VE during the Omicron-dominant period was 34% (95% CI -20 to 64) for participants who received dose 1 only or was ≤13 days since dose 2, 56% (95% CI 37 to 70) for participants with14 days to 3 months after dose 2, 52% (95% CI 40 to 62) for participants with 3 to 6 months after dose 2 and  49% (95% CI 34 to 61) for participants with at least 6 months after the second dose. VE estimated after third dose was 67% (95% CI: 47-79) ( ≤13 days after dose 3) and 74% (95% CI: 62-83) (≥14 days after dose 3) (*Aggregated data for Pfizer vaccine (55.8%), Moderna (40.4%), and other mRNA vaccines) [Arashiro T, 2022 ].

González S et al was a retrospective cohort study conducted in Argentina including 1,536,435 participants: 689,552 in the BIBP vaccine group and 846,883 in mRNA vaccine group (539,093 with Pfizer/Pfizer schedule, 15,552 with Pfizer/Moderna schedule and 44,862 with Moderna/Pfizer schedule. mRNA-1273 and BNT162b2 vaccines were administered to 12−17- year subjects; and BBIBP-CorV to 3−11-year subjects. Vaccine effectiveness for the mRNA vaccine group was 80.0% (95% CI 64.3 to 88.0) for the 12−17 age (mRNA vaccines) subgroup [González S, 2022 ].

Bansal D et al. was a case-control study that included individuals with first infection (irrespective of vaccination status) with SARS-CoV-2 reported in the state of Qatar between 1 January 2021 and 20 February 2022 (BNT162b2 30μg: 33,599; BNT162b2 10μg: 104; mRNA-1273: 17,767; ChAdOx1: 120). This study assessed how much the risk of requiring intensive care is decreased if someone does get detected with infection (conditional vaccine effectiveness). The predominant circulating variants in the wave in March to April 2021 were the alpha and beta variant, while in the December 2021 to January 2022 wave, omicron was the variant. From March to April 2021, the percentage of infections by month for alpha and delta variants increased by 30 and above, compared to 5 and under between December 2021 and January 2022 (Omicron Wave) [Bansal D, 2022 ].

Cohen-Stavi CJ was a comparative cohort study conducted in Israel. The study included 15,289 children aged 5 to 11 years: 94728 in the vaccinated group and 94,728 in the unvaccinated group. Vaccine effectiveness (VE) was estimated after the first and second vaccine doses during the Omicron wave. VE against documented infection was 17% (95% CI, 7 to 25) at 14 to 27 days after the first dose and 51% (95% CI, 39 to 61) at 7 to 21 days after the second dose. VE against symptomatic Covid-19 was 18% (95% CI, −2 to 34) at 14 to 27 days after the first dose and 48% (95% CI, 29 to 63) at 7 to 21 days after the second dose [Cohen-Stavi CJ, 2022 ].

Patalon T et al was a test-negative case-control study conducted in Israel. This study assessed the association between booster breakthrough infections with the Omicron variant and time-since-vaccination, leveraging data from Maccabi Healthcare Services (MHS). Vaccine effectiveness against infection of ‘newly’ vaccinated individuals was 53.4% (95% CI 47.7 to 8.6%). VE declined rapidly with each month since vaccination, with 35.7% (95% CI, 29.8–41.2%) VE for those who were vaccinated two months prior to the outcome period compared to the earliest vaccinees (of August 2021). [Patalon T, 2022 ].

Richterman A et al was a test-negative case-control study that analyzed data from 7098 tests during the Omicron period (2270 SARS-CoV-2 PCR Positive) and 7422 tests during the Delta period (506 SARS-CoV-2 PCR Positive). The aim of this study was to estimate BNT162b2 and mRNA1273 primary vaccination and booster effectiveness against SARS-CoV-2 infection and symptomatic coronavirus disease 2019 during an Omicron surge among employees of the University of Pennsylvania Health System. Vaccine effectiveness (VE) for 2 doses of Pfizer was 41% (95% CI −17% to 87%) during the Omicron period and 75% (95% CI 52% to 87%) during the Delta period. VE for 3 doses of Pfizer was 54% (95% CI 23% to 73%) during the Omicron period and 93% (95% CI 78% to 98%) during Delta period [Richterman A, 2022 ].

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario (Canada) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years), 16,087 were Omicron-positive cases, and 114 087 were test-negative controls. VE against Omicron symptomatic Infection was 60% (95% CI, 55-65), and 95% (95% CI 87-98) against Omicron-related severe disease [Buchan SA, 2022 ].

Lin DY et al was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness for two doses of Pfizer-BioNTech was 43.7% (95% CI, 42.3% to 45.1%) during the Omicron variant predominance [Lin DY, 2022 ].

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine healthcare system, the Michigan State Registry, and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA-based COVID-19 vaccines. During the Omicron dominant period December 2021 to March 2022. The effectiveness of the Pfizer-BioNtech vaccine during the Omicron period in immunocompetent participants was −6%(95% CI –14 to 4) for two doses and 35%(95CI 29 to 41) for three doses. In immunocompromised participants, the effectiveness was 13% (95%CI –19 to 39) for two doses and 50% (95% CI 31 to 64) for three doses. [Risk M, 2022 ].

Molteni et al was a prospective cohort study conducted in the United Kingdom, the study included 115,775 children and adolescents aged 12-17 years, among which, 25,971 received one dose of Pfizer-BioNTech. Based on data from the Covid Symptom Study between august 2021 and February 2022. Infection risk reduction 14-30 days after primary vaccination was -53.7% (95%CI -62 to -43) during the December-February (Omicron) period [Molteni E, 2022 ].

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Pfizer booster after AstraZeneca, Janssen, Moderna, or Pfizer primary schedule was 46.2% (95% CI 43.5–48.7). Vaccine effectiveness of an mRNA booster (Pfizer or Moderna) following a Pfizer primary schedule was 49.7% (95% CI, 48.3–51.1) [Monge S, 2022 ].

Stowe et al. conducted a test-negative case-control study in UK, to estimate Vaccine Effectiveness (VE) against hospitalisation with the Omicron and Delta variants using PCR testing linked hospital records (Emergency Care Data Set; ECDS). The total number of tests in the study period was 409,985 of which 115,720 were cases and 294,265 controls.  Vaccine effectivenes against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 18 to 64 years of age was 61.0% (95% CI 55.3-65.9) after 14-174 days and 33.0% (95% CI 21.3-42.9) after 175+ days. Vaccine effectiveness against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 65 years of age and older was 85.8% (95% CI, 69.4-93.4) after 14-174 days and 75.6% (95% CI, 61.4-84.6) after 175+ days. [Stowe J, 2022 ]

Rudan I et al was an observational study conducted in Scotland. The analysis of the vaccine uptake was based on information from the Turas Vaccination Management Tool, inclusive of Mar 1, 2022. Vaccine safety was evaluated using national data on hospital admissions and General Practice (GP) consultations, through a self-controlled case series (SCCS) design and Vaccine effectiveness (VE) against symptomatic COVID-19 disease for Delta and Omicron variants was estimated using a test-negative design (TND). Vaccine effectiveness against Delta variant for 16-17 year olds  was 96.7% (95% CI, 51.3-99.8) after at least 6 weeks from the second dose. Among 12-15 year olds for the Delta period, the first dose led to a 65.4% (95% CI, 61.5-68.8) reduction in the period 2-5 weeks after vaccination. No symptomatic cases were observed in the period 2-5 weeks after the second dose, suggesting a VE of 100%, which decreased to 92.9% (95% CI, 42.5-99.1) in the period 10-13 weeks after the second dose. Vaccine effectiveness against Omicron variant for 16-17 year olds  was 43.3% (95% CI, 26.9-56.2) after at least 6 weeks from the second dose. [Rudan I, 2022 ]

Chiew CJ et al was a national cohort study conducted in Singapore. This study assessed the incidence of confirmed SARS-CoV-2 infection and hospitalisation among adolescents aged 12–17 years vaccinated with BNT162b2 from Sept 1 to Dec 15, 2021, during the delta variant wave, and from Jan 21 to April 28, 2022, during the omicron variant wave. Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during delta variant wave was 0.66% (95% CI, 0.63-0.69). Vaccine effectiveness against hospitalisation during delta variant wave was 0.83 (95% CI, 0.74-0.89). Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during omicron variant wave was 0.25% (95% CI, 0.21-0.29) with 2 doses and 0.56 (95% CI 0.53-0.58) with homologous booster dose. Vaccine effectiveness against hospitalisation during omicron variant wave was 0.75 (95% CI, 0.56-0.86) and 0.94 (95% CI, 0.86-0.97) with homologous booster dose. [Chiew CJ, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Omicron-predominant period for Pfizer vaccine was 63% (95% CI, 46-74) (less than two months after the second dose) and 88% (95% CI, 86-90) with the third booster dose. [Ferdinands JM, 2022 ]

Ioannu et al was a retrospective matched-cohort study conducted in the United States. The study included 981,676 participants: 490,838 boosted individuals and 490,838 non-boosted individuals. Based on data from the Veterans Association's (VA) Corporate Data Warehouse, a database of VA enrollees' comprehensive electronic health records, and the VA COVID-19 Shared Data Resource. Including patients 18 years old and above, who received mRNA based COVID-19 boosters and a matched cohort of participants that did not. During the Omicron dominant period between December 2021 and March 2022. The effectiveness of Pfizer-BioNTech vaccine booster during the Omicron period was 39.0% (95% CI, 36.4% to 41.6%) against infection and 54.0% (95% CI, 46.1% to 60.8%) against hospitalization. [Ioannou GN, 2022 ]

Tartof et al was a case-control, test-negative study conducted in the United States, based on data from the Kaiser Permanente Southern California (KPSC), which is a large, integrated health-care system. The study included 16,994 participants: 10,620 cases and 8,503 controls. Eligible patients were admitted to one of 15 KPSC hospitals or Emergency Departments between December 27th 2021, and June 4th 2022. The effectiveness of the Pfizer-BioNTech vaccine against BA.1 variant was 40% (95% CI, 27% to 50%) for 2 doses and 79% (95% CI, 74% to 83%) for 3 doses against hospital admission. For Emergency Department admission the effectiveness was 29% (95% CI, 18% to 38%) for 2 doses and 72% (95% CI, 67% to 77%) for 3 doses. Effectiveness against BA.2 variant was 56% (95% CI, 31% to 72%) for 2 doses and  71% (95% CI, 55% to 81%) for 3 doses against hospital admission. Effectiveness against Emergency Department admission was 16% (95% CI, −5% to 33%) for 2 doses and 21% (95% CI, 1% to 37%) for 3 doses. [Tartof SY, 2022 ]

Fleming-Dutra et al was a test-negative case-control study conducted in the United States, based on data from the Increasing Community Access to Testing (ICATT) platform, including 121,952 tests during the Omicron variant period between December 2021 and February 2022, in participants between 5 and 15 years old who received the Pfizer-BioNTech vaccine. The effectiveness 2 months after the second dose for symptomatic infection was 28.9% (95% CI, 24.5% to 33.1%) for the 5-11 years old group and 16.6% (95% CI, 8.1% to 24.3%) for the 12-15 years old group. [Fleming-Dutra KE, 2022 ]

Tan SHX et al was a retrospective cohort study conducted in Singapore based on data from the national ministry of health registry, including 255,936 children between 5 and 11 years of age. The Pfizer-BioNTech vaccine effectiveness during Omicron variant predominance period in partially vaccinated children was 13.6% (95% CI, 11.7-15.5) against all SARS-CoV-2 infections, 24.3% (95% CI, 19.5-28.9) against PCR-confirmed infection and 42.3% (95% CI, 24.9 to 55.7) against hospitalization, in fully vaccinated children the effectiveness was 36.8% (95% CI, 35.3-38.2), 65.3% (95% CI, 62.0-68.3), and 82.7% (95% CI, 74.8-88.2), respectively. [Tan SHX, 2022 ]

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that included 16,208,600 participants, of which 7,589,080 received a Pfizer-BioNTech primary schedule and 8,619,520 participants received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform, during the Omicron period between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.33 (95% CI, 0.28-0.38) for the Pfizer-BioNTech primary schedule and booster group, 0.43 (95% CI, 0.37-0.50) for the ChAdOx1 primary schedule and Pfizer-BioNTech booster group and 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group. [Agrawal U, 2022 ]

Wan EYF was a case control study conducted in China. The study included data from 78,326 individuals: 7,293 death related to COVID-19 cases and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was 20.3% (95% CI, 18.4-22.1), 50.9% (95% CI, 49.6-52.1), -2.9% (95% CI, -24-14.6) and 30.9% (95% CI, 28.5-33.2) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. Vaccine effectiveness against COVID-19 related hospitalization was 74.9% (95% CI, 72.6-77), 91.4% (95% CI, 90.1-92.5), 87.4% (95% CI, 59.6-96.1) and 86.9% (95% CI, 84.3-89.1) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. [Wan EYF, 2022 ]

Cerqueira-Silva T et al was a case-control study with a test-negative design conducted in Brazil that enrolled 2,471,576 participants, including 1,431,108 cases and 1,040,468 controls, with data from the nationwide linked database during the Omicron period in Brazil (January to Appril 2022), including participants who received CoronaVac plus a Pfizer-BioNTech booster. Vaccine effectiveness against symptomatic infection was 1.7% (95% CI, 0.1% to 3.2%) and 89.4% (95% CI, 87.8% to 90.7%) against severe infection. [Cerqueira-Silva T, 2022 ]

Tartof SY et al was a case-control study with a test-negative design conducted in the United States that enrolled 24,356 participants, including 12,566 boosted individuals, 5,997 with the primary schedule and 5,793 unvaccinated individuals. The study was based on data from Kaiser Permanente, a health insurance provider from Southern California, including participants vaccinated with Pfizer-BioNTech and unvaccinated controls. This study analyzed data from May to August 2022 during the Omicron BA.4/5 outbreak. The adjusted effectiveness of Pfizer-BioNTech primary schedule was −4% (95% CI, −116% to 50%) against hospitalization, 44% (95% CI, 19% to 61%) against emergency department admission, 21% (95% CI, 11% to 30%) against outpatient care. The effectiveness of 3 Pfizer-BioNTech doses was 50% (95% CI, −1% to 76%) against hospitalization, 39% (95% CI, 14% to 57%) against emergency department admission and 17% (95% CI, 7% to 26%) against outpatient care, the effectiveness of 4 Pfizer doses was 60% (95% CI, 11% to 82%) against hospitalization, 69% (95% CI, 44% to 83%) against emergency department admission and 25% (95% CI, 7% to 39%) against outpatient care. [Tartof SY, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness (VE) against hospital admission during the Omicron period was 91% (95% CI, 83% to 95%) for the primary schedule, 94% (95% CI, 92% to 95%) for the Pfizer schedule + Pfizer booster, 91% (95% CI, 87% to 94%) for the Pfizer schedule + Moderna booster, 92% (95% CI, 80% to 97%) for the Moderna schedule + Pfizer booster and 99% (95% CI, 91% to 100%) for the AstraZeneca schedule + Pfizer booster. [Baum U, 2022 ]

Vaccine efficacy and effectiveness for booster dose

Immunogenicity outcomes
Tobudic S et al. was a clinical trial that evaluated the efficacy and safety of a booster dose in patients in whom serconversion did not occur after the second dose. The additional booster dose was delivered with the AstraZeneca or mRNA vaccines against COVID-19. Efficacy was measured by the difference in the SARS-CoV-2 antibody seroconversion rate between patients vaccinated with the AstraZeneca vaccine (heterologous) and the mRNA vaccines (homologous) at the fourth week. The results demonstrated that seroconversion rates at week four were comparable between patients who received the AstraZenaca vaccine (6/27 patients, 22%) versus the mRNA vaccines (9/28, 32%) (p = 0, 6). Overall, 27% of the patients seroconverted; furthermore, no serious adverse events related to immunization were observed [Michael Bonelli, 2021 ].

Eliakim-Raz N et al. was a before-after study conducted in Israel, assessing antispike (anti-S) IgG antibody titers before and after a third BNT162b2 dose in patients aged 60 years and older. Titers of anti-S IgG antibodies were determined with theSARS-CoV-2 IgG II Quant assay (Abbott Laboratories). The study enrolled 97 participants and the results showed a median titer level increased significantly after the third dose, froma median of 440 AU/mL (IQR, 294-923) to 25 468 AU/mL (IQR,14 203-36 618) [Eliakim-Raz N, 2021 ].

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for Omicron variant and compared to the ancestral strain (Wuhan-Hu-1) and Delta variant, in four groups of volunteers receiving 1) Two doses of mRNA vaccines plus an mRNA vaccine booster (Homologous mRNA vaccine booster) 2) Two doses of inactivated virus vaccines plus an inactivated virus vaccine booster (Homologous inactivated virus vaccine booster) 3) Two doses of mRNA vaccines plus an inactivated virus vaccine booster (Heterologous inactivated virus vaccine booster) and 4) Two doses of inactivated virus vaccines plus an mRNA vaccine booster (Heterologous mRNA vaccine booster). The study results showed that only the mRNA vaccine booster was able to effectively increase the median levels of neutralizing capabilities against the Omicron variant (Group 1, median 90.45% [IQR 78.71-94.33%]; Group 4, median 77.85% [IQR 47.80-92.18%]) by 4.5-fold and 3-fold, respectively. Inactivated virus booster shot was unable to significantly increase the median levels of neutralizing capabilities against the Omicron variant regardless of whether the individuals received 2 priming doses of mRNA vaccines (Group 3, median 30.65% [IQR 19.98- 36.03%]) or 2 priming doses of inactivated virus vaccines (Group 4, median 26.80% [IQR 18.35- 36.15%]) [Biyan Zhang, 2022 ]

Yavlinksy et al was a prospective community cohort study conducted in England and Wales. The study evaluated the immune response generated by a booster dose of the Pfizer COVID-19 vaccine on Pfizer or AstraZeneca primary vaccination recipients. The study included 8,680 adults aged 18 or older who received a Pfizer vaccine booster after either Pfizer or AstraZeneca primary vaccination. The study found the Pfizer booster dose increased peak antibody levels compared to after primary vaccination regardless of the primary regimen. For the Pfizer primary vaccination group anti S antibody levels increased from 2,386 U/mL (95%CI: 9,801-15,653) to 22,185 U/mL (95%CI: 21,406-22,990) after the booster dose. In the AstraZeneca group antibody levels increased from 1,192 U/mL (95%CI: 818-1735) to 19,203 U/mL (95%CI: 18,094-20,377) after the booster dose [Alexei Yavlinsky, 2022 ].

Poh et al. is an ongoing phase 4 randomized clinical trial, conducted in Singapore, assessing the humoral response elicited by homologous and heterologous booster vaccination regimens based on a primary regimen with Pfizer-BioNTech. Interim results of two groups have been published. The study recruited 100 participants who either received a Pfizer-BioNTech (n=51) booster or a Moderna booster (n=49). Results show a booster dose increases antibody titers in all participants by 35- to 49- fold at day 7 with only a modest increase by day 17. Antibody titers were higher in the Moderna group, particularly in the ≥60 years age subgroup. On day 28 antibody titers reached 29.751 (IC 95%: 25.281-35.011) UI/mL for the Moderna group and 22 382 (IC del 95 %: 18 210-27 517) UI/mL for the Pfizer-BioNTech group. Neutralization against the Omicron variant was higher in the Moderna group at day 7 but similar at day 28 [Xuan Ying Poh, 2022 ].

Medina-Pestana J et al was a comparative cohort study conducted in Brazil. This study included kidney transplant recipients without previous COVID-19. Patients received a third heterologous (BNT162b2) (n=307) or homologous dose (n=777) at least 4 weeks after 2 doses of the CoronaVac vaccine. Immediately before the third dose, IgG seroprevalence (36% versus 34%; P = 0.597) and antibody titers (246 versus 268 AU/mL; P = 0.279) were similar. After booster, seroconversion was higher in the heterologous group (49% versus 32%; P < 0.0001), resulting in a higher seroprevalence (67% versus 55%; P = 0.0003); however, 42% of all patients remained seronegative. Antibody titers after booster in seropositive patients were higher in the heterologous group (7771 versus 599 AU/mL; P < 0.0001) [Medina-Pestana J, 2022 ].

Heinzel et al was a secondary analysis of a randomized controlled trial conducted in Austria. The study enrolled  201 Kidney Transplant Recipients without detectable SARS-CoV-2 specific antibodies following two doses of an mRNA vaccine. Participants were randomized to a 3rd dose of the same mRNA vaccine (the mRNA group) or a dose of the vector vaccine Ad26COVS1. A total of 169 patients were available for the 3-month follow-up. Overall, seroconversion at 3 months was similar between both groups (45 vs. 50% for mRNA and the vector group, respectively; p = 0.539). However, when applying higher cut-off levels, a significantly larger number of individuals in the vector group reached antibody levels > 141 and > 264 BAU/ml at the 3-month follow-up (141 BAU/ml: 4 vs. 15%, p = 0.009 and 264 BAU/ml: 1 vs. 10%, p = 0.018 for mRNA vs. the vector vaccine group, respectively) [Heinzel A, 2022 ].

PRIBIVAC was a randomized controlled trial conducted in Singapore. 100 participants who had received a primary vaccine schedule with two doses of the Pfizer-BioNTech vaccine were randomized to either homologous (BNT162b2 + BNT162b2 + BNT162b2; 'BBB', n= 51) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; 'BBM'; n= 49). Primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and Variants of Concern (VOCs) at day 28 after the booster dose. The results demonstrated that there was a significant increase in wild-type SARS-CoV-2 antibody titers after the booster dose compared to baseline. Antibody titers were higher in the BBM group (22,382 IU/mL; 95% CI:18,210 to 27,517) compared to the BBB group (29,751 IU/mL; 95% CI: 25,281 to 35,011; p=0.034) [Poh XY, 2022 ].

Shinkai M et al was a phase 2/3 randomized clinical trial conducted in Japan. The study included 206 healthy adults vaccinated with 2 doses of Pfizer ≥ 6 months ago. 101 participants received a booster dose with S-268019-b vaccine and 103 with Pfizer vaccine. The primary objective of the study was to assess the noninferiority of S-268019-b versus BNT162b2 as a booster dose in inducing SARS-CoV-2 neutralizing antibodies against the live wildtype virus strain (WK-521) on day 29. The co-primary endpoints included day 29 geometric mean titer (GMT) and seroresponse rate (SRR) for SARS-CoV-2 neutralizing antibodies. SRR was defined as the proportion of participants with a post–vaccination antibody titer 4-fold higher than the baseline. GMTs (95% CIs) for neutralizing antibodies at baseline was 6.65 (95% CI 5.73 to 7.72) for Pfizer vaccine. GMT on day 29 after pfizer booster dose increased to 109.70 (95.73–125.70). The SRR was 100% for both groups (SRR difference 0.0; 95% CI 5.9 to 5.9; noninferiority P-value, 0.0004). [Shinkai M, 2022 ]

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild-type (WT) SARS-CoV-2, Delta variant, and Omicron variant. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628) [Choi JY, 2022 ].

Odile Launay et al was a randomized clinical trial conducted in France. The study included 247 participants who had received two doses of BNT162b2 of whom 85 received a Sanofi/GSK MV(D614) vaccine booster, 80 Sanofi/GSK MV(Beta) vaccine booster, and 82 BNT162b2 vaccine booster. The study evaluated the immunogenicity and safety of a homologous booster dose of BNT162b2 or recombinant vaccine with adjuvant (Sanofi/GSK MV(D614) formulation or MV B.1.351 (Beta) formulation) in recipients primed with two doses of BNT162b2 between 3 and 7 months earlier. The proportion of participants with at least a 10-fold increase of neutralizing antibody titers between day 0 and day 15 for the Wuhan (D614) SARS-CoV-2 strain (Pfizer BNT162b2) was 63.2% (95% CI 51.3 to 73.9) and for the B.1.351 (Beta) viral strain was 51.3% (95% CI 39.6 to 63.0). The geometric mean titer of anti-S1 increased from 253.6 at day 0 to 2405.4 BAU/mL at day 15 [Odile LAUNAY, 2022 ].

Puthanakit T et al was a phase 2 randomized clinicla trial conducted in Thailand. The study included 80 participants  aged 12 to < 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac (SV) 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Immunogenicity was determined using IgG antibody against spike-receptorbinding domain of wild type(anti-S-RBD IgG) and surrogate virus neutralization test(sVNT) against Delta variant at 14 days and 5 months after the 2nd dose. Neutralization tests(sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean(GM) of anti-S-RBD IgG in SV3w/PZ30lg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in SV6w/PZ30lg. The GMs of sVNT against Delta variants at day 14 among participants in SV3w/PZ30lg and SV6wk/PZ30lg arm were 95.3 % and 99.7 %inhibition, respectively. [Puthanakit T, 2022 ]

Cobovax study was a randomized clinical trial conducted in China. The study enrolled 219 adults who previously received two doses of CoronaVac and randomized to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomized to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). The aim was to assessed immunogenicity and cell-mediated immune responses and vaccine efficacy against infections during follow-up. Third-dose vaccination increased PRNT50 titers against ancestral virus 315 by 14-, 94-, 3- and 19-folds, and against Omicron BA.2 by 1-, 16-, 1- and 13-folds, in CC-C, CC-B, BB-C and BB-B arms respectively. Antibody responses to a BNT162b2 third dose were substantially and statistically significantly greater than responses to a CoronaVac third dose regardless of prior two-dose vaccine type. [Nancy H. L. Leung, 2022 ]

Behrens et al. conducted a longitudinal monitoring of ChAd/ChAd (n = 41) and ChAd/BNT (n = 88) vaccinated individuals and the impact of a third vaccination with BNT. Anti-SARS-CoV-2 spike IgG (anti-S IgG) levels were significantly higher in the ChAd/BNT group short after prime-boost vaccination when compared to the ChAd/ChAd group but declined significantly over time in both groups, with lower anti-S IgG after homologous vaccination prior to the third immunization. Following a third immunization, they found greatly increased anti-S IgG responses in both groups. Additional immunization of the homologous ChAd/ChAd immunized group led to a significant 46.9 -fold increase in anti-S IgG (p<0.0001) and 8.0-fold increase in individuals after heterologous ChAd/BNT vaccination (p<0.0001). In both groups, anti-S IgG levels were considerably higher when compared to the situation observed 14 days after the second vaccination (the third vaccination diminished previous differences between the heterologous ChAd/BNT and homologous ChAd/ChAd prime-boost vaccination groups, since anti-S IgG were comparable in both groups after the third vaccination). The numbers of spike-specific memory B cells generated after prime-boost vaccination gradually increased during the following months with no significant difference between the ChAd/ChAd and the ChAd/BNT group, in line with increased amounts of spike-specific antibodies, highlighting the impact of the third vaccination for better protection from SARS-CoV-2 infection. 2 weeks after a third immunization with BNT, spike-specific memory B cells were significantly higher in the ChAd/ChAd as compared to the ChAd/BNT prime-boost group. The frequencies of spike-specific CD4+ and CD8+ T cells in blood samples collected after the second vaccination were significantly higher in the ChAd/BNT than in the ChAd/ChAd group. Both cell populations declined over time after heterologous immunization, while they remained at low levels after homologous vaccination. Whilst spike-specific CD4+ T cells declined to frequencies similar to individuals after homologous ChAd/ChAd vaccination, spike-specific CD8+ T cells remained above the frequencies of the heterologous vaccinated group. A third immunization with BNT in the ChAd/ChAd group significantly raised numbers of spike-specific CD4+ T cells above levels observed after the second vaccination. A third vaccination of the ChAd/BNT group only regained spike-specific CD4+ T cell to levels present after the second vaccination. A third vaccination with with BNT did not result in an expansion of spike-specific CD8+ T cells above levels observed after second vaccination in ChAd/BNT vaccinees, but did so in ChAd/ChAd vaccinated individuals. Like for spike-specific CD4+ T cells, raised numbers in spike-specific IFN-γ-producing T cells in the ChAd/ChAd as well as the ChAd/BNT group after the additional BNT vaccination was confirmed by cytokine measurement in supernatants after SARS-CoV-2 spike peptide stimulation. The third vaccination did not further increase spike-specific IFN-γ-producing T cells in ChAd/BNT vaccinated subjects above levels obtained already after the second vaccination [Behrens GMN, 2022 ].

Renia L et al was a cohort study that included 312 participants vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine.  This study compared the kinetics of specific antibodies, B and T cell memory responses in a cohort of BNT162b2-vaccinated healthcare workers and elderly individuals in Singapore up to 6 months postimmunization and for a subset of elderly low responders after a third dose. After the second dose, all but one of the participants developed anti-Spike protein antibodies by day 90. Immunoglobulin isotyping showed that the proportion of vaccinees with detectable IgM (above both cohort and individual baseline) was >85% at day 21 but dropped to 12% by day 90 (12%) and was negligible by day 180. After the second dose, all individuals seroconverted by day 90. However, 36.5% of individuals mounted a poor anti-RBD IgG response. More than 79.1% of the plasma had neutralizing antibodies above individual baseline after the first dose, 99% after the second dose and 93% at day 180. The antibody response against the Delta variant was lower than the Wildtype ancestral strain and extremely low or non-existent against the Omicron variant. The third dose strongly boosted the antibody responses against the total Spike protein or its RBD. The boosting injection also induced a strong antibody response against the spike protein of the Delta and Omicron variants. [Renia L, 2022 ]

Gilboa M et al was a prospective cohort study conducted in Israel, including 3,972 healthcare workers who received 3 vaccine doses and 4,868 healthcare workers who received 2 doses. The study measured the neutralizing response against Omicron, 5 months after vaccination. The GMT of neutralizing antibodies with the booster dose was 4,315 (95% CI, 4,051-4,595) compared to 611 (95% CI, 557-671) after 2 doses, and the response waned to 132 (95% CI, 121-144) and 1,001 (95% CI, 895-1,119) with 3 and 2 doses respectively, after 140 days. [Gilboa M, 2022 ]

Efficacy outcomes
C4591031 was a phase 3 randomized trial. The study enrolled 10,136 participants: 5,081 in the vaccine group and 5,044 in the placebo group. Participants who had received two 30-μg doses of the BNT162b2 vaccine for at least 6 months were assigned to be injected with a third dose of the BNT162b2 vaccine or with placebo. The study assessed vaccine safety and efficacy against COVID-19 starting 7 days after the third dose. The main results showed that relative vaccine efficacy for individuals without evidence of infection 7 days before the third dose was 95.3% (95 CI 89.5 to 98.3). Relative vaccine efficacy for individuals with or without evidence of infection 7 days before the third dose was  94.6% (95% CI 88.5 to 97.9) [Moreira ED, 2022 ].

Effectiveness outcomes
Barda N et al. was a case-control study conducted in Israel. The study enrolled 1,158,269 participants: 728,321 third dose group; 728,321 second dose group. Based on data from Clalit Health Services, which provides mandatory health-care coverage for over half of the Israeli population, between July 30, 2020, and Sept 23, 2021, with outcomes measured 7 days after the third dose, the study results showed a vaccine effectiveness for admission to hospital of 93% (95% CI 88–97), for severe disease of 92% (95%CI  82–97) and for death of 81% (95%CI  59–97) [Barda N, 2021 ]. 

Arbel R et al. was a cohort study conducted in Israel. The study enrolled 843,208 participants: 758,118 third dose group, and 85,090 second dose group. Based on data for all members of Clalit Health Services who were 50 years of age or older at the start of the study and had received two doses of BNT162b2 at least 5 months earlier, between August and September 2021. Main outcomes were measured 7 days after the third dose. The study results showed a adjusted hazard ratio for death of 0.10 (95%CI 0.07 to 0.14) [Arbel R, 2021 ]. 

Bar-On YM et al. was a cohort study conducted in Israel. The study enrolled 4,696,865 participants and was based on data from the Israel Ministry of Health database regarding 4,696,865 persons 16 years of age or older who had received two doses of BNT162b2 at least 5 months earlier, for the period from July 30 to October 10, 2021. Outcome was measured 7 days after the third dose. The study results showed an adjusted rate difference ranging from 57.0 to 89.5 infections per 100,000 person-days for confirmed infection and an adjusted rate difference ranging from 5.4 and 1.9 cases of severe illness per 100,000 person-days for severe illness [Bar-On YM, 2021 ].
         
Andrews N et al. was a case-control study (Test-negative) conducted in United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against symptomatic disease, hospitalization, and death in adults in England. The study results showed that the booster dose was associated with an absolute vaccine efficacy from 14-34 days after a Pfizer booster of 94.4% (95% CI 94.1 to 94.7) following either an AstraZeneca or Pfizer primary scheme in individuals 50 years and older [Andrews N, 2022 ].


Muhsen K et al. is a randomized study">non-randomized study that assessed the incidence of COVID-19 among long-care residents who were 60 years of age or older. After 36 weeks, the incidence rate ratio reached 0.29 for overall infection and 0.20 for hospitalization, corresponding to a relative rate reduction of 71% and 80%, respectively. In addition, study results showed a consistent reduction in the COVID-19 mortality among persons in the same age group living in long-term care facilities [Muhsen K, 2021 ]."

mBoost was an open-label trial conducted in Qatar. The study included 2,232,224 vaccinated persons with at least two doses. This study compared protection afforded by booster dose of the Pfizer vaccine, compared to the primary series of only two doses in Qatar. Study results showed that there were fewer cases of severe COVID-19 in booster-dose cohorts than in primary-series cohorts, but cases of severe COVID-19 were rare in all cohorts. Booster effectiveness relative to primary series was 50.1% (95% CI: 47.3-52.8%).[Laith J Abu-Raddad, 2022 ].

Accorsi EK et al included 23 391 cases and 46 764 controls (3 doses= 12 476; 2 doses=19839; Unvaccinated= 17 177). Data were collected ≥14 days after dose 3 and ≥6 months between doses 2 and 3. The study showed that receiving three doses of Pfizer COVID-19 vaccine compared to not receiving any and receiving only two doses, was associated with protection against both the Omicron and Delta. Comparison of 3 Doses vs Unvaccinated showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.38) and for Delta variant OR 0.077 (95% CI 0.070 to 0.086). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.35 (95% CI 0.32 to 0.37) and for Delta variant OR 0.17 (95% CI,0.16 to 0.19) [Accorsi EK, 2022 ].
McConeghy KW et al. included 14,259 participants (8,538 control and 5,721 boosted residents). Data were collected 42 days after the booster dose. The combined results showed that a booster dose of Pfizer or Moderna COVID-19 vaccine reduced infections by 50.4% (95% CI 29.4% to 64.7%) in nursing homes residents and 58.2% (95% CI 32.3% to 77.8%) in veterans residing in community living centers. Nursing homes residents with booster dose also had a 97.3% (95% CI 86.9% to 100.0%) reduction in SARS-CoV-2 associated death, but too few events for comparison in veterans residing in community living centers [Kevin W McConeghy, 2022 ].

Buchan SA et al. included 20,348 tests (Omicron-positive cases=16,087;  Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021.  The study showed that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for Delta and Omicron variants. Vaccine efficacy against Delta variant was 97% (95% CI 96 to 98) and 60% (95% CI 55 to 65)  for Omicron in symptomatic infection 7 days after a third dose [Buchan, S. A., 2022 ].

The VISION Network study included 222,772 encounters from 383 emergency departments (ED) and urgent care (UC), and 87,904 hospitalizations from 259 hospitals. Data were collected during periods of Delta and Omicron variant predominance between august 2021to January 2022. Based on all results combined, during the Delta-predominant period, vaccine effectiveness against Lab-confirmed COVID-19 was significantly lower among patients who received the second dose ≥180 days earlier (76%; 95% CI 75 to 77) than among those who received the third dose (94%; 95% CI 93 to 94). In the omicron-predominant period, vaccine effectiveness against the same outcome was significantly lower among those who received the second dose ≥180 days earlier (38%; 95% CI 32 to 43) than those who received the third dose (82%; 95% CI 79 to 84). In addition, vaccine effectiveness against hospitalization was 90% (95% CI 89 to 90) in those who received the second dose <180 days earlier, 81% (95% CI 80 to 82) in those who received the second dose ≥180 days earlier and 94% (95% CI 93 to 95) in those who received the third dose, during Delta period. In the Omicron period, vaccine effectiveness against hospitalization was 81% (95% CI 65 to 90) in those who received the second dose <180 days earlier, 57% (95% CI 39 to 70) in those who received the second dose ≥180 days earlier and 90% (95% CI 80 to 94) in those who received a third dose [Thompson MG, 2022 ].

Drawz PE et al. was a case-control study conducted in the United States.  The study enrolled 4,547,945 participantes:1,732,112 were fully vaccinated with Pfizer and 1,066,645 were fully vaccinated with Moderna. A Pfizer booster was administered to 609,153 individuals and a Moderna booster was administered to 395,634 individualsThe study is based on statewide COVID-19 vaccination data from the Minnesota Immunization Information Connection (MIIC) linked via a privacy preserving record linkage process with distributed electronic health record (EHR) data from the 11 largest health systems in Minnesota. The main results showed that the booster dose effectiveness was 88% (95% CI 87 to 88) and 88% (95% CI 86 to 90)  for preventing Hospitalization for the  Pfizer-BioNTech vaccine [Drawz PE, 2022 ].

Chemaitelly H et al was a case-control study conducted in Qatar, it enrolled 85,623 participants: 58,274 cases and 27,419 controls. Based on data from a test negative design study that seeks to assess the duration of protection of Pfizer-BioNTech after second dose and after third/booster dose against symptomatic Omicron infection and against COVID-19 hospitalization and death, between December 23, 2021 and February 2, 2022.  The vaccine effectiveness waned after the second those to less than 10% five months after vaccination, the effectiveness four to five weeks after booster rose  to 56.6% (50.8% to 61.7%) [Hiam Chemaitelly, 2022 ].

Oster Y et al. was a comparative cohort study conducted in Israel, it included 5,371 healthcare workers: 398 received two doses and 4,973 received three doses. Based on data from healthcare workers at the Hadassah tertiary care medical center in Jerusalem, who had received two vaccine doses (Pfizer-BioNTech) in early 2021 and were not infected until August 2021. The follow-up period lasted 120 days after the last dose for each group. The effectiveness against breakthrough infection was 97% ( 95% CI, 95% to 99%) [Oster Y, 2022 ].

Kislaya I et al. was a case control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on dat from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal. The booster effectiveness against Delta variant was 94% (95% CI: 93.4 to 94.6) and for Omicron variant the booster effectiveness was  68.8% (95% CI: 46.4 to 81.7) [Irina Kislaya, 2022 ].

YM Bar-On et al. was a case-control study conducted in Israel, it included 57,705 cases: 42,693 with three doses, 5,445 with 4 to 7 days after the fourth dose, and 9,071 with at least 12 days after the fourth dose. Based on data from the Israeli Ministry of Health database regarding 1,138,681 persons aged over 60 years and eligible for the fourth dose from January 15 through January 27, 2022. The rate ratio compared to the third dose was 2.0 (95%CI 2.0 to 2.1) for those between 4 and 7 days after the fourth dose, and those with more than 12 days after the fourth dose had a rate ratio of 1.9 (95%CI 1.8 to 2.0) [Yinon M. Bar-On, 2022 ].

Shrestha NK et al. was a cohort study conducted in the United States, based on data from Cleveland Clinic Health System in Ohio, United States, all employees who had been vaccinated (with either Pfizer-BioNTech or Moderna) or had previous COVID-19 infection by November 26, 2021, were included. With a follow-up period of 90 days. The vaccine effectiveness during the Omicron surge was 57% (95%CI: 54% to 59%) for the complete scheme and a booster of mRNA vaccine [Nabin K Shrestha, 2022 ].

Tan SHX et al was a comparative cohort study conducted in China. Rates and severity of SARS-CoV-2 infections between September 15 and October 31, 2021, among those eligible to receive vaccine boosters between September 15 and October 15, 2021, were analyzed based on official data reported to the Singapore Ministry of Health. The adjusted incidence rate ratios (3 doses of BNT162b2) for individuals with PCR–confirmed infections was 0.272 (95% CI 0.258 to 0.286) and 0.047 (95% CI 0.026 to 0.084) for severe infections [Tan SHX, 2022 ].

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna, the study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Delta variant of the booster dose compared to the two dose regimen was 86.1% (95% CI 67.3 to 94.1) for symptomatic infection, the effectiveness against the Omicron variant of the booster dose compared to the two dose regimen was 49.4% (95% CI 47.1 to 51.6)  for symptomatic infection and 76.5% (95% CI 55.9  to 87.5) for hospitalization and death  [Abu-Raddad LJ, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  Pfizer-BioNTech effectiveness against Delta and Omicron variants for symptomatic infection 10 weeks after a Pfizer-BioNTech booster were 89.9% (95% CI 89.2 to 90.5) and 45.7% (95% CI 44.7 to 46.7) [Andrews N, 2022 ].

Arbel R was a comparative cohort study conducted in Israel. The study included 563,465 participants and 328,597 received a second-booster dose during the 40-day study period. The study included all members of Clalit Health Services, aged 60 or older, who received a BNT162b2 booster dose at least 4 months earlier. Mortality due to Covid-19 among participants who received the second-booster was compared with that among participants who received one booster dose. Adjusted hazard ratio for mortality was  0.22 (95% CI 0.17 to 0.28) [Ronen Arbel, 2022 ].

Grewal R et al was a case-control study (test negative design) conducted in the United States. The aim of this study was to estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of mRNA covid-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the omicron variant. Vaccine effectiveness of three doses of Pfizer vaccine against omicron variant against any infection was 32% (95%CI 24 to 38), against symptomatic infection was 53% (95%CI 39 to 63) and against severe outcomes 77% (95% CI 67 to 83) [Grewal R, 2022 ].

Low EV et al. was a retrospective cohort study conducted in Malaysia. The study included 13,840,240 individuals: 5,714,979 with 2 doses BNT162b2, 3,043,620 with 2 doses of CoronaVac, 1,265,436 with 3 doses of BNT162b2, 3,225,428 with 2 doses of CoronaVac plus BNT162b2 booster and 590 777 with 3 doses of CoronaVac. The aim of this study was to compare the odds of symptomatic SARS-CoV-2 infection and COVID-19–related outcomes after heterologous and homologous boosting of CoronaVac at 3-month intervals and homologous boosting of BNT162b2 at 6-month intervals, with BNT162b2 primary series (2 doses) as the reference group. The adjusted odds against symptomatic SAR-CoV-2 infection were lower for individuals who received the primary series CoronaVac plus a BNT162b2 (adjusted odds ratio [aOR], 0.06 [95% CI, 0.05-0.06]), 3 doses of CoronaVac (aOR, 0.08 [95% CI, 0.06-0.10]), or 3 doses of BNT162b2 (aOR, 0.01 [95% CI, 0.00-0.01]). Receipt of heterologous booster (primary series of CoronaVac plus a BNT162b2 booster) was associated with lower odds of SARS-CoV-2 infection (aOR, 0.17 [95% CI, 0.17-0.18]) compared with homologous booster (3 doses of CoronaVac) for individuals aged 60 years and older (aOR, 0.19 [95% CI, 0.19-0.20]) [Low EV, 2022 ].

Tartof SY et al was a test-negative case-control study conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records in the US. Participants included 3168 members ages 12 to 17 years with emergency department (ED) and urgent care (UC) encounters from November 1, 2021, through March 18, 2022. Vaccine effectiveness (VE) associated with 2 doses of BNT162b2 against ED or UC encounters was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, −7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3 [Tartof SY, 2022 ].

Ziv et al was a case-control study conducted in Israel, the study evaluated the effectiveness of PfizerBioNTech vaccination among 1639 adolescentes with juvenile-onset inflammatory rheumatic diseases, the control group comprised 524,471 adolescents without juvenile-onset inflammatory rheumatic diseases. The estimated vaccine effectiveness for adolescents with IRD was 99.2% after the Pfizer-BioNTech booster dose [Ziv A, 2022 ].

McMenamin et al was a cohort study conducted in Hong Kong based on individual level-case study, vaccination programme and census information. The study evaluated the effectiveness of Pfizer-BioNTech vaccination, including cases between December 31, 2021 and March 16, 2022. Vaccine effectiveness of three doses of Pfizer-BioNTech against mild or moderate disease was 73.5% (95 CI 66.6 to 79.2), and 98.8% (95 CI 97.5 to 99.5) against severe disease [McMenamin ME, 2022 ].

Berec L was a case-control study conducted in Czechia. The study used Czech national health data from the beginning of the Covid-19 pandemic till November 2021 to estimate risks of reinfection, breakthrough infection, hospitalization, and death among fully vaccinated individuals at two time points (0-2 months and 7-8 months after the second dose) and after a booster dose. The study analyzed 5,011,115 individuals vaccinated with the Pfizer-BioNTech vaccine. The vaccine effectiveness against any PCR-confirmed SARS-CoV-2 infection declined for from 87% (95% CI 86–87) 0–2 months after the second dose to 53% (95% CI 52–54) at 7–8 months; against hospitalizations, VE declined from 90% (95% CI 89–91) at 0–2 months to 75% (95% CI 73–76) at 7–8 months [Berec L, 2022 ].

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against infections for Pfizer homologous booster dose was 72.1% (95% CI 51.7 to 83.9) for residents (>65 years) and 78.9% (95% CI 69.6 to 85.4) for staff (>18 years)[Shrotri M, 2022 ].

Patalon T et al was a test-negative case-control study conducted in Israel. This study assessed the association between booster breakthrough infections with the Omicron variant and time-since-vaccination, leveraging data from Maccabi Healthcare Services (MHS). Vaccine effectiveness against infection of ‘newly’ vaccinated individuals was 53.4% (95% CI 47.7 to 8.6%). VE declined rapidly with each month since vaccination, with 35.7% (95% CI, 29.8–41.2%) VE for those who were vaccinated two months prior to the outcome period compared to the earliest vaccinees (of August 2021). [Patalon T, 2022 ].

Richterman A et al was a test-negative case-control study that analyzed data from 7098 tests during the Omicron period (2270 SARS-CoV-2 PCR Positive) and 7422 tests during the Delta period (506 SARS-CoV-2 PCR Positive). The aim of this study was to estimate BNT162b2 and mRNA1273 primary vaccination and booster effectiveness against SARS-CoV-2 infection and symptomatic coronavirus disease 2019 during an Omicron surge among employees of the University of Pennsylvania Health System. Vaccine effectiveness (VE) for 2 doses of Pfizer was 41% (95% CI −17% to 87%) during the Omicron period and 75% (95% CI 52% to 87%) during the Delta period. VE for 3 doses of Pfizer was 54% (95% CI 23% to 73%) during the Omicron period and 93% (95% CI 78% to 98%) during Delta period [Richterman A, 2022 ].

Butt AA et al was a retrospective study conducted in United States that included data from 2,165,107 individuals. 395 686 participants were matched who received a third dose of the same ARNm vaccine. This study  assessed effectiveness of a third dose against symptomatic infection, hospitalization, and intensive care unit (ICU) admission or death after SARS-CoV-2–positive test. Vaccine effectiveness against Symptomatic infection for the third dose of Pfizer vaccine (in comparisson with 2 doses) was 84% (95% CI 78 to 88). Vaccine effectiveness against hospitalization (3 versus 2 doses) was 77% (95% CI 65 to 85) [Butt AA, 2022 ].

Zee ST et al, was a retrospective study was performed to compare the rate and outcome of COVID-19 in healthcare workers with various vaccination regimes during a territory-wide Omicron BA.2.2 outbreak in Hong Kong between 1 February to 31 March 2022 . The study included 3167 healthcare workers.  Compared two-dose vaccination, three-dose vaccination reduced infection risk by 31.7% and 89.3% in household contact and non-household close contact, respectively. Vaccine effectiveness against infections for Pfizer homologous booster dose was (HR 0.4778 p< 0.0001) [Zee ST, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Booster dose vaccine effectiveness was  90.8% (95% CI: 83.4-94.9) in those aged ≥65, 94.3% (95% CI: 83.7-98.0)  in those aged 51-64 , 75.5% (95% CI: 38.9-90.2) in those aged 18-50 . The findings show that BNT162b2 vaccination were effective against COVID-19-related severe complications against the Omicron BA.2 [Yan VKC, 2022 ]

Ng OT et al was cohort study conducted in Singapore. The study included 2,441,581 eligible individuals. It was based on data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27th 2021 to March 10th 2022. Effectiveness of booster dose against COVID Infeccion was 31.7% (95% CI 30.0 to 33.4) and 85.2% (95% CI 80.2 to 88.9) against Severe COVID Infeccion. [Ng OT, 2022 ]

Wan EYF was a case-control study conducted in China. The study included 82,587 cases of COVID-19 infection, 10,241 COVID-19 related hospital admission cases, 539 cases of ICU admission and 135 cases of post-infection incident. This study evaluated the vaccine effectiveness (VE) of each dose of BNT162b2 and CoronaVac against any COVID-19 infection, COVID-19-related hospital admission, ICU admission, and incident cardiovascular disease (CVD) in the Hong Kong Hospital Authority outbreak dominated by Omicron BA.2 sublineage. Vaccine effectiveness against COVID-19 infection was -0.3% (95% CI -2.7 to -2.1) with 2 doses of CoronaVac, 22.1% (95% CI 20.0 to 24.2) with 2 doses of Pfizer, 19.8% (95% CI 17.2 to 22.3) with 3 doses of CoronaVac, 54.2% (95% CI 52.4 to 55.9) with 3 doses of Pfizer, 12.1% (-15.8 to 33.3) with Pfizer primary schedule and CoronaVac booster, and 39.9% (95% CI 36.6 to 42.9) with CoronaVac primary schedule and Pfizer booster. Vaccine effectiveness against COVID-19 hospitalization was 64.2 (95% CI 61.8 to 66.4) with 2 doses of CoronaVac, 74.2 (95% CI 71.7 to 76.4) with 2 doses of Pfizer, 85.4% (95% CI 83.2 to 87.3) with 3 doses of CoronaVac, 91.4% (95% CI 89.5 to 92.9) with 3 doses of Pfizer and 89.5% (95% CI 85.9 to 92.2) with CoronaVac primary schedule and Pfizer booster. [Wan EYF, 2022 ].

Lin DY et al was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the COVID-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of the Pfizer homologous booster was 61.2% (95%CI  60 to 62.4) after 1 month [Lin DY, 2022 ].

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine healthcare system, the Michigan State Registry and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA based COVID-19 vaccines. During the Omicron dominant period December 2021 to March 2022. The effectiveness of the Pfizer-BioNtech vaccine during the Omicron period in immunocompetent participants was −6%(95% CI –14 to 4) for two doses and 35%(95% CI, 29 to 41) for three doses. In immunocompromised participants the effectiveness was 13% (95% CI –19 to 39) for two doses and 50% (95% CI 31 to 64) for three doses [Risk M, 2022 ].

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Pfizer booster after AstraZeneca, Janssen, Moderna, or Pfizer primary schedule was 46.2% (95% CI 43.5–48.7). Vaccine effectiveness of an mRNA booster (Pfizer or Moderna) following a Pfizer primary schedule was 49.7% (95% CI, 48.3–51.1) [Monge S, 2022 ].

Stowe et al. conducted a test-negative case-control study in UK, to estimate Vaccine Effectiveness (VE) against hospitalization with the Omicron and Delta variants using PCR testing linked hospital records (Emergency Care Data Set; ECDS). The total number of tests in the study period was 409,985 of which 115,720 were cases and 294,265 controls. Vaccine effectivenes against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 18 to 64 years of age, 82.8% (95% CI 78.4-86.3) after 14-34 days, 67.7% (95% CI 58.2-75.0) after 105+ days. Vaccine effectiveness against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 65 years of age and older, 97.4% (95% CI 92.8-99.1) after 14-34 days and 88.0% (95% CI 83.4-91.4) after 105+ days.
[Stowe J, 2022 ]

Chiew CJ et al was a national cohort study conducted in Singapore. This study assessed the incidence of confirmed SARS-CoV-2 infection and hospitalization among adolescents aged 12–17 years vaccinated with BNT162b2 from Sept 1 to Dec 15, 2021, during the delta variant wave, and from Jan 21 to April 28, 2022, during the omicron variant wave. Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during delta variant wave was 0.66% (95% CI, 0.63-0.69). Vaccine effectiveness against hospitalization during delta variant wave was 0.83 (95% CI, 0.74-0.89). Adjusted vaccine effectiveness against Confirmed SARS-CoV-2 infection during omicron variant wave was 0.25% (95% CI, 0.21-0.29) with 2 doses and 0.56 (95% CI 0.53-0.58) with homologous booster dose. Vaccine effectiveness against hospitalization during omicron variant wave was 0.75 (95% CI, 0.56-0.86) and 0.94 (95% CI, 0.86-0.97) with homologous booster dose. [Chiew CJ, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Omicron-predominant period for Pfizer vaccine was 63% (95% CI, 46-74) (less than two months after the second dose) and 88% (95% CI, 86-90) with the third booster dose. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Delta-predominant period for Pfizer vaccine was 95% (95% CI, 93-96) (less than two months after the second dose) and 95% (95% CI, 94-96) with the third booster dose. [Ferdinands JM, 2022 ]

Tartof et al was a case-control, test-negative study conducted in the United States, based on data from the Kaiser Permanente Southern California (KPSC), which is a large, integrated healthcare system. The study included 16,994 participants: 10,620 cases and 8,503 controls. Eligible patients were admitted to one of 15 KPSC hospitals or Emergency Departments between December 27th 2021, and June 4th 2022. The effectiveness of the Pfizer-BioNTech booster vaccine against BA.1 variant was 79% (95% CI, 74% to 83%) against hospital admission, for Emergency Department admission the effectiveness was 72% (95% CI, 67% to 77%). Effectiveness against BA.2 variant was 71% (95% CI, 55% to 81%) for 3 doses against hospital admission and the effectiveness against Emergency Department admission was 21% (95% CI, 1% to 37%). [Tartof SY, 2022 ]

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that study included 16,208,600 participants, of which 7,589,080 received a Pfizer-BioNTech primary schedule and 8,619,520 received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform, during the Omicron period between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.33 (95% CI, 0.28-0.38). [Agrawal U, 2022 ]

Mehta HB et al was a retrospective cohort study conducted in the United States that included 3,940,475 boosted individuals and 3,940,475 controls. Based on data from Medicare beneficiaries who received 2 doses of the Pfizer vaccine or 2 doses of the Moderna vaccine as the primary vaccination series from December 11th 2020 to December 31st 2021. The vaccine effectiveness against hospitalization of an mRNA booster dose after an mRNA primary schedule was 81% (95% CI, 80% to 82%). [Mehta HB, 2022 ]

Wan EYF was a case control study conducted in China that included data from 78,326 individuals: 7,293 deaths related to COVID-19 and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was 20.3% (95% CI, 18.4% to 22.1%), 50.9% (95% CI, 49.6% to 52.1%), -2.9% (95% CI, -24.0% to 14.6%) and 30.9% (95% CI, 28.5% to 33.2%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule, respectively. Vaccine effectiveness against COVID-19-related hospitalization was 74.9% (95% CI, 72.6% to 77.0%), 91.4% (95% CI, 90.1% to 92.5%), 87.4% (95% CI, 59.6% to 96.1%) and 86.9% (95% CI, 84.3% to 89.1%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule, respectively. [Wan EYF, 2022 ]

Tartof SY et al was a case-control study with a test-negative design conducted in the United States that enrolled 24,356 participants, including 12,566 boosted individuals, 5,997 with the primary schedule and 5,793 unvaccinated individuals. The study was based on data from Kaiser Permanente, a health insurance provider from Southern California, including participants vaccinated with Pfizer-BioNTech and unvaccinated controls. This study analyzed data from May to August 2022 during the Omicron BA.4/5 outbreak. The adjusted effectiveness of 3 Pfizer-BioNTech doses was 50% (95% CI, −1% to 76%) against hospitalization, 39% (95% CI, 14% to 57%) against emergency department admission and 17% (95% CI, 7% to 26%) against outpatient care. The effectiveness of 4 Pfizer doses was 60% (95% CI, 11% to 82%) against hospitalization, 69% (95% CI, 44% to 83%) against emergency department admission and 25% (95% CI, 7% to 39%) against outpatient care. [Tartof SY, 2022 ]

Baum U et al was a cohort study conducted in Finland, the study included 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, starting on December 27th 2020 and ending on March 31st 2022. Vaccine effectiveness of the booster against hospital admission was 95% (95% CI, 94% to 96%) and 98% (95% CI, 95% to 99%) against ICU admission. [Baum U, 2022 ]

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity outcomes
Com-COV was a multi-center single-blind phase II randomized parallel study. The trial included 830 healthy adults 50 years and older: 115 Pfizer/ AstraZeneca vaccine; 114 ​​AstraZeneca/ Pfizer vaccine group; 234 Control group (Two doses of AstraZeneca or Pfizer COVID-19 vaccine). Immunogenicity was measured at anti-SARS-CoV-2-spike binding antibody (bAb) levels 28 days following the second dose. Results showed SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher versus homologous vaccine schedules [Liu X, 2021 ].

Com-Cov was an open-label randomized controlled trial that included 664 participants. Participants were divided into two groups: one group received the primary schedule with a 14-week interval between doses (83 participants received a ChAd-ChAd schedule, 83 ChAd-BNT schedule, 84 BNT-BNT schedule, and 83 BNT-ChAd schedule) and the other group received the primary schedule with a 12-week interval between doses (89 received ChAd-ChAd schedule, 77 ChAd-BNT schedule, 81 BN-BNT schedule and 78 BNT-ChAd schedule). The aim of the study was to assess the effect of priming interval on humoral response 28 days and 6 months post-second dose. Anti-spike IgG (ELU/mL) at 28 days after the second dose for the 4-week interval study groups were 1,444 (95% CI, 1,205−1,732), 12,979 (95% CI, 11,217−15,018), 14,349 (95% CI, 12,470−16,511) and  7,530 (95% CI, 6,811−8,325) for ChAd-ChAd schedule, ChAd-BNT schedule, BNT-BNT schedule, and BNT-ChAd schedule, respectively. Anti-spike IgG (ELU/mL) at 28 days after the second dose for the 12-week interval study groups were 2,622 (95% CI, 2,152−3,195), 13,465 (95% CI, 11,391−15,917), 19,011 (95% CI, 16,468−21,947) and 10,642 (95% CI, 8,936−12,673) for ChAd-ChAd schedule, ChAd-BNT schedule, BNT-BNT schedule, and BNT-ChAd schedule, respectively [Shaw RH, 2022 ].

CombiVacS was a phase 2, open-label, randomized, controlled trial. The trial included 676 adults aged 18-60 years: 450 Intervention group (ChAd/BNT ); 226 Control group. Immunogenicity was measured 14 days following the second dose. BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response  [Borobia AM, 2021 ].

ComFluCOV was a phase 4, randomized controlled trial. The trial included 679 volunteers aged ≥ 18 years: 139 Pfizer /QIVc group; 79 Pfizer/ aTIV group; 58 Pfizer/ QIVr group; 129 AstraZeneca /QIVc group; 146 AstraZeneca /aTIV group; 128 AstraZeneca /QIVr group. Immunogenicity was measured 21 days after receiving Pfizer COVID-19 vaccine. Results showed concomitant vaccination with Pfizer COVID-19 vaccine plus an age-appropriate influenza vaccine raises antibody responses [Lazarus R, 2021 ].

COV-ADAPT was a prospective cohort study conducted in Germany. The study assessed the immune response elicited by the use of heterologous and homologous vaccine schedules of Pfizer and AstraZeneca vaccines and included 382 participants 18 to 65 years old who received either 2 doses of Pfizer COVID-19 vaccine or 2 doses of AstraZeneca Covid-19 vaccine or 1 dose of each one. The study measured the neutralizing antibody levels and T-cell responses from blood samples taken up to 2 weeks prior to the second dose and 2 weeks to 3 months after the second dose. Results showed an increase in neutralizing antibody titers that were higher in the participants who received the Pfizer vaccine. After the first dose, all groups had similar T-cell responses, however, the Pfizer vaccine as a second dose yielded a significant increase in T-cell responses while the AstraZeneca vaccine generated no booster effect [Hollstein MM, 2022 ].

Nickel O et al. was a prospective cohort study conducted in Germany. The study compared antibody production against the S1 subunit and the RBD of the spike protein, the whole virion of SARS-CoV-2, and monitored neutralizing antibodies in sera and saliva of 104 participants vaccinated with Pfizer-BioNTech, 57 individuals with natural SARS-CoV-2 infection, and 11 participants who received a heterologous AstraZeneca/Pfizer schedule. After the first dose, the AstraZeneca cohort showed similar neutralizing titers compared to the Pfizer recipients. However, after the second dose neutralizing antibody levels were 4 times higher than for the homologous Pfizer group. No mucosal antibodies were detected two weeks after the second dose for any of the vaccine recipients while COVID-19 patients had detectable levels 15-30 days after symptoms onset [Olaf Nickel, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as second dose had significantly higher neutralizing titers against Delta and Beta than the groups that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and were 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against both the Delta and Omicron variants were significantly lower among groups who received Sinovac as a second dose compared to the other groups. Seropositivity rate for the Omicron variant was : 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and: Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].

García-Pérez et al was a secondary analysis of the CombiVac study. It was a phase 2 randomized controlled trial conducted in Spain. The study included 676 adults: 441 in the interventional group and 223 in the control group. Subjects primed with ChAdOx1-S were randomized to receive BNT162b2 as second dose or no vaccine. Subjects from the control group received BNT162b2 as second dose and also on day 28, as planned based on favorable results on day 14. At day 28 post vaccine, geometric mean titres (GMT) of RBD antibodies were 5616.91 BAU/mL (95% CI 5296.49–5956.71) in the IG and 7298.22 BAU/mL (6739.41–7903.37) in the CG (p < 0.0001). RBD antibodies titres decreased at day 180 (1142.0 BAU/mL [1048.69–1243.62] and 1836.4 BAU/mL [1621.62–2079.62] in the IG and CG, respectively; p < 0.0001). Neutralizing antibodies also waned from day 28 to day 180 in both the IG (1429.01 [1220.37–1673.33] and 198.72 [161.54–244.47], respectively) and the CG (1503.28 [1210.71–1866.54] and 295.57 [209.84–416.33], respectively). The lowest variant-specific response was observed against Omicron-and Beta variants, with low proportion of individuals exhibiting specific neutralizing antibody titres (NT50) >1:100 at day 180 (19% and 22%, respectively) [José Alcamí Pertejo, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received a first dose mRNA vaccine and a second dose of Pfizer-BioNTech or Moderna after 28 days. The primary outcome was to compare the immune response generated by the homologous Pfizer-BioNTech schedule to Pfizer-BioNtech/Moderna schedule. The titers of the anti-spike antibodies were higher in the BNT162b2/mRNA-1273 group with a geometric mean of 3706.1 (95% CI, 3201.5 to 42903) versus 2697.9 (95% CI, 2277.6 to 3195.7) for BNT162b2/BNT162b2. No difference was demonstrated on anti-spike antibodies between the BNT162b2/mRNA-1273 group (geometric mean, 3706.1; 95% CI, 3201.5 to 4290.3) and mRNA1273/BNT162b2 group (geometric mean, 2689.9; 95% CI, 2296.2 to 3151.1) groups. [Janssen C, 2022 ].

García-Pérez J was a randomized clinical trial conducted in Spain. The study included 676 adults primed with ChAdOx1-S. 441 participants were randomized to the intervention group and received Pfizer as a second dose and 223 participants were randomized to the control group and did not receive a second vaccine. Humoral immunogenicity, measured by immunoassay for SARS-CoV-2 receptor binding domain (RBD), antibody functionality using pseudovirus neutralization assays for the reference (G614), Alpha, Beta, Delta, and Omicron variants, as well as cellular immune response using interferon-g and IL-2 immunoassays, were assessed at day 28 after BNT162b2 in both groups, at day 90 (planned only in the interventional group) and at day 180. At day 28 post-vaccine, geometric mean titres (GMT) of RBD antibodies were 5616.91 BAU/mL (95% CI 5296.49−5956.71) in the IG and 7298.22 BAU/mL (6739.41−7903.37) in the CG (p < 0.0001). RBD antibody titers decreased at day 180 (1142.0 BAU/mL [1048.69−1243.62] and 1836.4 BAU/mL [1621.62−2079.62] in the IG and CG, respectively [García-Pérez J, 2022 ].

Bánki Z et al was a randomized clinical trial conducted in Austria. The study included 234 participants between 18 and 65 years with no prior history of SARS-CoV-2 infection and a first dose of AZ or BNT were included. The AZ/AZ and the AZ/BNT arms were randomized, the third arm (BNT/BNT) was observational. 116 participants received AstraZeneca as second dose and 118 Pfizer as second dose. This study compared the reactogenicity between the study groups and immunogenicity for the heterologous AZ/BNT compared to the homologous AZ/AZ regimen using neutralizing antibody titers as primary endpoint. The antibody levels after the boost vaccination were statistically significant higher in the heterologous AZ/BNT group than in the homologous AZ/AZ group (p<0.0001). Median IgG titers for AZ/BNT were 2538 BAU/ml (95% CI 2217 - 3045) at day 10 and 1478 BAU/ml (95% CI 1234 - 1826) at day 30 [Bánki Z, 2022 ].

Puthanakit T et al was a phase 2 randomized clinicla trial conducted in Thailand. The study included 80 participants  aged 12 to < 18 years without previous SARS-CoV-2 vaccination. Participants were randomized to be vaccinated with CoronaVac (SV) 3 ug as the first dose followed by BNT162b2 30 µg or 20 µg as the second dose, at 3-week (3w) or 6-week interval (6w). During the Omicron-predominant period, participants were offered a BNT162b2 booster dose 30, 15, or 10 µg. Immunogenicity was determined using IgG antibody against spike-receptorbinding domain of wild type(anti-S-RBD IgG) and surrogate virus neutralization test(sVNT) against Delta variant at 14 days and 5 months after the 2nd dose. Neutralization tests(sVNT and pseudovirus neutralization test; pVNT) against Omicron strain were tested pre- and 14 days post-booster dose.  At day 14, the geometric mean(GM) of anti-S-RBD IgG in SV3w/PZ30lg was 4713 (95 %CI 4127–5382) binding-antibody unit (BAU)/ml, while geometric mean ratio(GMR) was 1.28 (1.09–1.51) in SV6w/PZ30lg. The GMs of sVNT against Delta variants at day 14 among participants in SV3w/PZ30lg and SV6wk/PZ30lg arm were 95.3 % and 99.7 %inhibition, respectively. [Puthanakit T, 2022 ]

Niyomnaitham S et al was a randomized clinical trial conducted in Thailand. This study evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. 210 adults participated in the study: 30 with CoronaVac/AstraZeneca primary schedule, 30 with CoronaVac/Pfizer, 30 with AstraZeneca/CoronaVac, 30 with  AstraZeneca/Pfizer, 30 with Pfizer/CoronaVac, 30 with Pfizer/AstraZeneca and 30 with Pfizer/Pfizer. At 2 weeks after the second dose, the anti-RBD IgG levels were  2181.8 BAU/mL (95%CI 1558.2 to 3055.1) for CoronaVac/Pfizer schedule, 2132.7 BAU/mL (95%CI 1696.1 to 2,681.7) for AstraZeneca/Pfizer schedule, 2248.8 BAU/mL (95% CI 1691.3 to 2,990.0) for Pfizer/Pfizer schedule, 851.4 BAU/mL (95% CI 649.5 to 1116.1) for CoronaVac/AstraZeneca schedule, 1201.2 BAU/mL (95%CI 947.9 to 1522.1) for Pfizer/AstraZeneca schedule, 137.04 BAU/mL (95% CI 103.6 to 186.4) for AstraZeneca/CoronaVac schedule and 225.2 BAU/mL (95% CI 177.1 to 286.4) for Pfizer/CoronaVac schedule. [Niyomnaitham S, 2022 ]

Fernández-Ciriza et al. conducted a prospective study enrolling 709 healthcare workers receiving two doses of mRNA-1273, BNT162b2, ChAdOx1, ChAdOx1/BNT162b2 or ChAdOx1 single dose to compare humoral and cellular immunogenicity across 9 months. The mean age was 44 ± 11 years old and 85.9% were women. At 21 and 90 days after the second dose, mRNA-1273/mRNA-1273 and ChAdOx1/BNT162b2 were the most highly immunogenic schedules among COVID-19 naïve individuals, and ChAdOx1/ChAdOx1 yielded the lowest level of Anti-S-RBD up to 6 months after the second dose. The half-life of anti-S-RBS antibody concentration in those participants who received ChAdOx1/BNT162b2 was 36 days. For those who received ChAdOx1/BNT162b2 combinations, cellular immunity was found in 92.3%, after 6-months, among COVID-19 naïve participants. All tests to assess cellular immunity among individuals with a previous infection were reactive. [Fernández-Ciriza L, 2022 ]

Effectiveness outcomes
Suphanchaimat R et al was a test-negative case-control study conducted in Thailand. The study included 1,460,458 participants: 482,372 cases and 978,086 controls aimed to explore the vaccine effectiveness (VE) of various schedules against the SARS-CoV2 Delta variant in Thailand during September–December 2021. VE against any infection according to vaccine regimens was: 62.4% (95% CI 59.4 to 65.1) for BNT162b2 + BNT162b2, 88.7% (95% CI 85.6 to 91.1) for ChAdOx1 + BNT162b2, 82.3% (95% CI 74.3–87.7) and 94.0% (95% CI 93.4 to 94.6) for CoronaVac + BNT162b2 [Suphanchaimat R, 2022 ].

Chung et al. was a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11th and November 21st 2021 in Ontario, Canada. It included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for ChAdOx1/BNT162B2 7-59 days after second dose was 89% (95% CI, 87% to 91%) against any infection, 95% (95% CI, 92% to 97%) against symptomatic infection and 98% (95% CI, 94% to 99%) against severe outcomes (hospitalization/death). VE ChAdOx1/BNT162B2 120-179 days after second dose was 77% (95% CI, 73% to 80%) against any infection, 89% (95% CI, 86% to 91%) against symptomatic infection and 98% (95% CI, 96% to 99%) against severe outcomes (hospitalization/death). [Chung H, 2022 ].

Vaccine efficacy and effectiveness for heterologous booster schedule

Immunogenicity outcomes
Tobudic S et al. was a clinical trial that evaluated the efficacy and safety of a booster dose in patients in whom seroconversion did not occur after the second dose. The additional booster dose was delivered with the AstraZeneca or mRNA vaccines against COVID-19. Efficacy was measured by the difference in the SARS-CoV-2 antibody seroconversion rate between patients vaccinated with the AstraZeneca vaccine (heterologous) and the mRNA vaccines (homologous) at the fourth week. The results demonstrated that seroconversion rates at week four were comparable between patients who received the AstraZeneca vaccine (6/27 patients, 22%) versus the mRNA vaccines (9/28, 32%) (p = 0, 6). Overall, 27% of the patients seroconverted; furthermore, no serious adverse events related to immunization were observed [Michael Bonelli, 2021 ].

COV-BOOST et al. was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hereafter referred to as BNT). Efficacy was measured by neutralizing antibody titers at 28 days post-boost dose. The results demonstrated that all study vaccines boosted antibody and neutralizing responses after AstraZeneca/AstraZeneca initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

SWITCH  was a randomized trial sponsored by Erasmus Medical Center and conducted in the Netherlands between June 2021 to September 2022. Immunogenicity was assessed 28 days after homologous or heterologous booster vaccination. Results showed that Janssen COVID-19 vaccine and mRNA boosters vaccines were immunogenic in health care workers who had received a priming dose of the Janssen vaccine. In addition, the Moderna and Pfizer COVID-19 boosters vaccines led to higher T-cell responses than the Janssen COVID-19 booster vaccine. The immune response was 91.7% with the Moderna booster and 91.5% with the Pfizer booster; both performed better than the homologous booster (response, 72.7%) [Sablerolles RSG, 2022 ].

Angkasekwinai N et al. was a cohort study conducted in Thailand. Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that heterologous boosting vaccination with Pfizer following the Sinovac or AstraZeneca primary series is the most immunogenic against SARS-CoV-2 variants. A lower dose Pfizer may be used as a booster in settings with limited vaccine supply [ ].          

Andrews N et al. was a case-control study (Test-negative) conducted in United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against symptomatic disease, hospitalization, and death in adults in England. The study results showed that the booster dose was associated with an absolute vaccine efficacy from 14-34 days after a Pfizer booster of 94.4% (95% CI 94.1 to 94.7) following either an AstraZeneca or Pfizer primary scheme in individuals 50 years and older. With a Moderna booster, absolute vaccine effectiveness was 97.0 (95% CI 96.0 to 97.8) after an AstraZeneca primary scheme and 94.8% (95% CI 92.7 to 96.3%) Pfizer primary scheme. [Andrews N, 2022 ].

mBoost was an open-label trial conducted in China. The study included 436 adults aged ≥30 years who had previously received two doses of an inactivated COVID-19 vaccine. The study assessed the immunogenicity and reactogenicity of a third dose of Pfizer COVID-19 vaccine in adults who had previously received two doses of inactivated COVID-19 vaccination. Study results showed that a third dose of Pfizer COVID-19 vaccine substantially increased antibody titers measured by the various assays. Mean ELISA levels increased from a OD of 0.3 to 2.1 , and mean sVNT levels increased from an inhibition of 17% to 96% [Nancy H. L. Leung, 2022 ].

Vargas L et al. was an immunogenicity study conducted in Chile. The study included blood samples from different individuals; healthcare personnel volunteers from Hospital La Florida, and adult healthy volunteers aged 18 years and over. The study analyzed the impact of the booster doses of Sinovac, Pfizer, or AstraZeneca COVID-19 vaccines, administered to individuals vaccinated with the two-dose scheme with CoronaVac six months earlier. The study results showed that two doses of Sinovac COVID-19 vaccine induce antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the Pfizer vaccine. However, the response induced by Sinovac can be greatly potentiated with a heterologous booster scheme with Pfizer or AstraZeneca vaccines [Leonardo Vargas, 2022 ].

Cheng SMS et al. was an immunogenicity study conducted in China. The study included subsets of sera from 7 groups of vaccinated individuals, convalescent individuals, and individuals with breakthrough infections The study evaluated sera from vaccinated individuals with no evidence of prior COVID-19 infection 3-5 weeks after receiving two doses of Pfizer or two doses of Sinovac and individuals 3-5 weeks after receiving the third dose of Sinovac or a heterologous booster dose of Pfizer after two prior doses of Sinovac. The study results showed a markedly reduced serum antibody titres against the Omicron variant (GMT)<10 as compared to wild-type virus 3-5 weeks after two doses of Pfizer (GMT 218.8) or Sinovac COVID-19 vaccines (GMT 32.5). In addition, a Pfizer booster dose elicited Omicron PRNT50 titres ≥25.6 in 88% of individuals who previously received 2 doses of Pfizer and 80% of individuals who previously received Sinovac [Cheng SMS, 2022 ].

Pérez-Then E et al. was a cohort study conducted in Dominican Republic. The study included plasma samples from 101 adults who received a Pfizer booster after 2 doses of Sinovac. The study analyzed antibody levels and neutralizing activity of plasma samples taken after 2 doses of Sinovac COVID-19 vaccine after booster dose with Pfizer COVID-19 vaccine. The study results showed a 10.1 fold increase in neutralizing activity 28 days after the booster dose compared before the booster. However, this was not significantly different than the response obtained after a two-dose mRNA vaccination schedule (Pfizer or Moderna vaccine)[Pérez-Then E, 2022 ].

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for Omicron variant and compared to the ancestral strain (Wuhan-Hu-1) and Delta variant, in four groups of volunteers receiving 1) Two doses of mRNA vaccines plus an mRNA vaccine booster (Homologous mRNA vaccine booster) 2) Two doses of inactivated virus vaccines plus an inactivated virus vaccine booster (Homologous inactivated virus vaccine booster) 3) Two doses of mRNA vaccines plus an inactivated virus vaccine booster (Heterologous inactivated virus vaccine booster) and 4) Two doses of inactivated virus vaccines plus an mRNA vaccine booster (Heterologous mRNA vaccine booster). The study results showed that only the mRNA vaccine booster was able to effectively increase the median levels of neutralizing capabilities against the Omicron variant (Group 1, median 90.45% [IQR 78.71-94.33%]; Group 4, median 77.85% [IQR 47.80-92.18%]) by 4.5-fold and 3-fold, respectively. Inactivated virus booster shot was unable to significantly increase the median levels of neutralizing capabilities against the Omicron variant regardless of whether the individuals received 2 priming doses of mRNA vaccines (Group 3, median 30.65% [IQR 19.98- 36.03%]) or 2 priming doses of inactivated virus vaccines (Group 4, median 26.80% [IQR 18.35- 36.15%]) [Biyan Zhang, 2022 ].

Yavlinksy et al was a prospective community cohort study conducted in England and Wales. The study evaluated the immune response generated by a booster dose of the Pfizer COVID-19 vaccine on Pfizer or AstraZeneca primary vaccination recipients. Yavlinsky et al included 8,680 adults aged 18 or older who received a Pfizer vaccine booster after either Pfizer or AstraZeneca primary vaccination. The study found the Pfizer booster dose increased peak antibody levels compared to after primary vaccination regardless of the primary regimen. For the Pfizer primary vaccination group anti S antibody levels increased from 2,386 U/mL (95%CI: 9,801-15,653) to 22,185 U/mL (95%CI: 21,406-22,990) after the booster dose. In the AstraZeneca group antibody levels increased from 1,192 U/mL (95%CI: 818-1735) to 19,203 U/mL (95%CI: 18,094-20,377) after the booster dose [Alexei Yavlinsky, 2022 ].

Kanokudom et al. recruited 222 adults with a complete CoronaVac regimen who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54)or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. 28 days after the booster dose binding antibody levels were 28,413 U/mL and 31,793 U/mL for the reduced and standard Pfizer-BioNTech vaccines respectively and 41,171 U/mL and 51,979 U/mL for the reduced and standard Moderna vaccines. Boosting elicited an increase in median IFN-γ CD4+ T cell and CD4+ CD8+ T cell counts; there were no differences in T cell counts between the standard and reduced dose groups. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that was not affected by dosage [Kanokudom S, 2022 ].

Poh et al. is an ongoing phase 4 randomized clinical trial, conducted in Singapore, assessing the humoral response elicited by homologous and heterologous booster vaccination regimens based on a primary regimen with Pfizer-BioNTech. Interim results of two groups have been published. The study recruited 100 participants who either received a Pfizer-BioNTech (n=51) booster or a Moderna booster (n=49). Results show a booster dose increases antibody titers in all participants by 35- to 49- fold at day 7 with only a modest increase by day 17. Antibody titers were higher in the Moderna group, particularly in the ≥60 years age subgroup. On day 28 antibody titers reached 29.751 (IC 95%: 25.281-35.011) UI/mL for the Moderna group and 22 382 (IC del 95 %: 18 210-27 517) UI/mL for the Pfizer-BioNTech group. Neutralization against the Omicron variant was higher in the Moderna group at day 7 but similar at day 28 [Xuan Ying Poh, 2022 ].

RHH-001 was a phase 4 randomized study, conducted in Brazil and El Salvador, that analyzed the immune response generated by homologous and heterologous booster vaccines based on a primary vaccination regimen with the Sinovac vaccine.  The study recruited 1240 participants randomly assigned to receive a booster dose with Janssen (n=306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), and Sinovac (n=290) vaccines at least 6 months after the second dose. Results found all booster doses substantially increased binding and neutralizing antibody levels, the geometric fold-rise at day 28 post booster was 77 (67–88) for Janssen, 152 (134–173) for Pfizer-BioNTech, 90 (95% CI 77–104) for AstraZeneca, and 12 (11–14) for Sinovac. Heterologous booster regimens were superior to the homologous regimen with GMRs of 8.7 (5.9–12.9) for Janssen, 21.5 (14.5–31.9) for Pfizer-BioNTech, and 10.6 (7.2–15.6) for AstraZeneca. Neutralizing antibody titres were above the lower limit of detection in 75 (94%) of 80 participants tested at day 28 for the delta variant and in 61 (76%) of 80 participants for the omicron variant [Costa Clemens SA, 2022 ].

COV-BOOST  was a phase 2 randomized clinical trial conducted in the United Kingdom. This study enrolled 166 participants who had received Pfizer-BioNTech as their third dose and randomly assigned them to receive a fourth dose of either Pfizer-BioNTech (30 µg in 0.30 mL; full dose) or Moderna  (50 µg in 0.25 mL; half dose). Immunogenicity was compared at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. The geometric mean anti-spike protein IgG concentration on day 28 after the third dose of BNT162b2 was 23325 (ELU)/mL (95% CI 20030–27162). With the four dose Increased to 37460 ELU/mL (31996–43857) after the fourth dose. The fold change of the geometric mean was 1.59 (95% CI 1·41–1·78). [Munro APS, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901 (control). The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. Compared with pre-boost, all study vaccines elicited significantly higher anti-spike IgG at 28 days post-boost (P < 0.0001). Surrogate neutralizing antibodies by ELISA GMT after boost were 524 (481-573) IU/mL, with a fold change of 32.27 (27.38-38.04). Live virus neutralizing antibody (omicron), NT50 were 146 (119-179) IU/mL with fold change of Fold change 8.38 (6.82-10.29) [Chih-Hsien Chuang, 2022 ].

Suntronwong N et al was a cohort study conducted in Thailand. 167 participants primed with heterologous CoronaVac/Oxford-AstraZeneca vaccination were enrolled to receive a booster dose of Oxford-AstraZeneca (n= 60), Pfizer-BioNTech (n= 55) of Moderna (n= 52) vaccines. This study assessed the capability of the booster vaccination to induce an increase in neutralizing antibodies and T-cell responses against SARS-CoV-2, Omicron (BA.1 and BA.2), and Delta variants. Individuals boosted with mRNA vaccines demonstrated a higher level of neutralizing activity than those boosted with Oxford-AstraZeneca. Median neutralizing activity to Omicron (day 28) were 10,1% for AstraZeneca, 55,6 for Pfizer and 78,2% for Moderna. NAb titers at day 28 for Omicron BA.a variant were 40.3 (3.16-fold increase) for AstraZeneca, 171.0 (9.91-fold increase) for Pfizer, and 271.6 (24.78-fold increase) for Moderna. NAb titers at day 28 for Omicron BA.2 were 59.3 (2.43-fold increase) for AstraZeneca, 130.7 (4.63 fold-increase) for Pfizer, and 235.3 (19.67 fold-increase) for Moderna. [Suntronwong N, 2022 ]

Özyurda et al. was a case-control study conducted in Turkey, the study assessed the immunogenic response of a booster dose in 100 healthcare workers from the TOBB ETU Hospital who received a primary schedule of SinoVac vaccine and a booster dose of Pfizer-BioNTech (n=60) or a SinoVac booster dose (n=40). The study found that at 2.5 to 3.5 months after receiving the booster dose 25% of those vaccinated with a homologous booster ellicited a positive humoral immune response, as opposed to 93.3% in those vaccinates with a Pfizer-BioNTech booster. The cellular immune response was positive in 70% of the participants who received a SinoVac booster dose and in 88.3% of those who received a Pfizer-BioNTech booster. [Özyurda F, 2022 ].

Catry et al was a study conducted in Belgium assessing the immunogenicity after a Pfizer-BioNTech booster dose in 49 Lung Transplant Recipients who had a previously received an AstraZeneca primary schedule vaccination. At day 238 the Anti-SARS-CoV-2 IgG titers reached 197.8 BAU/mL (0.0–491.4) which represents a seropositivity of 32.3%, the NAbs titers reached 76.6 AU/mL (0–159.6) which represents a 32.2% of seropositivity [Catry E, 2022 ].

Choi JY et al was a comparative cohort study conducted in Korea. The study analyzed 170 samples of sera from 75 participants: 50 samples from ChAd-ChAd-BNT, 60 samples from ChAd-BNT-BNT, and 60 samples from BNT-BNT-BNT. Neutralizing activities were evaluated using plaque-reduction neutralization test (PRNT) against wild-type (WT) SARS-CoV-2, Delta variant, and Omicron variant. After the 2nd vaccine dose, geometric mean titers of PRNT ND50: against wild type, Delta, and Omicron were highest after ChAd-BNT vaccination (2,463, 1,097, and 107) followed by BNT-BNT (2,364, 674, and 38) and ChAd-ChAd (449, 163, and 25). After the 3rd dose of BNT, the increase of PRNT ND50 against WT, Delta, and Omicron was most robust in ChAd-ChAd-BNT (4,632, 988, and 260), while the BNT-BNT-BNT group showed the most augmented neutralizing activity against Delta and Omicron variants (2,315 and 628) [Choi JY, 2022 ].

CVIM 4 was a randomized controlled trial conducted in Thailand. The study included 77 kidney transplant recipients (per protocol analysis) who had already been vaccinated with a primary regimen of ChAdOx1, or CoronaVac and boosted with the ChAdOx1 vaccine. The participants were randomized two receive an additional dose of either an mRNA vaccine (Moderna or Pfizer BioNTech, n= 40,) or a viral vector vaccine (ChAdOx1, n= 37). The rate of seroconversion for the mRNA group was 70%, and 61% viral-vector group; the median interquartile range (IQR) of anti-RBD IgG levels were 51.8 (95% CI 5.1 to 591) and 28.3 (95% CI 2.4 to 87.1), respectively. Median (IQR) for S1-specific T cells for the mRNA group was 230 (I41 to 420), and 232 (116 to 400) for the viral-vector group [Bruminhent J, 2022 ].

Nantanee R et al was a randomized clinical trial conducted in Thailand. The study included 100 adults with a median age of 59.3 years with two-dose AZD1222: 50 received a half-Dose BNT162b2 Booster (15 µg/Dose) and 50 received a standard-Dose BNT162b2 Booster (30 µg/Dose). The immunogenicity was evaluated by a surrogate virus neutralization test (sVNT) against Omicron variants and anti-spike-receptor-bindin-domain IgG (anti-S-RBD IgG). At day 14, the geometric means of sVNT against the omicron variant were 74.4% (95% CI 68.8–80.5)  inhibition post-half-dose BNT162b2 boosters and 67.3% inhibition (95% CI 57.9 to 78.1) post-standard-dose boosters. At day 14, anti-S-RBD IgGs were comparably boosted with GMs of 2329.8 BAU/mL (95% CI 2109.3–2573.4) post-half-dose BNT162b2 boosters and 2574.7 BAU/mL (2262.5–2929.9) post-standard-dose boosters. At 14 days after boosters, the T cell responses were significantly enhanced to 406 SFU/106 PBMCs (IQR 206–718, p < 0.001) in the half-dose and 402 SFU/106 PBMCs (148–678, p < 0.001) in the full-dose groups, without a difference between the dosage groups (p 0.80) [Nantanee R, 2022 ].

Odile Launay et al was a randomized clinical trial conducted in France. The study included 247 participants who had received two doses of BNT162b2 of whom 85 received a Sanofi/GSK MV(D614) vaccine booster, 80 Sanofi/GSK MV(Beta) vaccine booster, and 82 BNT162b2 vaccine booster. The study evaluated the immunogenicity and safety of a homologous booster dose of BNT162b2 or recombinant vaccine with adjuvant (Sanofi/GSK MV(D614) formulation or MV B.1.351 (Beta) formulation) in recipients primed with two doses of BNT162b2 between 3 and 7 months earlier. The proportion of participants with at least a 10-fold increase of neutralizing antibody titers between day 0 and day 15 for the Wuhan (D614) SARS-CoV-2 strain (Pfizer BNT162b2) was 63.2% (95% CI 51.3 to 73.9) and for the B.1.351 (Beta) viral strain was 51.3% (95% CI 39.6 to 63.0). The geometric mean titer of anti-S1 increased from 253.6 at day 0 to 2405.4 BAU/mL at day 15 [Odile LAUNAY, 2022 ].

Bonelli et al conducted a randomized controlled trial in Austria. This study assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 or mRNA-1273, to receive a third dose, either using the same mRNA (28/30) or the vector vaccine ChAdOx1 nCoV-19 (27/30). Seroconversion rates at week 4 were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccines (p=0.6). Overall, 27% of patients seroconverted; specific T cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. 3/37 (8%) of patients without and 12/18 (67%) of the patients with detectable peripheral B cells seroconverted. No serious adverse events, related to immunization, were observed [Bonelli M, 2022 ].

BOOST-TX was a randomized controlled trial conducted in Austria, of a third dose of vaccine against SARS-CoV-2 in kidney transplant recipients who had not developed SARS-CoV-2 spike protein antibodies after 2 doses of an mRNA vaccine. 197 patients were analyzed, 99 receives a homologous booster (mRNA) vaccine, 98 received a heterologous (Ad26COVS1) vaccine. The 39% developed SARS-CoV-2 antibodies after the third vaccine. There was no statistically significant difference between groups, with an antibody response rate of 35% and 42% for the mRNA and vector vaccines, respectively. Only 22% of seroconverted patients had neutralizing antibodies. Similarly, T-cell response assessed by IGRA was low with only 17 patients showing a positive response after the third vaccination. Receiving nontriple immunosuppression (odds ratio [OR], 3.59; 95% CI, 1.33-10.75), longer time after kidney transplant (OR, 1.44; 95% CI, 1.15-1.83, per doubling of years), and torque teno virus plasma levels (OR, 0.92; 95% CI, 0.88-0.96, per doubling of levels) were associated with vaccine response. The third dose of an mRNA vaccine was associated with a higher frequency of local pain at the injection site compared with the vector vaccine, while systemic symptoms were comparable between groups. [Reindl-Schwaighofer R, 2021 ]

Cobovax study was a randomized clinical trial conducted in China. The study enrolled 219 adults who previously received two doses of CoronaVac and randomized to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomized to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). The aim was to assessed immunogenicity and cell-mediated immune responses and vaccine efficacy against infections during follow-up. Third-dose vaccination increased PRNT50 titers against ancestral virus 315 by 14-, 94-, 3- and 19-folds, and against Omicron BA.2 by 1-, 16-, 1- and 13-folds, in CC-C, CC-B, BB-C and BB-B arms respectively. Antibody responses to a BNT162b2 third dose were substantially and statistically significantly greater than responses to a CoronaVac third dose regardless of prior two-dose vaccine type. [Nancy H. L. Leung, 2022 ]

Fadlyana et al was a randomized controlled trial conducted in Indonesia. The study included 949 participants primed with CoronaVac that received one booster dose: 193 Half-Dose ChAdOx1, 192 Full-Dose ChAdOx1, 190 Half-Dose BNT162b2, 193 Full-Dose BNT162b2 and 192 Full-Dose Parameter CoronaVac. The primary outcome was to evaluate the seroconversion rate and geometric mean titres (GMTs) of IgG anti S-RBD 28 days after the booster in the per-protocol population. Seroconversion rates were highest for BNT162b2 (97.8% and 92.0% for full and half-dose), followed by ChAdOx1-S (87.9% and 81.5% for full and half dose) and CoronaVac (41.3% to 66.3%). For participants primed within 6–9 months before booster, GMT values 28 days post-booster were highest for BNT162b2 (19999.84 and 17017.62 for full and half-dose), followed by ChAdOx1-S (11258 and 7853.04 for full and half-dose) and CoronaVac (1440.55). [Eddy Fadlyana, 2022 ]

Intapiboon P et al was a randomized clinical trial conducted in China. The study included 80 participants who had received two doses of CoronaVac: 40 with Pfizer booster and 40 with CoronaVac booster. The primary outcome was antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) measured by surrogate Virus Neutralization Test (sVNTs), plaque reduction neutralization tests (PRNTs), and N-terminal domain (NTD) ELISA in plasma samples collected 1 month after the third dose of vaccination. One month after the third dose of vaccination, the mean percentage of inhibition in the sVNT in the plasma for the BNT1626 and CoronaVac groups was 96.83% and 57.75%, respectively (P < 0.0001). The 90% plaque reduction neutralization (PRNT90) geometric mean titers in the BNT162b2 and CoronaVac groups were 207.49 and 16.53, respectively. PRNT50 geometric mean titers were 303.79 and 56.67, respectively. [Mok CKP, 2022 ]

Niyomnaitham S et al was a randomized clinical trial conducted in Thailand. This study evaluated the immunogenicity and reactogenicity of heterologous COVID-19 primary schedules in healthy adults, as well as booster response to BNT162b2 following heterologous CoronaVac and ChAdOx1 nCoV-19 regimens. 210 adults participated in the study: 30 with CoronaVac/AstraZeneca primary schedule, 30 with CoronaVac/Pfizer, 30 with AstraZeneca/CoronaVac, 30 with  AstraZeneca/Pfizer, 30 with Pfizer/CoronaVac, 30 with Pfizer/AstraZeneca and 30 with Pfizer/Pfizer. At two weeks after the booster dose with Pfizer, the anti-RBD IgG levels against the ancestral strain were 2518.8 BAU/mL ( 95%CI 1960.4 to 3236.4) for participants primed with CoronaVac/AstraZeneca and 2610.6 BAU/mL (95%CI 2037.7–3344.5) for participants primed with AstraZeneca/CoronaVac. GMR were 2.5 and 18.9 for CoronaVac/AstraZeneca/Pfizer  and AstraZeneca/CoronaVac/Pfizer groups, respectively. [Niyomnaitham S, 2022 ]

Buathong et al conducted an observational study to determine the levels of neutralizing antibodies against the SARS-CoV-2 ancestral strain, Delta and Omicron variants of concern (VOCs), in 125 healthcare workers who received CoronaVac as their primary vaccination and later received either a single ChAdOx1 or a combination of two consecutive boosters using either two ChAdOx1 doses or a ChAdOx1 or BNT162b2 as the primary and second boosters, respectively, or two doses of BNT162b2. Coronavac Coronavac + ChAdOx1 Pfizer: - 100% of the subjects were NT positive against the ancestral strain at day 0 (MI of 84.5%, 95% CI: 80.5–88.6%; and MI of 84.6%, 95% CI: 73.2–95.9%, respectively) and at 1 week (MI of 85.2%, 95% CI: 81.8–88.7%; and MI of 93.3%, 95% CI: 86.3–100.3%, respectively) after their second booster dose. Coronavac Coronavac + Pfizer Pfizer: - 100% of the subjects were NT positive against the ancestral strain at day 0 (MI of 84.5%, 95% CI: 80.5–88.6%; and MI of 84.6%, 95% CI: 73.2–95.9%, respectively) and at 1 week (MI of 85.2%, 95% CI: 81.8–88.7%; and MI of 93.3%, 95% CI: 86.3–100.3%, respectively) after their second booster dose. [Buathong R, 2022 ].

Niyomnaitham et al was a phase 2 randomized clinical trial conducted in Thailand. The study included 1243 participants with CoronaVac primary schedule: 312 in the AstraZeneca booster (half dose) group, 307 in the AstraZeneca booster (full dose) group, 316 in the Pfizer booster (half dose) group, and 308 in the Pfizer booster (half dose) group. Vaccination-induced immunogenicity to Ancestral, Delta, and Omicron BA.1 strains were evaluated by assessing anti-spike (‘anti-S’), anti-nucleocapsid antibodies, pseudovirus neutralization (‘PVNT’), micro-neutralization titers, and T-cells assays. Within platforms and irrespective of dose or platform, seroconversions were greater than 97%, and greater than 90% for neutralizing antibodies against pseudovirus, but similar against SARS-CoV-2 strains. Anti Spike RBD IgG Geometric means concentration (U/mL) at day 28 were 8237.0 (95% CI, 7679.3-8835.2) for the AstraZeneca half dose group, 8973.6 (95% CI, 8328.1-9669.2) for the AstraZeneca full dose group, 14073.9 (95% CI, 13236.4-14964.4) for the Pfizer half dose group and 15920.7 (95% CI, 15135.7-16746.4) for the Pfizer full-dose group. Pseudovirus Neutralizing Antibody Titer (PVNT50) against Omicron (GMT) were 118.9 (95% CI, 97.3-145.2) for the AstraZeneca full-dose group and 255.9 (95% CI, 222.9-293.7) for the Pfizer full-dose group. Immunogenicity according to Pseudovirus Neutralizing Antibody Titer (PVNT50) against delta variant at day 28 were 468.3 (95% CI, 409.8-535.2) for AstraZeneca half dose group, 530.6 (95% CI, 470.4-598.5) for AstraZeneca full dose group, 801.5 (95% CI, 715.4-897.8) for Pfizer half dose group and 856.1 (95% CI, 777.8-942.1) for Pfizer full-dose group [Suvimol Niyomnaitham, 2022 ].

Effectiveness outcomes
Andrews N et al. was a case-control study (Test-negative) conducted in United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against symptomatic disease, hospitalization, and death in adults in England. The study results showed that the booster dose was associated with an absolute vaccine efficacy from 14-34 days after a Pfizer booster of 94.4% (95% CI 94.1 to 94.7) following either an AstraZeneca or Pfizer primary scheme in individuals 50 years and older. With a Moderna booster, absolute vaccine effectiveness was 97.0 (95% CI 96.0 to 97.8) after an AstraZeneca primary scheme and 94.8% (95% CI 92.7 to 96.3%) Pfizer primary scheme. [Andrews N, 2022 ].

Sritipsukho P et al was a case-control study conducted in Thailand. The study enrolled 3,353 participants. Based on a test negative design of consecutive individuals (age ≥18 years) at-risk for COVID-19 who presented for nasopharyngeal real-time polymerase chain reaction (RT-PCR) testing between 5 July 2021 and 23 October 2021 that were prospectively enrolled and followed up for disease development, the study results showed a vaccine effectiveness with two doses of sinovac+ one dose of Astrazeneca vaccine of 86% (95% CI, 74–93) and with two doses of Sinovac+one dose of Pfizer vaccine of 98% (95% CI, 87–100) [Sritipsukho P, 2022 ].

Silva T et al. was a case-control study conducted in Brazil. The study included 7,314,318 participants: 3,279,280 in the vaccine group and 4,035,038 in the control group. Based on national Brazilian databases, the study assessed the effectiveness of two doses of CoronaVac against confirmed SARS-CoV-2 infection and severe COVID-19 outcomes (hospitalization and death). Also estimated the effectiveness of the BNT162b2 mRNA vaccine as a booster dose. The main results showed that Vaccine effectiveness with booster (BNT162b2) was 92.7% (95% CI 91.0–94.0) 14-30 days after receiving the booster dose. Effectiveness against hospitalization or death with booster (BNT162b2) was 97.3% (95% CI 96.1–98.1) 14–30 days after booster dose [Cerqueira-Silva T, 2022 ].

Mallow C et al. It was a case-control study conducted in the United States. The study analyzed data from 13,203 adult (age ≥ 18 years) visits to the emergency department: 3,134 were fully vaccinated and negative for COVID-19, 108 were fully vaccinated and positive for COVID-19, 8,817 were unvaccinated and were negative for COVID-19, and 1,144 were unvaccinated and were positive for COVID-19. The objective of the study was to evaluate the effectiveness of messenger RNA vaccines against SARS-COV-2 in the emergency department. Data was collected from January 1 to August 25, 2021, from subjects with PCR tests for SARS-COV-2 and symptoms of acute respiratory infection. The main results showed that the effectiveness of the Pfizer vaccine was 73.9% (95% CI: 66.3 to 79.8) [Mallow C, 2022 ].

Tan SHX et al was a comparative cohort study conducted in China. Rates and severity of SARS-CoV-2 infections between September 15 and October 31, 2021, among those eligible to receive vaccine boosters between September 15 and October 15, 2021, were analyzed based on official data reported to the Singapore Ministry of Health. The adjusted incidence rate ratio (2 doses of BNT162b2 plus mRNA-1273 booster) for PCR–confirmed infections was  0.177 (95% CI 0.138 to 0.227) and 0.078 (95% CI 0.011 to 0.560) for severe infection. The Adjusted incidence rate ratio (2 doses of mRNA-1273 plus BNT162b2) for PCR–confirmed infections was 0.140 (95% CI 0.052 to 0.376) [Tan SHX, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants  from November 25, 2021, through January 12, 2022.  The effectiveness of the Pfizer-BioNTech booster after AstraZeneca primary scheme against the Delta variant for symptomatic infection was 88.1% (95% CI 86.7 to 89.3) and 39.6% (95% CI 38.0 to 41.1) for Omicron. The effectiveness of the Pfizer-BioNTech booster after Moderna primary vaccination was 94.7% (95% CI 89.3 to 97.3) against the Delta variant and 64.9% (95% CI 62.3 to 67.3) for Omicron [Andrews N, 2022 ].

Low EV et al. was a retrospective cohort study conducted in Malaysia. The study included 13,840,240 individuals: 5,714,979 with 2 doses BNT162b2, 3,043,620 with 2 doses of CoronaVac, 1,265,436 with 3 doses of BNT162b2, 3,225,428 with 2 doses of CoronaVac plus BNT162b2 booster and 590 777 with 3 doses of CoronaVac. The aim of this study was to compare the odds of symptomatic SARS-CoV-2 infection and COVID-19–related outcomes after heterologous and homologous boosting of CoronaVac at 3-month intervals and homologous boosting of BNT162b2 at 6-month intervals, with BNT162b2 primary series (2 doses) as the reference group. The adjusted odds against symptomatic SAR-CoV-2 infection were lower for individuals who received the primary series CoronaVac plus a BNT162b2 (adjusted odds ratio [aOR], 0.06 [95% CI, 0.05-0.06]), 3 doses of CoronaVac (aOR, 0.08 [95% CI, 0.06-0.10]), or 3 doses of BNT162b2 (aOR, 0.01 [95% CI, 0.00-0.01]). Receipt of heterologous booster (primary series of CoronaVac plus a BNT162b2 booster) was associated with lower odds of SARS-CoV-2 infection (aOR, 0.17 [95% CI, 0.17-0.18]) compared with homologous booster (3 doses of CoronaVac) for individuals aged 60 years and older (aOR, 0.19 [95% CI, 0.19-0.20]) [Low EV, 2022 ].

Young-Xu Y et al. was a case-control study with matched test-negative design conducted in the United States. The study used records and COVID-19 laboratory test data from the Veterans Health Administration (VHA), which includes 1293 healthcare facilities that attend US veterans. Positive tests during January 2022 were presumed to be Omicron SARS-CoV-2 infections. Each case (positive test) was matched with up to four controls (negative tests). Vaccine effectiveness was estimated through the number of infections, hospitalizations, and death within 30 days of a positive test. The vaccine effectiveness (VE) against omicron infection after two mRNA vaccine doses was 12% (95% CI 10 to 15) and increased to 64% (95% CI 63 to 65) after the booster mRNA dose. The VE against hospitalizations was 63% (95% CI 58 to 67) after two mRNA vaccine doses and increased up to 89% (95% CI 88 to 91) after the booster mRNA dose. The VE against death after 2 mRNA vaccine doses was 77% (95% CI 67 to 83) and increased to 94% (CI 95% CI 90 to 96) after the booster mRNA dose [Young-Xu Y, 2022 ].

Vokó Z et al was a comparative cohort study conducted in Hungary. The study population included 8,087,988 individuals who were 18–100 years old at the beginning of the pandemic. This study examined vaccine effectiveness (VE) and durability of primary immunization and single booster vaccinations in the prevention of SARS-CoV-2 infection, Covid-19-related hospitalization, and mortality during the Delta wave, compared to an unvaccinated control population without prior SARS-CoV-2 infection. Adjusted VE against registered SARS-CoV-2 infection during the Delta wave was 70.3% (95% CI 69.2 to 71.3) for primary Pfizer vaccination at 14 to 120 days, and 82.2% (95% CI 81.5 to 82.8) for the homologous booster vaccination (Pfizer/Pfizer) during the Delta wave [Vokó Z, 2022 ].

Sonmezer MC et al was a comparative cohort study conducted in Turkey. The study included 5243 participants: 1047 with two doses of CoronaVac, 3727 with two doses of CoronaVac and one dose of Pfizer, and 469 with three doses of CoronaVac. Effectiveness of the third dose of CoronaVac or BNT162b2 following a two-dose CoronaVac regimen in preventing COVID-19 cases after 14 days was  87.27%(95% CI 84.21 to 89.74) for two doses of CoronaVac and one dose of Pfizer and 58.24% (95% CI 43.43 to 69.17) for Three doses of CoronaVac [Sonmezer MC, 2022 ].

Suphanchaimat R et al was a test-negative case-control study conducted in Thailand. The study included 1,460,458 participants: 482,372 cases and 978,086 controls aimed to explore the vaccine effectiveness (VE) of various schedules against the SARS-CoV2 Delta variant in Thailand during September–December 2021. VE against any infection according to vaccine regimens was: 62.4% (95% CI 59.4 to 65.1) for BNT162b2 + BNT162b2, 88.7% (95% CI 85.6 to 91.1) for ChAdOx1 + BNT162b2, 82.3% (95% CI 74.3–87.7) and 94.0% (95% CI 93.4 to 94.6) for CoronaVac + BNT162b2 [Suphanchaimat R, 2022 ].

Shrotri M et al was a comparative cohort study conducted in England. The study included data from participants from 331 long-term care facilities: 15518 residents aged 65 years or older and 19515 staff aged 18 years or older. This study estimated vaccine effectiveness against SARS-CoV-2 infection, COVID-19-related hospitalization, and COVID-19-related death after one, two, and three vaccine doses, separately by previous SARS-CoV-2 exposure. Vaccine effectiveness against infections for Pfizer heterologous booster dose (AstraZeneca primary schedule and Pfizer booster) was 72.8% (95% CI 51.9 to 84.6) for residents (>65 years) and 76.1% (95% CI 62 to 85) for staff (>18 years).Vaccine effectiveness against hospitalization after heterologous booster dose was 93.5% (95% CI 83.3 to 97.4). [Shrotri M, 2022 ].

Zee ST et al, was a retrospective study was performed to compare the rate and outcome of COVID-19 in healthcare workers with various vaccination regimes during a territory-wide Omicron BA.2.2 outbreak in Hong Kong between 1 February to 31 March 2022 . The study included 3167 healthcare workers. Vaccine effectiveness against infections for Pfizer heterologous booster dose (CoronaVac primary schedule and Pfizer booster)  (HR 0.4862 p = 0.0157) were associated with a lower risk of infection.  [Zee ST, 2022 ]

Yan VKC et al was a case-control study conducted in Hong Kong. The study included 14, 984 participants to evaluate the risk of severe complications following 1-3 doses of CoronaVac and BNT162b2 using electronic health records database. Cases were adults with their first COVID-19-related severe complications between 1 January and 31 March 2022. Vaccine effectiveness heterologus booster doses (Sinovac +  BNT162b2) was 95.2% (95% CI: 80.5-98.8) in those aged ≥65, 88.6% (95% CI: 50.4-97.4)  in those aged 50-64, 73.9% (95% CI: -106.8-96.7)  in those aged 18-50. Further risk reduction with the third dose was observed especially in those aged ≥65 years, against severe complications in the Omicron BA.2 pandemic. [Yan VKC, 2022 ]

Ng OT et al was cohort study conducted in Singapore. The study included 2,441,581 eligible individuals. It was based on data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27th 2021 to March 10th 2022. Effectiveness Heterologous Booster against COVID-19 Infeccion was 35.6% (95%CI 32.8-38.3) (wo doses of Moderna and  booster dose with Pfizer.[Ng OT, 2022 ].

Wan EYF was a case-control study conducted in China. The study included 82,587 cases of COVID-19 infection, 10,241 COVID-19 related hospital admission cases, 539 cases of ICU admission and 135 cases of post-infection incident. This study evaluated the vaccine effectiveness (VE) of each dose of BNT162b2 and CoronaVac against any COVID-19 infection, COVID-19-related hospital admission, ICU admission, and incident cardiovascular disease (CVD) in the Hong Kong Hospital Authority outbreak dominated by Omicron BA.2 sublineage. Vaccine effectiveness against COVID-19 infection was -0.3% (95% CI -2.7 to -2.1) with 2 doses of CoronaVac, 22.1% (95% CI 20.0 to 24.2) with 2 doses of Pfizer, 19.8% (95% CI 17.2 to 22.3) with 3 doses of CoronaVac, 54.2% (95% CI 52.4 to 55.9) with 3 doses of Pfizer, 12.1% (-15.8 to 33.3) with Pfizer primary schedule and CoronaVac booster, and 39.9% (95% CI 36.6 to 42.9) with CoronaVac primary schedule and Pfizer booster. Vaccine effectiveness against COVID-19 hospitalization was 64.2 (95% CI 61.8 to 66.4) with 2 doses of CoronaVac, 74.2 (95% CI 71.7 to 76.4) with 2 doses of Pfizer, 85.4% (95% CI 83.2 to 87.3) with 3 doses of CoronaVac, 91.4% (95% CI 89.5 to 92.9) with 3 doses of Pfizer and 89.5% (95% CI 85.9 to 92.2) with CoronaVac primary schedule and Pfizer booster. [Wan EYF, 2022 ]

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario (Canada) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years), 16,087 were Omicron-positive cases, 4261 Delta-positive cases, and 114 087 were test-negative controls. VE against symptomatic infection was 60% (95% CI, 55-65) for omicron, and 97% (95% CI, 96-98) for delta-related disease. VE for severe COVID-19 was 95% (95% CI 87-98) against Omicron, and 99% (95% CI 98-99) against Delta-related severe disease [Buchan SA, 2022 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of Moderna booster after Pfizer-BioNTech primary schedule was 68.4% (95% CI, 66.2-70.5) after 1 month, the effectiveness of Pfizer-BioNTech vaccine booster after Moderna primary schedule was 
66.1% (95% CI, 61.9-70.0) [Lin DY, 2022 ].

Vivaldi et al conducted a population-based cohort study (COVIDENCE UK) to identify risk factors for SARS-CoV-2 infection after primary and booster vaccinations. This UK study in adults (≥16 years) vaccinated against SARS-CoV-2, assessed the risk of breakthrough SARS-CoV-2 infection up to February 2022, for participants who completed a primary vaccination course (ChAdOx1 nCoV-19 or BNT162b2) and those who received a booster dose (BNT162b2 or mRNA-1273). Primary vaccination with ChAdOx1 (vs BNT162b2) was associated with higher risk of infection in both post-primary analysis (adjusted hazard ratio 1,63, 95% CI 1,41–1,88) and after an mRNA-1273 booster (1,26 [1,00–1,57] vs primary and booster BNT162b2 schedules) [Vivaldi G, 2022 ].

Monge S et al was a nationwide cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no-booster group. The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. The vaccine effectiveness of Pfizer booster after AstraZeneca, Janssen, Moderna, or Pfizer primary schedule was 46.2% (95% CI 43.5–48.7). Vaccine effectiveness of an mRNA booster (Pfizer or Moderna) following a Pfizer primary schedule was 49.7% (95% CI, 48.3–51.1) [Monge S, 2022 ].

Stowe et al. conducted a test-negative case-control study in the UK, to estimate Vaccine Effectiveness (VE) against hospitalization with the Omicron and Delta variants using PCR testing linked hospital records (Emergency Care Data Set; ECDS). The total number of tests in the study period was 409,985 of which 115,720 were cases and 294,265 controls. Vaccine effectiveness against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 18 to 64 years of age of primary schedule BNT162b2 booster mRNA-1273 was 87.3% (95% CI, 81.2-91.3) after 14-34 days and 60.6% (95% CI, 27.7-78.5) after 70+ days.  Vaccine effectiveness against hospital admissions ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 65 years of age and older of primary schedule BNT162b2 booster mRNA-1273 89.0% (95% CI, 17.2-98.5) after 7-13 days and 91.2% (95% CI 75.5-96.9) after 14-34 days. [Stowe J, 2022 ]

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that included 16,208,600 participants, 7,589,080 who received a Pfizer-BioNTech primary schedule and 8,619,520 participants who received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform during the Omicron period between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.43 (95% CI, 0.37-0.50) for the ChAdOx1 primary schedule and Pfizer-BioNTech booster group and 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group. [Agrawal U, 2022 ]

Wan EYF was a case control study conducted in China that included data from 78,326 individuals: 7,293 deaths related to COVID-19 and 71,033 controls. This study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Vaccine effectiveness against COVID-19 infection (60-79 years old) was 20.3% (95% CI, 18.4% to 22.1%), 50.9% (95% CI, 49.6% to 52.1%), -2.9% (95% CI, -24% to 14.6%) and 30.9% (95% CI, 28.5% to 33.2%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. Vaccine effectiveness against COVID-19-related hospitalization was 74.9% (95% CI, 72.6% to 77%), 91.4% (95% CI, 90.1% to 92.5%), 87.4% (95% CI, 59.6% to 96.1%) and 86.9% (95% CI, 84.3% to 89.1%) for 2 Pfizer doses schedule, 3 Pfizer doses schedule, Pfizer primary schedule with CoronaVac booster and CoronaVac primary schedule with Pfizer booster schedule respectively. [Wan EYF, 2022 ]

Cerqueira-Silva T et al, was a case-control study with a test-negative design conducted in Brazil, the study enrolled 2,471,576 participants, including 1,431,108 cases and 1,040,468 controls, including data from the nationwide linked database during the Omicron period in Brazil, including participants who received CoronaVac plus a Pfizer-BioNTech booster, from January to April 2022. The vaccine effectiveness against symptomatic infection was 1.7% (95% CI 0.1 to 3.2) and 89.4% (95% CI 87.8 to 90.7) against severe infection. [Cerqueira-Silva T, 2022 ]

Ranzani O et al was a case-control study (test negative design) conducted in Brazil including 1,386,544 positive antigen/PCR SARS-CoV-2 tests and matched controls. The study estimated the vaccine effectiveness (VE) for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac during the Omicron predominance period. VE against symptomatic COVID-19 for the homologous CoronaVac booster was 8.1% (95% CI, 4.6% to 11.4%) and 57.3% (95% CI, 56.8% to 57.9%) for the Pfizer heterologous booster, measured 8-59 days after the third dose. For hospitalization or death, VE was 86% (95% CI, 71.7% to 93.1%) and 92.1% (95% CI, 90.2% to 93.7%) after 8-59 days of the homologous and heterologous booster schedules, respectively. [Ranzani OT, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness (VE) against ICU admission was 92% (95% CI, 79% to 97%) for the Pfizer schedule + Moderna booster, 100% for the Moderna schedule + Pfizer booster, and 100% for the AstraZeneca schedule + Pfizer booster. [Baum U, 2022 ]

Vaccine safety

Safety of the vaccine in preclinical studies

Risk of DNA modification or infection

The mRNA platform is by definition a non-infectious, non-integrating platform. So, there is no potential risk of infection or insertional mutagenesis. The mRNA component from the vaccine does not enter the nucleus of the cell and does not affect or interact with a person’s DNA. The mRNA is quickly degraded by normal cellular processes [Pardi N, 2018 ].

 

mRNA vaccine pharmacology

Naked mRNA is quickly degraded by extracellular RNase and is not internalized efficiently [Tsui NB, 2002 ].

Several modifications of the mRNA and delivery method [ Kauffman KJ, 2016 ],[Guan S, 2017 ] have been introduced to regulate degradation of mRNA by normal cellular processes, facilitate integration and promote translation, including:

The mRNA is assembled using N1-methyl-pseudouridine (m1Ψ), a nucleoside variant naturally occurring in the body that reduces the response of dendritic cells, interferon-associated genes and other components of the immune system to trigger an inflammatory response. [Annette Vogel, 2020 ].

The use of sequence-engineered mRNA avoids using chemical nucleoside modifications to obtain sufficient protein expression and avoid activation of the innate immune system [Thess A, 2015 ].

The purification of the mRNA component with high performance liquid chromatography results in mRNA that does not induce an inflammatory response and is translated at 10- to 1000-fold greater levels in primary cells [Karikó K, 2011 ] [Karikó K, 2011 ].

 

Allergic reactions

Most immediate allergic reactions associated with vaccines are associated with excipients [Stone CA, 2019 ]. Polyethylene glycols (PEG) are frequently used as excipients in many liquid and solid formulations of medications and are also used to stabilize the lipid nanoparticle containing the mRNA of Pfizer-BioNTech COVID-19 vaccine. There for, PEG constitutes the main candidate for explaining the cause of allergic reactions to this vaccine [Stone CA, 2019 ].

PEG itself has not previously been used in other vaccines but polysorbate, a closely related compound, has been implicated in allergic reactions to other vaccines [Stone CA, 2019 ] [Stone CA, 2019 ].

Safety of the vaccine in clinical trials

Key messages

Pfizer-BioNTech COVID-19 vaccine increase the risk of any adverse events.

Pfizer-BioNTech COVID-19 vaccine increase the risk of serious adverse events.

Main safety outcomes of Pfizer-BioNTech COVID-19 vaccine

Any adverse events (measured at 2 months )

The relative risk of any adverse events in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 2.19 (95% CI 2.1 to 2.28). This means that, in relative terms, Pfizer-BioNTech COVID-19 vaccine increased the risk of any adverse events in 119%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse events. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the available trial, 2638 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21631 presented this outcome (1220 per 10000) versus 5770 out of 21621 in the group that did receive it (2670 per 10000). In other words, 1450 more people per 10000 did develop the outcome because of the vaccine. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 7.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.

Non-serious adverse events

The total number of non-serious adverse events was not reported as a group, so it was not possible to estimate the effect for this outcome.

The most common adverse reactions associated with Pfizer-BioNTech COVID-19 vaccine were fatigue (59% versus 23% among younger vaccine recipients and 51% vs 17% in older recipients%); headache (52% versus 24% among younger vaccine recipients and 39% versus 14% in older recipients) and fever after the second dose (16% among younger vaccine recipients and 11% in older recipients) [Walsh EE, 2020 ].

Serious adverse events (measured at 2 months )

The relative risk of serious adverse events in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 1.14 (95% CI 0.88 to 1.46). This means that, in relative terms, Pfizer-BioNTech COVID-19 vaccine increased the risk of serious adverse events in 14%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: serious adverse events. Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the available trial, 111 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21631 presented this outcome (51 per 10000), versus 126 out of 21621 in the group that did receive it (58 per 10000). In other words, 1 more person per 1000 experienced serious adverse events due to receiving the vaccine. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 1429.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The reason for downgrading the certainty of the evidence is imprecision because of the low number of events and wide confidence interval. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence or publication bias.



Safety of the vaccine in subgroups

Any adverse events (5-15y) (measured at 2 months )

The relative risk of any adverse events (5-15y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 1.12 (95% CI 0.91 to 1.37). This means Pfizer-BioNTech COVID-19 vaccine increased the risk of any adverse events (5-15y) by 12%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse events (5-15y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 136 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 1879 presented this outcome (724 per 10000) versus 234 out of 2649 in the group that did receive it (807 per 10000). In other words, 83 more people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 12%, or that the intervention increased the risk of any adverse events (5-15y) by 12 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 120. Which means that 120 people need to receive the vaccine for one of them to not any adverse events (5-15y).

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high.


Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the C4591001 trial was 49.4% (18631 out of 37706 participants) [Polack, Fernando P., 2020 ].

The proportion of females that experienced adverse effects with Pfizer-BioNTech COVID‑19 Vaccine versus the group that received placebo vaccine was not reported in detail. However, no specific safety concerns were identified in this subgroup.

Other comparative studies
The phase 4, non-randomized study Shieldvacc2 is currently evaluating the effectiveness/safety of the vaccine in women of child-bearing potential using contraception, 12 years of age and older, vaccinated with two-doses of Comirnaty [Medizinische Universität Innsbruck, Institut für Virologie, 2021 ].

Dagan et al. report an increased risk of myocarditis mostly among young male adolescents and adults (16 to 39 years of age), with 8.62 excess events per 100,000 persons (95% CI,  2.82 to 14.35) among vaccinated individuals [Dagan N, 2021 ].

Li LL et al. included 3,118,802 participants who had received one dose of a SARS-CoV-2 mRNA vaccine and 2,979,326 who had received two doses (1,389,401 Pfizer and  1,589,925 Moderna). Data were collected during the period from December 12, 2020, to August 21, 2021. The study results showed that, Overall, two-dose mRNA vaccine regimens are safe in a population with many comorbidities.  Weakness, muscle aches, fever, mental status changes, falls, dehydration and acute kidney injury were transiently increased after vaccination, especially after the second dose. Among patients with prior SARS-CoV-2 infection, there was an increased risk of hospitalization (absolute risk 1:1000).

Age
Randomized trials
The proportion of patients >55 years in study C4591001 was 25% (15,921 of 37,706 participants) [Polack, Fernando P., 2020 ].

Pain at the injection site was the most commonly reported local reaction, and occurred more frequently in the younger group (participants 16-55 years of age) than in the older group (>55 years of age) [FDA, 2020 ].

Systemic adverse events were more frequently reported in the younger group compared with the older age group. Across all age groups, systemic adverse events resolved within a median duration of 1 day [Polack, Fernando P., 2020 ].

The phase 3, randomized, double-blind trial B7471026 is currently evaluating the efficacy/safety of the vaccine in vaccinated adults 65 years of age and older [Pfizer, 2021 ].
            
The proportion of participants 65-85 years in the BNT162-03 was 50% (72 out of 144 participants) [Li J, 2021 ].
           
In the 65-85 years old group, 83% of participants in the 10 µg BNT162b1 dose group, 92% of participants in the 30 µg BNT162b1 dose group, and 8% of participants in the placebo group reported at least one solicited adverse reaction. Reactogenicity was dose-level dependent and was most evident in the group receiving 30 µg, BNT162b1. Older participants did not have increased reactogenicity after the BNT162b1 boost dose [Li J, 2021 ]. 
        
Grade 3 fever was reported in 8% of older participants who received 30 µg BNT162b1. One male participant in the older age group experienced an episodic grade 3 fever accompanied by pain and pruritus at the injection site after the prime BNT162b1 dose at 30 µg and electively withdrew before receiving the boost vaccination   [Li J, 2021 ].

Other comparative studies
The interventional, non-randomized study COGEVAX-BIO is currently evaluating the effectiveness/safety of the vaccine in people over age 75 institutionalized in the long-term care units [Gérond'if, 2021 ].

The non-randomized study Covid-19-Abs is currently evaluating the effectiveness/safety of the vaccine in residents and staff associated with nursing homes, extended care facilities, and over 55 communities [Dr. Sidney J. Stohs, 2021 ].
    
Dagan et al. report an increased risk of myocarditis mostly among young male adolescents and adults (16 to 39 years of age), with 8.62 excess events per 100,000 persons (95% CI,  2.82 to 14.35) among vaccinated individuals [Dagan N, 2021 ].

Li LL et al. included 3,118,802 participants who had received one dose of a SARS-CoV-2 mRNA vaccine and 2,979,326 who had received two doses (1,389,401 Pfizer and  1,589,925 Moderna). Data were collected during the period from December 12, 2020, to August 21, 2021. The study results showed that, Overall, two-dose mRNA vaccine regimens are safe in a population with many comorbidities.  Weakness, muscle aches, fever, mental status changes, falls, dehydration and acute kidney injury were transiently increased after vaccination, especially after the second dose. Among patients with prior SARS-CoV-2 infection, there was an increased risk of hospitalization (absolute risk 1:1000).

Chen PY et al. was a comparative cohort study that included 30,832 people who received booster doses in the Taipei Veterans General Hospital.  The study analyzed the reported incidence rate, and factors associated with adverse events, including short-term serious adverse events and short-term non-serious adverse events, among different vaccine products through the hospital-based Vaccine Adverse Event Reporting System. A total of 7,432 records were collected during the three-month study period.  Respondents under 39 years of age had a higher incidence rate of adverse events (61.9%) than those between 40 and 64 years of age (48.7%), and those over 65 years of age (26.3%). The incidence of adverse events in Moderna COVID-19 vaccine is higher than in Pfizer COVID-19 vaccine and MVC-COV1901 (IRR Moderna vs. Pfizer COVID-19 vaccine: 1.22, 95% CI: 1.11 to 1.34; Pfizer COVID-19 vaccine vs. MVC-COV1901: 2.77, 95% CI: 2.27 to 3.3 [Chen PY, 2022 ]

Children and adolescents
Randomized trials
In the phase 2/3 components of the C4591001 trial, reactogenicity was measured in a subset that included 8183 participants (≥12 years of age). Reactogenicity data were collected by participants’ e-diary reporting local reactions and systemic events for 7 days after each dose.
This preliminary data provides support of safety on adolescents 12 to 15 years of age [FDA, 2020 ].

Younger adolescents 12 to 15 years of age (49/100 in the vaccine group and 51/100 in the placebo group) contributed to a preliminary reactogenicity data analysis. In this age group, pain at the injection site was the most frequent local reaction, reported in 71.4% of participants in the vaccine group, compared to 17.6% in the placebo group after Dose 1 [FDA, 2020 ].

Most systemic events in younger adolescents were mild to moderate in severity. Severe events were relatively infrequent in both groups, occurring in no more than 1 or 2 participants after either dose [FDA, 2020 ]

The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants)  [Frenck RW, 2021 ]. 
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants)  [Frenck RW, 2021 ].
In both age cohorts (12-5 years and 16-25 years), BNT162b2 recipients reported more local events than placebo recipients. Local events were generally mild to moderate in severity, reported at similar frequencies in both age cohorts ), and typically resolved within 1 or 2 days. Injection-site pain was the most common local reaction in all groups. Severe injection-site pain after any BNT162b2 dose was reported in 1.5% of 12-to-15-year-old participants and in 3.4% of 16-to-25-year-old participants; no severe pain was reported after placebo administration  [Frenck RW, 2021 ].
In both age cohorts (12-5 years and 16-25 years), headache and fatigue were the most frequently reported systemic events. After BNT162b2 injection, severe headache and severe fatigue were reported in a lower percentage of 12-to-15-year-old participants than of 16-to-25-year-old participants. Fever with a temperature ≥38°C occurred after the second dose of BNT162b2 in 20% of 12 to 15-year-old recipients and in 17% of 16 to 25 years old recipients. Fever with a temperature higher than 40°C occurred 1 day after the first dose of BNT162b2 in 0.1% of the 12-to-15-year-old participants [Frenck RW, 2021 ].

Other comparative studies
C4591007 is an ongoing non-randomized study evaluating the safety in healthy children ages 12 years and less [BioNTech SE, 2021 ]
The non-randomized study COVA is currently evaluating the effectiveness/safety of the vaccine in healthy or clinically stable participants aged 11 years and older [The University of Hong Kong, 2021 ].

Cheng DR  et al was a comparative study conducted in Australia. The study included 454,974 12 to 17 years old participants who had received 871,689 mRNA doses (782,964 Pfizer and 88,725 Moderna). The aim was to describe myocarditis adverse events following any COVID-19 mRNA vaccines in the adolescent population. Confirmed myocarditis reporting rates were 8.3 per 100 000 doses in this age group (aggregated data for both mRNA vaccines) [Cheng DR, 2022 ].

CoVacU5 was a retrospective cohort study conducted in Germany that included 7,806 children younger than 5 years old who received 3 to 10 μg of the BNT162b2 vaccine. The study aimed to report short-term safety data in children from birth to younger than 60 months. In the active-comparator analysis of symptoms occurring after Pfizer-BioNTech vaccination versus non-Pfizer-BioNTech vaccination showed ORs of 1.62 (95% CI, 1.43-1.84) for any symptoms, 1.68 (95% CI, 1.38-2.05) for local injection-site symptoms, 2.55 (95% CI, 1.32-4.94) for musculoskeletal symptoms, 2.18 (95% CI, 10.7-4.45) for dermatologic symptoms and 6.37 (95% CI, 1.50-27.09) for otolaryngological symptoms. [Toepfner N, 2022 ].
    
Pregnancy
Randomized trials
A total of 23 participants reported pregnancy during the trial. Nine of them withdrew from the study but the follow-up on these participants continues in order to assess pregnancy outcomes [Polack, Fernando P., 2020 ].

C4591015 is an ongoing phase 2/3, randomized trial evaluating the safety in this subgroup [BioNTech SE, 2021 ].
     
Other comparative studies 
Shimabukuro et al. (CDC report) was a safety monitoring non-comparative study that enrolled 16,439 pregnant women that received Moderna or Pfizer COVID-19 vaccine. Results showed that the most frequent local and systemic reactions wer: 95.6% injection-site pain, 80.6% fatigue, 65.0% headache, 46.0% fever or felt feverish. Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported (Data based on 827 participants in the v-safe pregnancy registry who received an mRNA Covid-19 vaccine, BNT162b2 or mRNA-1273). Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases) [Shimabukuro TT, 2021 ].

An analysis of the CDC v-safe COVID-19 Pregnancy Registry in 19,252 pregnant people who received the vaccine did not show obvious safety signals [Shimabukuro TT, 2021 ].

Nakahara A et al.  included 83 vaccinated pregnant women that received mRNA COVID-19 vaccines (Moderna or Pfizer). These pregnant women were age-matched with 166 female controls. Safety was assessed as any vaccine-related complaint as defined in the original safety data. Results showed a frequency of complaint following vaccine administration of  18.1% in the pregnant group and  16.9% in the non-pregnant group. The most frequent local and systemic reactions in Pregnant females were:  fever 4.8%, Cough/Shortness of Breath 4.8 %, Vomiting/Diarrhea 4.8%. Complaint frequency was higher after the second dose (12.3 %) than after the first dose (6%) [Nakahara A, 2022 ].

Aharon D et al. included 222 vaccinated (Pfizer =119 or Moderna =103) patients and 983 unvaccinated patients who underwent controlled ovarian hyperstimulation cycles between February and September 2021. Data collected included oocyte, fertilization, and embryo development parameters, as well as results of preimplantation genetic testing for aneuploidy among cycles in which testing was performed. The study showed that the administration of Pfizer or Moderna COVID-19 vaccine was not associated with an adverse effect on stimulation or early pregnancy outcomes after in vitro fertilization. The fertilization rate for the controlled ovarian hyperstimulation cohort was  80.7% (95% CI 78.4 to 83.0) in the vaccinated group and 78.7% in unvaccinated groups (95% CI 77.5 to 80.0). No differences were observed between vaccinated and unvaccinated patients on univariate analysis in the secondary outcomes of eggs retrieved, mature oocytes retrieved, mature oocytes ratio, or blastulation rate. In cycles in which preimplantation genetic testing for aneuploidy was performed, vaccinated patients had a proportion of euploid embryos of 48.8% (95% CI 44.1 to 53.6) compared with 42.5% (95% CI 40.2 to 44.9) in unvaccinated patients [Aharon D, 2022 ].

Montalti M et al. was a cross-sectional study that enrolled 600 female physicians aged from 24 to 60  years old; 131 pregnant and 469 breastfeedings that received Moderna or Pfizer COVID-19 vaccine. Results showed that 16  of the 31 immunized pregnant women,  reported at least one symptom after the first, and 14  after the second vaccine dose. After the first dose, 64.5% had nausea/vomiting, 25.8% fatigue, and 12.9% headache and arthralgia/myalgia; flushing and low back pain were rare. After the second dose, 76.5% of respondents had nausea/vomiting, 70.6% fatigue, and 41.2% arthralgia/myalgia [Montalti M, 2022 ].

Botton J et al. was a self-controlled case series conducted in France. The study included participants  (8,358  first dose of ChAdOx1; 4,887 Second dose of ChAdOx1; and5 third ChAdOx1 dose) aged 18 to 74 years hospitalized for pulmonary embolism, acute myocardial infarction, hemorrhagic stroke, or ischemic stroke between December 27, 2020, and December 20, 2021. This study assessed the short-term risk for severe cardiovascular events after COVID-19 vaccination in France's 46.5 million adults. The primary outcome was hospitalizations for cardiovascular events (Myocardial infarction, pulmonary embolism, or stroke). There was an increase in the incidence of myocardial infarction and pulmonary embolism after adenoviral-based vaccines (ChAdOx1 nCoV-19 vaccine). The RI during the second week after the dose of the ChAdOx1 vaccine for Myocardial Infarction was 0.84 (95% CI, 0.53-1.34),  1.29 (95% CI, 0.94-1.78) for Pulmonary Embolism,  0.88 (95% CI, 0.69-1.12) for  Ischemic Stroke, and  1.36 (95% CI, 0.89-2.07) for  Hemorrhagic Stroke [Botton J, 2022 ].

Rottenstreich et al conducted a multicenter retrospective study. Parturients who delivered in Israel between August and December 2021 with complete records of COVID-19 disease and vaccination status were included. A total of 2583 women were included in the analysis: 626 received the third booster dose of the BNT162b2, 1094 received two doses of the vaccine, and 863 were unvaccinated. Receiving the third booster was not associated with an increase in either composite adverse maternal or neonatal outcome (aOR 0.9; 95% CI [0.65–1.22], p= 0.47; aOR 0.7; 95% CI [0.53–1.035], p=0.09, respectively) when compared to those who received two doses of the vaccine. Administration of the third booster dose during pregnancy was associated with a reduced composite adverse neonatal outcome compared to unvaccinated women (aOR 0.6; 95% CI [0.42–0.86], p=0.01) [Rottenstreich M, 2022 ].

Kachikis et al analyzed a convenience sample of adults enrolled in the online prospective study. Participants who were pregnant, lactating, or neither pregnant nor lactating at the time of their booster or third dose were eligible for this follow-up survey; 17,014 (97.2%) completed the follow-up survey. 16,989 individuals reported their vaccine type for booster or third dose, most of them received the BNT162b2 (10,319 [60.7%]) or mRNA-1273 (6651 [39.2%]) vaccines. After a COVID-19 booster or third dose, 82.8% reported a local reaction, and 67.9% reported at least 1 systemic symptom. Compared with individuals who were neither pregnant nor lactating, pregnant participants were more likely to report any local reaction to a COVID-19 booster or third dose (aOR 1.2, 95% CI, 1.0-1.4; p = 0.01) but less likely to report any systemic reaction (aOR 0.7, 95% CI, 0.6-0.8; p<0.001). Most pregnant (1961 of 2009 [97.6%]) and lactating (9866 of 10,277 [96.0%]) individuals reported no obstetric or lactation concerns after vaccination. aOR = adjusted odds ratio [Kachikis A, 2022 ]

Sadarangani M et al was a cohort study conducted in Canada. This study aimed to determine the frequency and nature of significant health events among pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals. Data were collected primarily by self-reported survey after both vaccine doses. Most pregnant participants had received BNT162b2 (3414 received dose one and 1892 received dose two) or mRNA-1273 (2183 received dose one and 1216 received dose two) COVID-19 vaccines. Pregnant vaccinated females had decreased odds of a significant health event compared with non-pregnant vaccinated females after both dose one (aOR 0.63 95% CI 0.55 to 0.72]) and dose two (aOR 0.62 [0.54 to 0.71]) of any mRNA vaccination. Pregnant vaccinated females had an increased odds of a significant health event within 7 days of the vaccine after dose two of mRNA-1273 (adjusted odds ratio 4.4 95% CI 2.4 to 8.3]) compared with pregnant unvaccinated controls and 1.3 (95% CI 0.67 to 2.42) after the second dose of Pfizer vaccine. [Sadarangani M, 2022 ].

DeSilva et al. was a retrospective matched-cohort study including 45,232 pregnant women between 16-49 years, who received Pfizer-BioNTech, Moderna or Janssen vaccines and matched unvaccinated controls. The adjusted Rate Ratios (aRR) for acute maternal outcomes during days 0-21 after receiving Pfizer-BioNTech vaccines were 1.71 (95% CI, 1.08-2.7) for skin and soft tissue or local allergic reactions, 1.87 (95% CI, 0.96-3.65) for fever, 1.77 (95% CI, 1.22-2.56) for malaise and 2.39 (95% CI, 1.37-4.17) for lymphadenopathy. [DeSilva M, 2022 ]

Breastfeeding
Randomized trials
Breastfeeding females were excluded from the C4591001 trial, so no data are available for this subgroup [Polack, Fernando P., 2020 ].

Other comparative studies
The cohort O'Connor DL et al is currently evaluating the effectiveness/safety of the vaccine in lactating mothers [Deborah O'Connor, 2021 ].
    
Golan et al. was a prospective cohort study that enrolled 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Results showed no severe maternal or infant adverse effects. Vaccine-related products, PEGylated proteins, were not found at significant levels in milk after vaccination [Golan Y et al., 2021 ].

Kachikis et al . analyzed a convenience sample of adults enrolled in the online prospective study. Participants who were pregnant, lactating, or neither pregnant nor lactating at the time of their booster or third dose were eligible for this follow-up survey; 17,014 (97.2%) completed the follow-up survey. 16,989 individuals reported their vaccine type for their booster or third dose, most received the BNT162b2 (10,319 [60.7%]) or mRNA-1273 (6651 [39.2%]) vaccines. After a COVID-19 booster or third dose, 82.8% reported a local reaction, and 67.9% reported at least 1 systemic symptom. Compared with individuals who were neither pregnant nor lactating, pregnant participants were more likely to report any local reaction to a COVID-19 booster or third dose (aOR 1.2; 95% CI, 1.0-1.4; p = 0.01) but less likely to report any systemic reaction (aOR 0.7; 95% CI, 0.6-0.8; p<0.001). Most pregnant (1961 of 2009 [97.6%]) and lactating (9866 of 10,277 [96.0%]) individuals reported no obstetric or lactation concerns after vaccination. aOR = adjusted odds ratio [Kachikis A, 2022 ]

Montalti M et al. was a cross-sectional study that enrolled 600 female physicians aged from 24 to 60  years old; 131 pregnant and 469 breastfeedings that received Moderna or Pfizer COVID-19 vaccine. Among 315 immunized breastfeeders, 75.2% (n = 237) reported at least one symptom after the first dose, and 81.6% (n = 142) after the second. The most common adverse events occurring after the first dose were nausea/vomiting (60%), fatigue (28.3%), and headache (26.3%). Rarer events included dizziness, shivering, and limb paresthesia. After the second dose, 51.1% of them reported nausea/vomiting, 48.9% fatigue, and 49.4% arthralgia/myalgia [Montalti M, 2022 ].

Persons with comorbidities
Randomized trials
Available data are currently insufficient to assess safety in individuals with comorbidities.

Other comparative studies
The phase 4, non-randomized study HHCTC_COVID-19_VACCINE_Ab is currently evaluating the effectiveness/safety of the vaccine in adults with chronic liver disease or Underlying CLD, aged 18 years and older [Humanity & Health Medical Group Limited, 2021 ].

Apaydin H et al. was a cross-sectional study that enrolled 450 Behçet syndrome patients followed in a clinic who met the criteria of the International Study Group that received the Pfizer or Sinovac COVID-19 vaccine. 287 patients received at least one dose of the COVID-19 vaccine. Adverse events were reported by 151 (52.6%) patients after the first dose, 135 (49.4%) after the second vaccine dose, 29 (42.6%) after the third vaccine dose, and 3 (30%) patients after the fourth vaccine dose. Injection site pain/swelling was the most common adverse effect at all vaccine doses, followed by fatigue, and arthralgia [Apaydin H, 2022 ].

Immunocompromised persons
Randomized trials
The phase 4, a single-center, open-label, investigator-initiated randomized controlled, superiority trial BECAME is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [dafna yahav, 2021 ].

The phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial COVERALL is currently evaluating the efficacy/safety of the vaccine in patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study [University Hospital, Basel, Switzerland, 2021 ].

The phase 2, randomized, single-blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].
           
Other comparative studies
The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna and Astra-Zeneca vaccines [University Hospital, Strasbourg, France, 2021 ].

The non-randomized study COVAC-IC is currently evaluating the effectiveness/safety of the vaccine in immunocompromised and immunocompetent haematology patients aged 18 years and older [University Hospitals of North Midlands NHS Trust, 2021 ].

The monocentric observational study ANTICOV is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older, to evaluate the effectiveness of BNT162b2 or mRNA-1273 vaccine [Azienda Socio Sanitaria Territoriale di Cremona, 2021 ].

The non-randomized study UNICO is currently evaluating the effectiveness/safety of the vaccine in cancer patients aged 18 years and older [Ente Ospedaliero Ospedali Galliera, 2021 ].

The non-randomized study COViNEPH-1 is currently evaluating the effectiveness/safety of the vaccine in patients on chronic dialysis vaccinated with BNT162b2 [Medical University of Gdansk, 2021 ].

The prospective, cohort, non-interventional, single-center clinical study ImmunoHaema-COVID-VAX-21 is currently evaluating the effectiveness/safety of the vaccine in patients with haematological malignancies 18 years of age and older [Ospedale di Circolo - Fondazione Macchi, 2021 ].

The phase 2, non-randomized study C4591024 is currently evaluating the effectiveness/safety of the vaccine in immunocompromised participants ≥2 Years Of Age [BioNTech SE, 2021 ].

The non-randomized study IROC is currently evaluating the effectiveness/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].

The non-randomized study LymphVAX is currently evaluating the effectiveness/safety of the vaccine in women with a history of breast cancer [Massachusetts General Hospital, 2021 ].

The non-randomized study VIOLA is currently evaluating the effectiveness/safety of the vaccine in COVID-negative Multiple Sclerosis patients treated with ocrelizumab [NYU Langone Health, 2021 ].

The phase 4, non-randomized study Covid Vaccin Allo is currently evaluating the effectiveness/safety of the vaccine in patients allo-hematopoietic cell transplantation recipients [University of Liege, 2021 ].

The non-randomized study VAX4FRAIL is currently evaluating the effectiveness/safety of the vaccine in frail subjects with impaired immuno-competence, due to their underlying diseases or ongoing therapies that received SARS-CoV-2 with Pfizer-BioNTech or Moderna vaccines [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].

The phase 4, non-randomized study EREVA is currently evaluating the effectiveness/safety of the vaccine in adults immunocompromised or non-immunocompromised volunteers [Centre Hospitalier Régional d'Orléans, 2021 ].

The phase 1 and 2, interventional, non-randomized study PACIFIC is currently evaluating the effectiveness/safety of the vaccine in children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old) [Assistance Publique - Hôpitaux de Paris, 2021 ].

The non-randomized study CPAT is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

Shulman et al. was a comparative study conducted in the United States [Shulman RM, 2022 ], which recorded short-term adverse reactions to the COVID-19 vaccine in patients with cancer; it also compared the magnitude and duration of these reactions with those of patients without cancer and determined whether these adverse reactions are related to active cancer therapy. The study included patients with and without a history of cancer at an NCI-designated Comprehensive Cancer Center between February 16, 2021 and May 15, 2021. Post-vaccination symptoms were common and reported with similar frequencies by patients with and without cancer (73.3% vs 72.5%). There were no significant differences between patients with and without cancer in the frequency of adverse events when responses to the first and second vaccine dose were tabulated separately (dose 1: 61.3% vs 60.2%; dose 2: 64.2% vs 62.8%). The adverse event profile for patients with cancer receiving active treatment did not differ by treatment type for either dose 1 or dose 2. The authors suggest that the mRNA COVID-19 vaccine is well tolerated by patients with a history of cancer, including those receiving active treatment. Adverse events occurring shortly after vaccination closely resemble those seen in patients without cancer [Shulman RM, 2022 ].

Vinante L et al. was a comparative cohort that included 361 patients with 756 administered COVID-19 vaccinations (Pfizer:529 doses; Moderna: 194 doses; AstraZeneca: 28 doses; Janssen 5 doses). The study assessed the incidence of radiation recall dermatitis after COVID-19 vaccination in breast cancer patients previously treated with postoperative radiation therapy. Results showed that breast symptoms were reported by 7.5% of patients, while radiation recall dermatitis was considered for 5.5%. Radiation recall dermatitis was more common in the first dose compared to the second (4.4%) or third (1%), especially when administered within the first month after irradiation (12.5% vs 2.2%). Symptoms were generally self-limited, and anti-inflammatory medications were required in a few cases [Vinante L, 2022 ].

Persons living with HIV
Randomized trials
Available data are currently insufficient to assess safety in persons living with HIV.

Safety of the vaccine post-authorization

Comparative post-authorization studies
Albalawi O et al. was a study conducted in the United States. The study enrolled the general population that received Pfizer-BioNTech, Moderna, and Janssen vaccines. Based on data from Vaccine Adverse Event Reporting System (VAERS) between 15 December 2020 to 19 March 2021. Total non-serious reporting rate was 34.8 per 100,000 doses administered and total serious reporting rate was 5.4 per 100,000 doses administered. Results of the study showed that the Moderna group had more deaths than the Pfizer-BioNTech group (7% 95% CI-14% to 33%). [Albalawi OM, 2021 ].

Maxime Taquet et al. was a retrospective cohort study conducted in the United States. The study enrolled 537 913 participants: 389,034 with COVID-19 and 389,034 with mRNA vaccine. The aim was to estimate the absolute risk of cerebral venous thrombosis (CVT) and portal vein thrombosis (PVT) in the two weeks following a diagnosis of COVID-19, and to assess the relative risks (RR) compared to influenza or the administration of an mRNA vaccine against COVID-19. Relative Risk (RR) for cerebral sinus and venous thrombosis (CVT) was RR 6.33 (95% CI, 1.87-21.4) for Pfizer or Moderna vaccine versus COVID-19 (control) and RR 2.67 (95% CI, 1.04-6.81) for Pfizer or Moderna vaccine versus Influenza (control). Relative risk of Portal vein thrombosis (PVT) was RR 4.46 (95% CI, 3.12-6.37) for Pfizer or Moderna vaccine versus COVID-19 (control) and RR 1.43 (95% CI, 1.10-1.88) for Pfizer or Moderna vaccine versus Influenza (control) [Taquet M, 2021 ].

Barda N, 2021 reported an observational study conducted in Israel. 1,736,832 individuals aged 16 years or older were included in this study to evaluate the safety of the BNT162b2 mRNA vaccine. Results showed that vaccination was most strongly associated with an elevated risk of myocarditis RR 3.24 (CI 95% 1.55 to 12.44), lymphadenopathy RR 2.43 (CI 95% 2.05 to 2.78), appendicitis RR 1.40 (CI 95% 1.02 to 2.01), and herpes zoster infection RR 1.43  (CI 95% 1.20 to 1.73). On the other hand, SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis RR 18.28   (CI 95% 3.95 to 25.12) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia [Barda N, 2021 ].


Hippisley-Cox J et al. is a comparative study conducted in England. The study enrolled 29,121,633 patients with the first dose of Ox-AstraZeneca, Pfizer vaccines or with a positive test of SARS-CoV-2. Based on data from electronic health records, the Office for National Statistics and the United Kingdom's health service (NHS) between 1 December 2020 and 24 April 2021. The authors compared the incidence rate ratio (IRR) pre-post vaccination. The results of the study showed that the Pfizer vaccine had an increased risk of thrombocytopenia (IRR 1.08 95%CI 0.94 to 1.23), lower risk of venous thromboembolism (IRR 0.89 95%CI 0.81 to 0.99) and had no difference in arterial thromboembolism (IRR 1,02 95%CI 0.95 to 0.99). [Hippisley-Cox J, 2021 ]
 

Mevorach D. et al. was a retrospective cohort study carried out in Israel. This study was based on electronic data from the Ministry of Health database including clinical and laboratory records from December 20, 2020, until May 31, 2021. Among the 9,289,765 participants, 5,442,696 received the first COVID-19 vaccine and 5,125,635 received two doses. Myocarditis was confirmed in 283 cases, which included 142 cases that occurred after vaccination. The rate ratio 30 days after the second dose was 2.35 (95% CI, 1.10 to 5.02) in fully vaccinated recipients compared with unvaccinated participants. The rate ratio was higher in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83) with a ratio of 1 in 6637 [Mevorach D, 2021 ].

Wan EYF et al. was a Nested case-control study conducted in China. The study enrolled 1,479 participants, with 45 participants receiving Pfizer-BioNTech vaccine and was based on data from electronic helth records from the voluntary surveillance hospital system, between February 23 and May 4, 2021. The study results showed an adjusted Odds Ratio (OR) of 1.76 (95%CI 0.88–3.47) for Bell’s Palsy in the vaccineted group. [Wan EYF, 2021 ]

Magnus MC et al. was a case control study conducted in Norway. The study enrolled 13,956 participants, with 609 participants receiving Pfizer-BioNTech vaccine and was based on data from Norwegian registries on first-trimester pregnancies, Covid-19 vaccination, background characteristics, and underlying health conditions of all women who were registered between February 15 and August 15, 2021. The study results showed an adjusted Odds Ratio (OR) for Miscarriage of 0.80 (95%CI 0.67 to 0.96) in vaccinated individuals. 253b825b5abd617b646045615aeedaf6bce11ab8]

Kharbanda EO et al. was a case control study conducted in United states. The study enrolled 105 ,446 participants and was based on a validated pregnancy algorithm, which incorporates diagnostic and procedure codes and electronic health record from 8 health systems data to identify and assign gestational ages for spontaneous abortions and ongoing pregnancies, between December 15, 2020, and June 28, 2021. The study results showed an adjusted Odds Ratio (OR) for spontaneous abortions of 1.03 (95%CI 0.95 to 1.11) in vaccinated individuals [Kharbanda EO, 2021 ]

Patone M et al was a case control study conducted in United Kingdom. The study enrolled 32,552,534 participants, with 12,134,782 receiving Pfizer-BioNTech vaccine. Based on The English National Immunisation (NIMS) Database of COVID-19 vaccination, authors linked individual patient data to national data for mortality, hospital admissions and SARS-CoV-2 infection data between 1 December 2020 and 31 May 2021 with the objective of assessing the associations between the first dose of ChAdOx1nCoV-19 or BNT162b2 vaccines and neurological complications. The study results showed an incidence rate ratio (IRR) of 1.02 (95%CI 0.75 to 1.40) for Acute CNS demyelinating events, of 1.14 (95%CI 0.86 to 1.51) for encephalitis, meningitis and myelitis, of 0.86 (95%CI 0.54 to 1.36) for Guillain–Barré syndrome, of 1.06 (95%CI 0.90 to 1.26) for Bell’s palsy, of 1.18 (95%CI 0.88 to 1.59) for myasthenic disorder, of 1.24 (95% CI 1.07 to 1.43)  for Hemorrhagic stroke and of 1.05 ( 95%CI 0.84 to 1.30) for subarachnoid hemorrhage in vaccinated individuals. [Patone M, 2021 ]

Shibli R et al. was a cohort study conducted in Israel. The study enrolled 2,434,674 participants and was based on data from the computerized database of Clalit Health Services (CHS) of Israel, between 20 December 2020 and 30 April 2021. The study results showed a Standardized incidence ratio (SIR) after 1st dose of 1.36 (95%CI 1.14 to 1.61) and of 1.16 (95%CI 0.99 to 1.36) after the 2nd dose for Bell’s palsy in vaccinated individuals [Shibli R, 2021 ].

Shemer A et al. was a case control study conducted in Israel. The study enrolled 111 participants, with 65 received Pfizer-BioNTech vaccine. The study was based on data from the emergency department of a tertiary referral center in central Israel, between January 1 to February 28, 2021, with the objective of assessing whether the BNT162b2 vaccine is associated with an increased risk of acute-onset peripheral facial nerve palsy. The study results showed an Adjusted odds ratio of 0.84 (95%CI 0.37 to 1.90) for Facial nerve palsy in vaccinated individuals [Shemer A, 2021 ].

Edelman A et al. was a cohort study conducted in the United States. The study enrolled 3,959 participants: 2,403 vaccine group (55% Pfizer, 35% Moderna, 7% Janssen); 1,556 control group. Based on prospectively tracked menstrual cycle data using the application "Natural Cycles”, between October 2020 and September 2021, the study assessed whether coronavirus disease 2019 (COVID-19) vaccination is associated with changes in cycle or menses length in those receiving vaccination as compared with an unvaccinated cohort. The study results showed a change in menstrual cycle length of less than 1 day compared with prevaccine cycles. The study also reports a mean change of 0.64 days, (98.75% CI 0.27-1.01) after the first dose and a mean change of 0.79 days, (98.75% CI 0.40-1.18) after the second dose when comparing with unvaccinated individuals [Edelman A, 2022 ].

Wesselink AK et al. was a cohort study conducted in the United States and Canada. The study enrolled 2,126 participants: 1,299 vaccine group; 897 control group. Based on questionnaires on sociodemographics, lifestyle, and reproductive and medical histories with follow-up every 8 weeks during December 2020-September 2021 and followed them through November 2021, the study objective was to examine the associations of female and male COVID-19 vaccination with fecundability, the per-cycle probability of conception. The study results showed that COVID-19 vaccination was not appreciably associated with fecundability, with a female Fecundability Rate (FR) of 1.08 (95% CI 0.95 to 1.23) and a male FR=0.95 (95% CI 0.83 to 1.10) in vaccinated individuals [Wesselink AK, 2022 ].

Tsun Lai FT et al. was a case-control study conducted in China. The study enrolled 1,693 participants: 152 vaccine group; 1,541 control group. Based on health care records provided by the Hospital Authority (HA) of Hong Kong that were linked with population-based vaccination records at the Department of Health to allow identification of vaccination status as of 2 August 2021 with the objective of examining the association of BNT162b2 and CoronaVac vaccination with carditis, the study results showed an adjusted odds ratio (OR) for Carditis of 3.57 (95% CI 1.93 to 6.60) in vaccinated individuals [Tsun Lai FT, 2022 ].

Sing CW et al. was a case-control study conducted in China. The study enrolled 3,983,529 participants: 1,643,419 vaccine group; 2,340,110 control group and was based on data from the Hong Kong Hospital Authority and the Department of Health between 1 January 2018 and 31 July 2021, with the objective of evaluating the association between COVID-19 vaccines (CoronaVac and BNT162b2) and hematological abnormalities. The study results showed a risk of thrombocytopenia of OR 0.79 (95% CI 0.56 to 1.12), a risk of leukopenia of OR 0.91 (95% CI 0.58 to 1.42) and a risk of neutropenia of OR 0.60 (95% CI 0.25 to 1.46) in vaccinated individuals [Sing CW, 2022 ].

Lai FTT et al. was a retrospective cohort study conducted in China. The study enrolled 3,983,529 participants: 1,643,419 vaccine group; 2,340,110 control group. Based on electronic medical records of patients aged 16 years or older provided by the sole provider of public inpatient services in Hong Kong, between 1 January 2018 and 31 July 2021, the study objective was to examine the association between vaccination and the risk of AESI 28-day post-vaccination as well as the effect modification by multimorbidity status. The study results showed a Hazard Ratio (HR) for adverse events of 0.66 (95%CI 0.58 to  0.75) in vaccinated individuals [Lai FTT, 2022 ].

Li X et al. was a cohort study conducted in China. The study enrolled 2,137 participants: ​​941 vaccine group; 1,196 control group. Based on electronic medical records with vaccination linkage database in Hong Kong, between March 2021 and 30 September 2021, the study examined the association between Pfizer COVID-19 vaccination and Inflamatory Bowel Disease flare, showing a Incidence rate ratio (IRR) for unplanned IBD-related hospitalisation of  0.69 (0.35 to 1.36) in vaccinated individuals [Li X, 2022 ].

Knowlton KU et al was a cohort study conducted in the United States. The study enrolled 67 participants: 21 vaccine group; 46 control group; and was based on data from Intermountain Healthcare, a not-for-profit healthcare system throughout Utah and parts of Idaho and Nevada between December 15, 2020 and June 15, 2021 with the objective of examining the risk of inflammatory heart disease, including pericarditis and myocarditis, after SARS-CoV-2 vaccination. The study results showed an inflamatory heart disease Relative Rate (RR) of 1.63 (95%CI 0.95 to 2.71) in vaccinated individuals (Data from COVID-19  vaccines analyzed: aggregated data from Pfizer, Janssen, and Moderna)[Knowlton KU, 2022 ].

Goddard K et al. was a comparative cohort study conducted in the United States. The study included 2,891,498 individuals with administered doses of the BNT162b2 vaccine and 1,803,267 with doses of the mRNA-1273 vaccine. Participants aged 18 to 39 years were followed with weekly updated data, supplemented by a review of medical records for cases of myocarditis and pericarditis. The adjusted RR of myocarditis and pericarditis for the 0–7 day risk interval was 6.9 after the Pfizer vaccine. After dose 2 of BNT162b2, the RR comparing risk versus comparison interval was 14.3 (95% CI 6.5–34.9). [Goddard K, 2022 ].

Montalti M et al. was a cross-sectional study that enrolled 600 female physicians aged from 24 to 60  years old; 131 pregnant and 469 breastfeedings that received Moderna or Pfizer COVID-19 vaccine. Results showed that 16  of the 31 immunized pregnant women,  reported at least one symptom after the first, and 14  after the second vaccine dose. After the first dose, 64.5% had nausea/vomiting, 25.8% fatigue, and 12.9% headache and arthralgia/myalgia; flushing and low back pain were rare. After the second dose, 76.5% of respondents had nausea/vomiting, 70.6% fatigue, and 41.2% arthralgia/myalgia. Among 315 immunized breastfeeders, 75.2% (n = 237) reported at least one symptom after the first dose, and 81.6% (n = 142) after the second. The most common adverse events occurring after the first dose were nausea/vomiting (60%), fatigue (28.3%), and headache (26.3%). Rarer events included dizziness, shivering, and limb paresthesia. After the second dose, 51.1% of them reported nausea/vomiting, 48.9% fatigue, and 49.4% arthralgia/myalgia [Montalti M, 2022 ].

Massari M et al. was a self-controlled case study conducted in Italy. The study included 2,861,809 persons aged 12 to 39 years received mRNA vaccines: 2,405,759 received Pfizer–BioNTech vaccine and 456,050 received Moderna vaccine. This study used data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Within the 21-day risk interval, 74 myocarditis/pericarditis events occurred after the BNT162bnb vaccination. The relative incidence (RI) was 1.08 (95% CI: 0.70 to 1.67) and 1.99 (95% CI: 1.30 to 3.05) after the first and second dose of BNT162b2, respectively.  The majority of the cases occurred during the 0 to 7 days risk period (n. 70, 61.4%), with an increased risk of myocarditis/pericarditis observed after the second dose of de BNT 162b2 vaccine (RI 3.39; 95% CI: 2.02 to 5.68) [Massari M, 2022 ].

Apaydin H et al. was a cross-sectional study that enrolled 450 Behçet syndrome patients followed in a clinic who met the criteria of the International Study Group that received the Pfizer or Sinovac COVID-19 vaccine. 287 patients received at least one dose of the COVID-19 vaccine. Adverse events were reported by 151 (52.6%) patients after the first dose, 135 (49.4%) after the second vaccine dose, 29 (42.6%) after the third vaccine dose, and 3 (30%) patients after the fourth vaccine dose. Injection site pain/swelling was the most common adverse effect at all vaccine doses, followed by fatigue, and arthralgia [Apaydin H, 2022 ].

Chen PY et al. was a comparative cohort study that included 30,832 people who received booster doses in the Taipei Veterans General Hospital.  The study analyzed the reported incidence rate, and factors associated with adverse events, including short-term serious adverse events and short-term non-serious adverse events, among different vaccine products through the hospital-based Vaccine Adverse Event Reporting System. A total of 7,432 records were collected during the three-month study period.  Respondents under 39 years of age had a higher incidence rate of adverse events (61.9%) than those between 40 and 64 years of age (48.7%), and those over 65 years of age (26.3%). The incidence of adverse events in Moderna COVID-19 vaccine is higher than in Pfizer COVID-19 vaccine and MVC-COV1901 (IRR Moderna vs. Pfizer COVID-19 vaccine: 1.22, 95% CI: 1.11 to 1.34; Pfizer COVID-19 vaccine vs. MVC-COV1901: 2.77, 95% CI: 2.27 to 3.3 [Chen PY, 2022 ]

Wong CKH et al. was a self-controlled case series study conducted in China. The study included 4,677 adults who had incident acute liver injury and vaccinated (2,473 with at least one dose of Pfizer and 2,204 with at least one dose of CoronaVac) and 13,766 adults who had incident acute liver injury and did not receive any vaccination. This study used the vaccination records in Hong Kong with data linkage to electronic medical records from a territory-wide healthcare database. Incidence rate ratios (IRRs) for ALI outcome in the 56-day period following first and second doses of COVID-19 vaccines in comparison to the non-exposure period were estimated and compared to the ALI risk in patients with SARS-CoV-2 infection. Compared with the non-exposure period, no increased risk  was observed in the 56-day risk period. For the first dose of BNT162b2 IRR was 0.800 (95% CI 0.680 to 0.942) and IRR was 0.949 (95% CI 0.816 to 1.091) for the second dose of BNT162b2. [Wong CKH, 2022 ]

Wang S et al. was a comparative cohort that included 3,858 premenopausal women in the Nurses’ Health Study 3 living in the United States or Canada who received biannual follow-up questionnaires between January 2011 and December 2021 and completed additional monthly and quarterly surveys related to the COVID-19 pandemic between April 2020 and November 2021 (Unvaccinated: 281; mRNA vaccine: 2,746; Adenovirus-vectored vaccine: 75). The study examined the associations of SARS-CoV-2 infection and COVID-19 vaccination with changes in usual menstrual cycle characteristics. Results showed that vaccinated women had a higher risk of increased cycle length than unvaccinated women in OR 1.48 (95% CI 1.00 to 2.19), after adjusting for sociodemographic and behavioral factors. COVID-19 vaccination was only associated with the change to longer cycles in the first 6 months after vaccination and among women whose cycles were short, long, or irregular before vaccination. This change was associated with messenger RNA and adenovirus-vectored vaccines. Menstrual cycle characteristics were not affected by SARS-CoV-2 infection [Wang S, 2022 ].

Vinante L et al. was a comparative cohort that included 361 patients with 756 administered COVID-19 vaccinations (Pfizer:529 doses; Moderna: 194 doses; AstraZeneca: 28 doses; Janssen 5 doses). The study assessed the incidence of radiation recall dermatitis after COVID-19 vaccination in breast cancer patients previously treated with postoperative radiation therapy. Results showed that breast symptoms were reported by 7.5% of patients, while radiation recall dermatitis was considered for 5.5%. Radiation recall dermatitis was more common in the first dose compared to the second (4.4%) or third (1%), especially when administered within the first month after irradiation (12.5% vs 2.2%). Symptoms were generally self-limited, and anti-inflammatory medications were required in a few cases [Vinante L, 2022 ].

Chui CSL et al was a self-controlled case series study conducted in China. The study included 1536 hemorrhagic stroke cases and 9707thromboembolic events. This study aimed to evaluate the association between thromboembolic events and hemorrhagic stroke following BNT162b2 and CoronaVac vaccination. The results showed an increased risk of hemorrhagic stroke with BNT162b2 with an adjusted IRR of 2.53 (95% CI 1.48 to 4.34) at14-27 days after the first dose and adjusted IRR of  2.69 (95% CI 1.54 to 4.69) at 0-13 days after the second dose. There was no statistically significant risk was observed for thromboembolic events for both vaccines [Chui CSL, 2022 ].

CVIM 4 was a randomized controlled trial conducted in Thailand. The study included 77 kidney transplant recipients (per protocol analysis) who had already been vaccinated with a full primary regimen with ChAdOx1 or that had been vaccinated with a primary regimen with CoronaVac and boosted with the ChAdOx1 vaccine. The participants were randomized two receive an additional dose of either a mRNA vaccine (Moderna of Pfizer BioNTech, n= 40, group M) or a viral vector vaccine (ChAdOx1, n= 37, group V). The immunogenicity outcome was the measurement of anti-SARS-CoV-2 RBD IgG antibody levels and the surrogate viral neutralization test (%SVNT); the cell-mediated immunity was evaluated through SARS-CoV-2 specific- interferon-γ (IFN-γ)-producing T and B cell. Both responses were measured 2 weeks after the intervention. Solicited adverse events (AEs) were assessed via phone call on days 3 and 7 post-vaccination, and unsolicited AEs were self-recorded by participants. At day 7, AEs were reported by 10 (25%) of the M group's participants and 9 (24%) of the V group's participants. No grade 3 AEs were reported by any group at day 7 [Bruminhent J, 2022 ].

Nantanee R et al was randomized clinical trial conducted in Thailand. The study included 100 adults with a median age of 59.3 years (IQR 33.4–65.5) with two-dose AZD1222: 50 received half-Dose BNT162b2 Booster (15 µg/Dose) and 50 received a standard-Dose BNT162b2 Booster (30 µg/Dose). The full-dose recipients tended to have more moderate–severe systemic reactogenicities, e.g., myalgia, arthralgia, fatigue, and headache. Myalgia occurred more frequently in the standard-dose group (42% vs. 32% in the half-dose group, p 0.04) [Nantanee R, 2022 ].

Terentes-Printzios D et al was a randomized cross over trial conducted in Greece. The study included 32 participants that received the BNT162b2 mRNA vaccine (2 doses, 30 μg per dose with a 3-week period between the 1st and the 2nd doses) in a sequence-randomized, sham-controlled, assessor-blinded, three-period (1st vaccine dose, 2nd vaccine dose, placebo), crossover design. There was a washout period of at least 7 days. The aim of this study was  to investigate the short-term effect of mRNA vaccine administration on endothelial function and arterial stiffness. The primary outcome was endothelial function (assessed by brachial artery flow-mediated dilatation (FMD)), and the secondary outcomes were aortic stiffness (evaluated with carotid-femoral pulse wave velocity (PWV)) and inflammation (measured by high-sensitivity C-reactive protein (hsCRP) in blood samples). There was an increase in hsCRP after the 1st dose (−0.60 (95% CI −1.60 to −0.20) (p = 0.013) and the 2nd dose (maximum median difference at 48 h −6.60 (95% CI −9.80 to −3.409) (p < 0.001) compared to placebo. FMD remained unchanged during the 1st dose but decreased significantly by 1.5% (95% CI: 0.1% to 2.9%, p = 0.037) at 24 h after the 2nd dose. The vaccine did not change PWV. [Terentes-Printzios D, 2022 ].

Wong HL et al was a retrospective cohort study conducted in United States. The study included data from 15,148,369 people aged 18–64 years with 411 myocarditis or pericarditis cases reported. This study used active surveillance from large health-care databases to quantify and enable the direct comparison of the risk of myocarditis or pericarditis, or both, after mRNA-1273 (Moderna) and BNT162b2 (Pfizer–BioNTech) vaccinations. Incidence rates (IR) for myocarditis or pericarditis in the first 1 to 7 days after COVID-19 mRNA vaccination after dose 2 was 2.17 (95% CI 1.55 to 3.04) per 100,000 person-days for mRNA-1273 vaccine and 32.2 (95% CI –33.90 to 98.30) per 100,000 person-days for Pfizer vaccine. [Wong HL, 2022 ]

Simone A et al was a comparative retrospective study conducted in the United States. The study included 3,076,660 participants with at least one dose of COVID-19 mRNA vaccines, 2,916,739 with at least two doses of COVID-19 mRNA vaccines, and 1,146,254 with at least three doses of COVID-19 mRNA vaccines. This study aimed to evaluate whether the third dose of the COVID-19 mRNA (BNT162b2 or mRNA-1273 mRNA) vaccine was associated with an increased risk of myocarditis. Incidence rate ratios of myocarditis in vaccinated individuals compared to control groups were 0.86 (95% CI 0.31 to 1.93) after the first dose, 4.22 (95% CI 2.63 to 6.53) after the second dose, and 2.61 (95% CI 1.13 to 5.29) after the third dose (aggregated data from Pfizer-BioNTech and Moderna COVID-19 vaccines) (Aggregated data from Pfizer-BioNTech and Moderna COVID-19 vaccines). [Simone A, 2022 ].

Lloyd PC et al was a retrospective cohort study conducted in the United States. The study included data from 9,604,918 doses from the Optum database, 14,146,413 doses from the HealthCore database, and 14,146,413 doses from the CVS Health database. This study utilized sequential testing to detect potential safety signals following vaccination by comparing observed rates of adverse events following vaccination to historical background rates.  Rate ratios (RR) of observed adverse events rates compared to historical (or expected) rates prior to COVID-19 vaccination from the Optum, HealthCore, and CVS Health Databases were RR 0.94, 0.89, and 1.08 for acute myocardial infarction, RR 0.88, 0.84 and 0.97 for deep vein thrombosis, RR 1.05, 1.28, 1.33 for pulmonary embolism and RR 0.68, 1.04, 0.75 for Disseminated Intravascular Coagulation. [Lloyd PC, 2022 ].

Buchan SA et al was a retrospective cohort study conducted in Canada. The study included data from 19,740,741 doses of mRNA vaccines from Ontario’s COVID-19 vaccine registry and passive vaccine-safety surveillance system. This study aimed to estimate rates of reported myocarditis or pericarditis following receipt of a COVID-19 mRNA vaccine (BNT162b2 or mRNA-1273). The adjusted Rate Ratios (aRR) for myocarditis or pericarditis comparing Moderna with Pfizer-BioNTech by age group for females were 9.6 (95% CI, 1.9-48.8) in the 18-24 years old group, 1.6 (95% CI, 0.4-6.3) in the 25-39 years old group and  0.5 (0.04-4.3) in the 40 and above years old group. For males 6.6 (95% CI, 3.3-13.2) in the 18-24 years old group, 5.1 (95% CI, 2.3-11.5) in the 25-39 years old group and 0.8 (95% CI, 0.3-2.7) in the 40 years and above group. [Buchan SA, 2022 ]

Kim JE et al was a retrospective cohort study conducted in South Korea. The study included data from 1,731,147 adverse drug reaction reports related to COVID-19 vaccines from VigiBase, a WHO database, and aimed to evaluate the association between COVID-19 vaccination and the occurrence of Neuralgic Amyotrophy (NA). The Reporting Odds Ratio (ROR) for NA after mRNA vaccination was 4.35 (95% CI, 3.2-4.06). [Kim JE, 2022 ]

Calvert C et al was a comparative cohort study conducted in Scotland. The study included data from the COPS study database, including 93,900 pregnant women, 18,780 vaccinated and 75,120 controls. The study assessed the incidence of adverse pregnancy outcomes after COVID-19 vaccination. The adjusted odds ratio after Pfizer-BioNTech vaccination for miscarriage was 0.99 (95% CI, 0.89–1.09), and 1.12 (95% CI, 0.86–1.46) for ectopic pregnancy. [Calvert C, 2022 ]

Wong CKH was a self controlled case series study conducted in China that included data from 2,288,239 vaccinated individuals: 1,321,753 with at least one dose of BNT162b2 and 966,486 with at least one dose of CoronaVac. This study used data from individuals who received COVID-19 vaccination between February 23rd and September 30th 2021 from a population-based electronic health database in Hong Kong, linked to vaccination records. Following the second dose of COVID-19 vaccination, there was no increase in the risks of anti-thyroid drug initiation. Incidence rate ratio of anti-thyroid drug initiation was 0.972 (95% CI, 0.770–1.227). Incidence rate ratio of Levothyroxine initiation was 1.019 (95% CI, 0.833–1.246). [Wong CKH, 2022 ]

Le Vu S et al was a case control study conducted in France that used data from National Health Data System (SNDS), the study focused on the period from May 12th to October 31st 2021. It included 1,612 cases of myocarditis and 16,120 matched controls; 1,613 cases of pericarditis and 16,130 matched controls. The adjusted OR 1-7 days following the second vaccine dose for developing myocarditis was 8.1 (95% CI, 6.7–9.9), and for pericarditis 2.9 (95% CI, 2.3–3.8). [Le Vu S, 2022 ]

Li x et al was a cohort study conducted in China. The study included 332,707 participants vaccinated with 2 doses of the CoronaVac vaccine, 388,881 participants with 2 doses of the Pfizer vaccine and 1,892,783 unvaccinated participants. In this study, territory-wide longitudinal electronic medical records of Hong Kong Hospital Authority users (≥16 years) were linked with COVID19 vaccination records between February 23rd and June 30th 2021. Cumulative incidences for all autoimmune conditions were below 9 per 100,000 persons, for both vaccines and both doses. [Li X, 2022 ].

Wan EYF et al was a self-controlled case series with a case-control nested study conducted in China that included 1,451,858 participants with the Pfizer-BioNTech vaccine primary schedule. The case-control analysis included 517 cases and 4,945 controls, while the self-controlled case series analysis included 529 participants. The adjusted Odds Ratio for the development Bell’s Palsy was 1.543 (95% CI, 1.123–2.121) and the Incidence Rate Ratio 14-27 days after second dose was 0.97 (95% CI, 0.37–2.58). [Wan EYF, 2022 ].

Torabi F et al was a self-controlled case series study conducted in Wales that included data from the SAIL Databank: 2,062,144 individuals, of which, 1,738,427 received a primary vaccine schedule. This study assessed thrombocytopenic, thromboembolic, and hemorrhagic events following COVID-19 vaccination. The incidence rate ratio (IRR) 22-28 days after the second dose of Pfizer-BioNTech was 3.15 (95% CI, 0.96-10.32) for thrombocytopenia, 1.35 (95% CI, 0.93-1.96) for hemorrhage, 0.81 (95% CI, 0.56-1.17) for venous thromboembolism (VTE), 1.10 (95% CI, 0.27-4.5) for idiopathic thrombocytopenic purpura (ITP), 1.02 (95% CI, 0.82-1.28) for arterial thrombosis, 1.26 (95% CI, 0.85-1.88) for ischaemic stroke and 1.26 (95% CI, 0.83-1.93) for myocardial infarction. The IRR after a third dose was 0.70 (95% CI, 0.17-2.91) for hemorrhage, 0.46 (95% CI, 0.14-1.48) for venous thromboembolism (VTE), 0.91 (95% CI, 0.42-1.96) for arterial thrombosis, 0.48 (95% CI, 0.06-3.79) for ischaemic stroke and 2.08 (95% CI, 0.62-6.97) for myocardial infarction. [Torabi F, 2022 ]

Patone et al. was a case series study of 42,842,345 people aged 13 years and older receiving at least 1 dose of COVID-19 vaccines in England between December 1st 2020 and December 15th 2021. It evaluated the association between vaccination and myocarditis. The risk of myocarditis in the first 1-28 days after a first dose of Pfizer showed an incidence rate ratio of 1.52 (95% CI, 1.24-1.85), 1.57 (CI 95%, 1.28-1.92) after 1 to 28 days of the second dose and 1.72 (95% CI, 1.33–2.22) after a booster dose [Patone M, 2022 ].

Hui L et al was a cohort study conducted in Australia that included 32,536 births from 17,365 vaccinated women and 15,171 unvaccinated women. The study was based on data from 12 maternity hospitals in Melbourne. This study assessed perinatal outcomes by vaccination status. Adjusted odds ratio for perinatal outcomes comparing vaccinated and unvaccinated women was 0.18 (95% CI, 0.09-0.37) for stillbirth, 0.60 (95% CI, 0.51-0.71) for preterm births <37 weeks, 0.73 (95% CI, 0.56-0.96) for spontaneous preterm birth, 0.52 (95% CI, 0.41-0.65) iatrogenic preterm birth and 0.72 (95% CI, 0.56-0.94) for major congenital anomaly. [Hui L, 2022 ]

Ye X et al. was a self-controlled case series conducted in China that included 32,490 heart failure patients. The study was based on data from the Hong Kong Hospital Authority, and evaluated the risk of hospitalization for heart failure after vaccination. The incidence Rate Ratio (IRR) for hospitalization for heart failure 14-27 days after vaccination was 0.73 (95% CI, 0.35–1.52) after the first dose, 0.95 (95% CI, 0.49–1.84) after the second dose and 0.60 (95% CI, 0.06–5.76) after the booster dose. [Ye X, 2022 ]

Corrao G et al. was a retrospective cohort study conducted in Italy that included 9,184,146 vaccine recipients. The study was based on data from the Lombardy Vaccine Integrated Platform and evaluated the risk of myocarditis and pericarditis after vaccination. The adjusted hazard ratio for developing myocarditis was 1.54 (95% CI, 1.08–2.2) after the first dose, 1.57 (95% CI, 1.13–2.19) after the second dose and 1.1 (95% CI, 0.34–3.54) after the booster dose. [Corrao G, 2022 ]


Non-comparative studies
Schulz JB et al. was a non-comparative study carried out in Germany, which included 7,126,424 first doses (Pfizer-BioNTech, Moderna, AstraZeneca vaccines). The study aimed to estimate the incidence of cerebral sinus and venous thrombosis (CVT) within 1 month from the first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination. All reported cases occurred after vaccination with ChAdOx1 (85.5%) and BNT162b2 (14.5%). No cases were reported with mRNA-1273.[Schulz JB, 2021 ].

David Presby et al. is a retrospective cohort conducted in United States. The study enrolled 50977 (AstraZeneca (AZ, n=2093), Janssen/Johnson & Johnson (J&J&J, n=3888), Moderna (n=23776; M1, 14553 first dose; M2, 9223 second dose), or Pfizer/BioNTech (n=35929; P&B1, 22387 first dose; P&B2, 13542 second dose) participants{. }Based on data from subscribers to the WHOOP platform using data collected through April 14, 2021 [David Presby, 2021 ].

Maria Abbattista et al. conducted a non-comparative study in Europe, which included 748,248 reports of adverse drug reactions (Pfizer-BioNTech, Janssen, Moderna and AstraZeneca vaccines). The notification rate of cerebral venous thrombosis (CVT) per 1 million vaccinated persons-days was 1.92 (95% CI, 1.71-2.12) for Tozinameran, 5.63 (95% CI, 4, 74-6.64) for CX-024414, 21.60 (95% CI, 20.16-23.11)) for CHADOX1 NCOV-19 and 11.48 (95% CI, 9.57-13, 67) for AD26.COV2.S. CVT occurred in conjunction with thrombocytopenia for all four vaccines. The observed-to-expected (OE) analysis ratio was greater than one for all four vaccines, both with the lowest and highest background incidence of CVT [Abbattista M, 2021 ].

Kaur RJ et al. was a non-comparative study that reported 4863 cardiovascular adverse events. Common adverse events observed with the study vaccines were tachycardia (16.41%), flushing (12.17%), hypertension (5.82%), hypotension (3.60%), and peripheral coldness (2.41%). According to the disproportionality analysis (IC025 values), acute myocardial infarction, cardiac arrest, and circulatory collapse were associated with vaccines in the age group> 75 years. Hypertension, severe hypertension, supraventricular tachycardia, sinus tachycardia, and palpitations were associated in all age groups and in both sexes [Jeet Kaur R, 2021