Pfizer-BioNTech COVID-19 vaccine

Extended version of the vaccine

Pfizer-BioNTech COVID-19 vaccine

Authorization

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, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency use in individuals 5 years of age and older [World Health Organization, 2021 ].

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.

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
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

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

Manufacturing

Manufacturer

Drug substance [WHO, 2021 ]
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, 2021 ]
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.

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

Dose-finding studies

BNT162-03 was a randomized, placebo-controlled, observer-blind phase I trial sponsored by BioNTech RNA Pharmaceuticals GmbH and conducted in China between August 2020 - August 2021. It was registered with NCT04523571. The trial included healthy adults aged ≥18 and ≤55 and adults aged ≥65 and ≤85. The sample size was 144. The mean age of the younger participants ranged from 37.9 to 42.0 years, and the mean age among the over participants ranged from 68.5 to 70.7 years in the treatment groups. The proportion of women was 50% across treatment groups. Participants were randomly assigned in a 1:1:1 ratio to receive the low-dose BNT126b1 or high-dose BNT126b1 or placebo. The intervention was administered as a prime dose and a boost dose of vaccine candidate BNT162b1 at either 10μg in 0.5ml or 30μg in 0.5ml, or 0.5ml placebo, administered into the deltoid, 21 days apart. The vaccine-induced highest neutralizing titers were observed on day 43 (21 days after the BNT162b1 boost dose) for the younger and over adults in the BNT162b1 group. Participants who received the 30 μg dose appeared to have a relatively higher virus-neutralizing antibody response than those who received the 10 μg dose. The over participants generally had a lower peak neutralizing antibody response than the younger participants. Moreover, BNT162b1 induced robust interferon-γ T cell responses to a peptide pool including the RBD in younger and over adults. Geometric mean neutralizing titers reached 2.1-fold in the young adult's group and 1.3-fold in the over 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 ].

BNT162-01 evaluated four prophylactic SARS-CoV-2 RNA vaccines against COVID-19 using different dosing regimens and showed that BNT162b2 prime/boost vaccination at 1 to 30 g dose levels elicited a combined adaptive humoral and cellular immune response [Ugur Sahin, 2020 ].

Heterologous (mix-and-match) studies are ongoing with regard to the interchangeability of Pfizer-BioNTech COVID-19 vaccine with other COVID-19 vaccines. Preliminary results from a heterologous primary schedule where BNT162b2 was given as the second dose following the first dose of ChAdOx1- S (recombinant) vaccine showed a slightly increased but acceptable reactogenicity with superior or similar immunogenicity results, thus supporting the use of such a heterologous priming schedule in settings where the second dose for the ChAdOx1-S (recombinant) vaccine is not available due to vaccine supply constraints or other concerns [World Health Organization, 2021 ].

Recommendations will be updated as further information becomes available on interchangeability between vaccine products and platforms.

Indications and contraindications

Indications

Pfizer - BNT162b2 COVID-19 vaccine is indicated for individuals 5 years of age and older [World Health Organization, 2021 ].

Children 5-17 years of age with comorbidities that put them at significantly higher risk of serious COVID-19 disease, alongside other high-risk groups, may be offered vaccination [World Health Organization, 2021 ].

For healthy children and adolescents (aged 5 to 17), WHO recommends using Pfizer - BNT162b2 only when high vaccine coverage with 2 doses has been achieved in the high priority groups as identified in the WHO Prioritization Roadmap [World Health Organization, 2021 ].

WHO recommends the use of Pfizer COVID-19 vaccine in pregnant individuals. WHO does not recommend pregnancy testing before vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2021 ].

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. In particular, should not be administered to individuals with a known history of severe allergic reaction to polyethylene glycol (PEG) or related molecules [World Health Organization, 2021 ] [World Health Organization, 2021 ]. (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 [World Health Organization, 2021 ].



Precautions

Allergic reactions [World Health Organization, 2021 ].
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 [World Health Organization, 2021 ].

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 BNT162b2 vaccination, all vaccinees should be observed for at least 15 minutes after vaccination [World Health Organization, 2021 ].

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, BNT162b2 could be provided under close medical supervision if it is the only available vaccine for persons at high risk of severe COVID-19 [World Health Organization, 2021 ].

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 [World Health Organization, 2021 ].

Myocarditis
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 [World Health Organization, 2021 ].

Breastfeeding [World Health Organization, 2021 ].
Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults. As BNT162b2 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 the use of the BNT162b2 vaccine in breastfeeding women. WHO does not recommend stopping breastfeeding due to vaccination.

Immunocompromised persons [World Health Organization, 2021 ].
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 [World Health Organization, 2021 ].
Persons living with HIV who are well controlled on highly active 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
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection [World Health Organization, 2021 ].
The optimal minimum interval between a natural infection and vaccination is not yet known, but an interval of 3-6 months could be considered [World Health Organization, 2021 ].

Persons with current acute COVID-19
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 [World Health Organization, 2021 ].

Other precautions
Syncope (fainting) may occur in association with administration of injectable vaccines, in particular in adolescents. Procedures should be in place to avoid injury from fainting [FDA].
Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5 °C) or acute infection [World Health Organization, 2021 ].
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
Inactivated influenza vaccine
The Pfizer-BioNTech COVID-19 vaccine can be co-administered with inactivated influenza vaccines. Evidence suggest that neither adverse effects and reactogenicity, nor immunogenicity are increased as a result of co-administration [World Health Organization, 2021 ].
Different arms for injection should be used when both vaccines are delivered during the same visit [World Health Organization, 2021 ].

Other vaccines
There is no evidence yet about the effects of the coadministration of Pfizer-BioNTech COVID-19 vaccine with other vaccines included in routine vaccination programs. A minimum interval of 14 days between administration of this vaccine and any other vaccines is recommended [World Health Organization, 2021 ].

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

Storage and logistics


Storage

The Pfizer-BioNTech COVID-19 vaccine is provided as a concentrated frozen dispersion 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:

Undiluted vaccine at storage temperature -90°C to -60°C (-130°F to -76°F): 9 months after the time of manufacturing [WHO, 2021 ].
The storage period of the unopened thawed vial at 2−8 °C (36°F to 46°F) is up to 1 month (31 days) [World Health Organization, 2021 ] [FDA, 2021 ]
Diluted vaccine at 2°C to 30°C (36°F to 86°F): 6 hours after dilution
Do not refreeze thawed vials.
Do not freeze diluted vaccine.
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 and use.

Administration logistics
Concentrated formulation
Thaw before dilution: [World Health Organization, 2021 ]

Before dilution, vials must reach room temperature and be diluted within 2 hours
Thaw vaccine up to 3 hours at 2°C to 8°C (36°F to 46°F) in refrigerator or for 30 minutes at 25°C (77°F) before dilution.

Dilute before use: [World Health Organization, 2021 ]

1. Before dilution, invert vaccine vial gently 10 times, do not shake.
2. Draw into the mixing syringe 1.8 mL of diluent.
3. Add 1.8 mL of diluent into the vaccine vial; level/equalize the pressure in the vial before removing the needle by withdrawing 1.8 mL 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.

Storage after first puncture

Record the date and time the vial should be discarded.
Use within 6 hours of dilution or at the opening of the vial.

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 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 a sixth dose from the same vial.
3. Gently invert the vial with the diluted vaccine to mix and withdraw the 0.3 mL dose. If the amount of vaccine remaining in the vial cannot provide a full 0.3 mL 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.

Discard the unused vaccine within 6 hours of dilution.
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 ].

Clinical studies - general characteristics

Randomized trials

C4591001 is a phase 1/2/3 randomized trial sponsored by BioNTech and conducted in the United States between May 2020 and November 2020. It was registered with the number NCT04368728 [Biontech SE, 2020 ]. The phase 1 component of the trial included 195 healthy adults 18 years of age or older. Participants were randomly assigned to 13 groups comprising 15 participants each; in each group, 12 participants received vaccine and 3 received placebo. The vaccines were administered in different doses and schedules [Walsh EE, 2020 ]. The phase 2/3 component included 37706 adults 16 years of age or older who were healthy or had stable chronic medical conditions. The mean age of the participants was 52 years old, and the proportion of females was 49%. Participants were randomly assigned in a 1:1 ratio to receive the vaccine (30 μg, 0.3 mL volume per dose) or placebo [Polack, Fernando P., 2020 ].

C4591001 was a phase 2/3, randomized trial sponsored by BioNTech SE and conducted at 162 sites worldwide (United States, Argentina, Brazil, South African, Germany, and Turkey) April 2020-March 2021. It was registered with NCT04368728. The trial included healthy persons 12 years of age or older. The sample size was 6,035. The mean age of the participants was 13 years in the 12-15 years group, and 19 years in the 16-25 years group years. The proportion of women was 49.9% (BNT162b2) and 48.2% (placebo) in the 12-15 years group, and 52% in the 16-25 years group. Participants were randomly assigned in a 1:1 ratio to receive BNT162b2 or placebo. The intervention was administered as 30 μg of BNT162b2 or placebo (saline) 21 days apart [Frenck RW, 2021 ].

Com-COV was a multi-centre single-blind phase II randomized parallel study sponsored by University of Oxford and conducted United Kingdom between October 2020 to November 2022. It was registered with ISRCTN69254139. The trial included participants are 50 years and older with no or mild-to-moderate, well-controlled comorbidity. The sample size was 830. The mean age of the participants was 57.8 years and the proportion of women was 46%. Participants were randomly assigned in a 1:1 ratio to receive ChAd/ChAd, ChAd/BNT, BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals. The intervention was administered as a intramuscular injection of 0.5 ml dose of ChAdOx1 nCOV-19 or 0.3 ml dose of BNT162b2 to the following arms:

1. Immunology cohort (receiving their booster vaccine dose after 28 days)
1. Prime ChAdOx1 nCOV-19, Boost ChAdOx1 nCOV-19
2. Prime ChAdOx1 nCOV-19, Boost BNT162b2
3. Prime BNT162b2, Boost BNT162b2
4. Prime BNT162b2, Boost ChAdOx1 nCOV-19 2. General cohort:
1. Prime ChAdOx1 nCOV-19, Boost ChAdOx1 nCOV-19 (28 day boost)
2. Prime ChAdOx1 nCOV-19, Boost BNT162b2 (28 day boost)
3. Prime BNT162b2, Boost BNT162b2 (28 day boost)
4. Prime BNT162b2, Boost ChAdOx1 nCOV-19 (28 day boost)
5. Prime ChAdOx1 nCOV-19, Boost ChAdOx1 nCOV-19 (84 day boost)
6. Prime ChAdOx1 nCOV-19, Boost BNT162b2 (84 day boost)
7. Prime BNT162b2, Boost BNT162b2 (84 day boost)
8. Prime BNT162b2, Boost ChAdOx1 nCOV-19 (84 day boost) [Liu X, 2021 ].

BNT162-03 was a randomized, placebo-controlled, observer-blind phase I trial sponsored by BioNTech RNA Pharmaceuticals GmbH and conducted in China between August 2020 - August 2021. It was registered with NCT04523571. The trial included healthy adults aged ≥18 and ≤55 and adults aged ≥65 and ≤85. The sample size was 144. The mean age of the younger participants ranged from 37.9 to 42.0 years, and the mean age among the older participants ranged from 68.5 to 70.7 years in the treatment groups. The proportion of women was 50% across treatment groups. Participants were randomly assigned in a 1:1:1 ratio to receive the low-dose BNT126b1 or high-dose BNT126b1 or placebo. The intervention was administered as a prime dose and a boost dose of vaccine candidate BNT162b1 at either 10μg in 0.5mL or 30μg in 0.5mL, or 0.5mL placebo, administered into the deltoid, 21 days apart [Li J, 2021 ].

CombiVacS was a phase 2, open-label, randomized, controlled trial sponsored by Spanish Clinical Research Network - SCReN and conducted in Spain between April 2021- April 2022. It was registered with NCT04860739.
The trial included healthy, or clinically stable adults aged 18–60 years who had received a prime ChAdOx1-S vaccination between 8 weeks and 12 weeks before the screening visit. The sample size was 676. The mean age of the participants was 43.98 years and the proportion of women was 57%. Participants were randomly assigned in a 2:1 ratio to receive BNT162b2 or observation. The intervention was administered as one intramuscular injection of BNT162b2 (0.3 mL) or maintain observation [Borobia AM, 2021 ].

ComFluCOV was a multicentre, randomized, controlled, phase 4 trial sponsored by University Hospitals Bristol NHS Foundation Trust and conducted United Kingdom between March 2021- August 2021. It was registered with ISRCTN14391248. The trial included adults in receipt of a single dose of AstraZeneca or Pfizer COVID-19 vaccine. The sample size was 679. The median age of participants by influenza vaccine type was 51 years for those receiving the cellular quadrivalent vaccine, 52 years for those receiving the recombinant quadrivalent vaccine, and 69 years for those receiving the MF59C adjuvanted, trivalent vaccine. The proportion of women was 58%. Participants were randomly assigned in a 1:1 ratio to receive concomitant administration of either an influenza vaccine or placebo alongside their second dose of AstraZeneca or Pfizer COVID-19 vaccine. The intervention was administered as an age-appropriate influenza vaccine or a placebo injection in addition to alongside their second dose of a COVID-19 vaccine homologous to their first dose (AstraZeneca or Pfizer COVID-19 vaccine). At the second visit between 21 and 28 days later, those who received an influenza vaccine at day 0 received a placebo injection and vice versa [Lazarus R, 2021 ].

COV-BOOST was a blinded, multicentre, randomized, controlled, phase 2 trial sponsored by University Hospital Southampton NHS Foundation Trust and conducted in United Kingdom between May 2021 - August 2022. It was registered with ISRCTN73765130. The trial included adults aged 30 years or older, in good physical health (mild to moderate well-controlled comorbidities were permitted), who had received two doses of either Pfizer or AstraZeneca COVID-19 vaccine. The sample size was 2883. The median age of ChAd/ChAd-primed group was 53 years in the younger age group and 76 years in the older age group. In the BNT/BNT-primed group, the median age was 51 years in the younger age group and 78 years in the older age group. The proportion of females was 46.7% in the ChAd/ChAD-primed and 53.6% in BNT/BNT-primed group. Participants were randomly assigned in a 1:1:1:1 ratio in group A, 1:1:1:1:1 in group B, and 1:1:1:1 in Group C to receive an experimental vaccine or control. The intervention was administered as:

  1. Group A received NVX-CoV2373( Novavax), a half dose of NVX, AstraZeneca, or control quadrivalent meningococcal conjugate vaccine (MenACWY).
  2. Group B received Pfizer, VLA2001 (Valneva), a half dose of VLA, Ad26.COV2.S (Janssen) or MenACWY.
  3. Group C received mRNA1273 (Moderna), CVnCov (CureVac), a half dose of BNT, or MenACWY [Munro, Alasdair P S, 2021 ].

 SWITCH was a single-blind, multicenter, randomized, controlled trial sponsored by Erasmus Medical Center and conducted Netherlands between June 2021 to September 2022. It was registered with NCT04927936. The trial included Health care workers between 18 and 65 years of age. The sample size was 461. The mean age of the participants was 40 years and the proportion of women was 65%. Participants were randomly assigned in a 1:1:1:1 ratio to receive no booster, an Janssen booster, a Moderna booster, or a Pfizer booster. The intervention was administered as Janssen COVID-19 vaccine (≥8.92×1010 viral particles), Moderna COVID-19 vaccine (100 μg), and Pfizer COVID-19 vaccine (30 μg) [Sablerolles RSG, 2022 ].

MIACoV is an ongoing phase 3 randomized study (registered with the number NCT05228730 [Murdoch Childrens Research Institute, 2022 ]) sponsored by Murdoch Childrens Research Institute that is being conducted in Australia. It was first registered in February 2022 and plans to enroll 800 individuals 18 years and over that will receive a booster dose of the vaccine Pfizer-BioNTech or Moderna after having completed a primary vaccination series of either Pfizer-BioNTech or AstraZeneca COVID-19 vaccines. It is expected to run until April 2023.

Ongoing randomized trials

C4591017 is an ongoing phase 3, randomized trial (registered with the number NCT04713553 [BioNTech SE, 2021 ]) sponsored by BioNTech SE that is being conducted in the United States. It was first registered in January 2021 and plans to enroll 1,530 healthy individuals, of 12 through 50 years of age, that will receive vaccine candidate (BNT162b2) as a 30-microgram dose administered from 1 of 4 manufacturing lots (batches), as a 20-microgram dose administered from 1 of the manufacturing lots or as a 2-dose. It is expected to run until May 2021.

C4591020 is an ongoing phase 3 randomized trial (registered with the number NCT04816669 [BioNTech SE, 2021 ]) sponsored by BioNTech SE that is being conducted in the United States. It was first registered in March 2021 and plans to enroll 550 healthy adults, of 18 through 55 years of age, that will receive lyophilized BNT162b2 presented in single-dose vials and of frozen liquid BNT162b2 in multidose vials. It is expected to run through May 2021.

C4591015 is an ongoing phase 2/3, randomized trial (registered with the number NCT04754594 [BioNTech SE, 2021 ]) sponsored by BioNTech SE that is being conducted in the United States. It was first registered in February 2021 and plans to enroll 4,000 healthy pregnant females, of 18 years of age or older, vaccinated at 24 to 34 weeks' gestation that will receive 30 μg of BNT162b2 or placebo administered in 2 doses, 21 days apart. It is expected to run through June 2022.

C4591005 is an ongoing phase 1/2, randomized trial (registered with the number NCT04588480 [BioNTech SE, 2020 ] and jRCT2071200045 [Nagashima Masahito, 2020 ]) sponsored by BioNTech SE that is being conducted in Japan. It was first registered in October 2020 and plans to enroll 160 adults of 20 to 85 years of age, that will receive the vaccine as 2 doses, separated by 21 days, and as a single dose. It is expected to run through November 2021.

Zhu et al is an ongoing phase 2, randomized trial (registered with the number ChiCTR2000040044 [Jiangsu Provincial Center for Disease Prevention and Control, 2020 ]) sponsored by Jiangsu Provincial Center for Disease Prevention and Control that is being conducted in China. It was first registered in November 2020 and plans to enroll 960 healthy participants between the ages of 18 and 85 years old, that will receive BNT162b2 or placebo. It was expected to run until December 2020.

BNT162-06 is an ongoing phase 2, randomized trial (registered with the number NCT04649021 [BioNTech SE, 2020 ]) sponsored by BioNTech SE that is being conducted in China. It was first registered in December 2020 and plans to enroll 950 healthy participants between the ages of 18 and 85 years, that will receive two doses of the BNT162b2, separated by 21 days, or placebo. It is expected to run until December 2021.

COVID-19-004 is an ongoing phase 2 randomized trial (registered with the number NCT04761822 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases (NIAID) that is being conducted in the United States. It was first registered in February 2021 and plans to enroll 3400 participants with High-Allergy/Mast Cell Disorder (HA/MCD) in order to estimate the proportions of systemic allergic reactions to the Pfizer-BioNTech COVID-19 Vaccine and the Moderna COVID-19 Vaccine. If the risk in the HA/MCD is demonstrable, an additional aim is to determine whether the proportions are higher in the HA/MCD compared to a non-atopic population.

HeVacc is an ongoing phase 2, randomized trial (registered with the number NCT04907331 [Medical University Innsbruck, 2021 ]) sponsored by Medical University Innsbruck that is being conducted in Austria. It was first registered in May 2021 and plans to enroll 3,000 participants aged ≥ 18 and ≤ 65 years that will receive Vaxzevria or BNT162b2 as a boost. It is expected to run until December 2021.

ARNCOMBI is an ongoing multicenter, randomized, open-label trial (registered with the number NCT04900467 [Assistance Publique - Hôpitaux de Paris, 2021 ]) sponsored by Assistance Publique - Hôpitaux de Paris that is being conducted in France. It was first registered in May 2021 and plans to enroll 400 patients aged 18 years and older that will receive vaccine regimens combining Pfizer-BioNTech or Moderna vaccines. It is expected to run until January 2022.

BNT162-14 is an ongoing phase 2, randomized trial (registered with the number NCT04949490 [BioNTech SE, 2021 ]) sponsored by BioNTech SE that is being conducted in Germany. It was first registered in July 2021 and plans to enroll 549 patients 18 years of age and over that will receive one or two boosting doses of Comirnaty or one dose of BNT162b2s01. It is expected to run until July 2023.

B7471026 is an ongoing phase 3, randomized, double-blind trial (registered with the number NCT04887948 [Pfizer, 2021 ]) sponsored by Pfizer that is being conducted in United States. It was first registered in May 2021 and plans to enroll 600 vaccinated adults 65 years of age and older that will receive 20vPnC and a booster dose of BNT162b2. It is expected to run until November 2021.

MOSAIC is an ongoing phase 2, randomized trial (registered with the number NCT04894435 [Canadian Immunization Research Network, 2021 ]) sponsored by Canadian Immunization Research Network that is being conducted in Canada. It was first registered in May 2021 and plans to enroll 1,200 healthy adults or with mild or moderate stable comorbidities 18 years of age and over that will receive Pfizer-BioNTech BNT162b2 and Moderna mRNA-1,273. It is expected to run until March 2023.

VATICO is an ongoing open-label, randomized trial (phase 4) (registered with the number NCT04969250 [International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), 2021 ]) sponsored by International Network for Strategic Initiatives in Global HIV Trials that is being conducted in United States, Denmark, Greece, India, Nigeria, Poland, Singapore, Spain, Switzerland, Uganda, and United Kingdom. It was first registered in July 2021 and plans to enroll 640 participants of the ACTIV-3/TICO clinical trial (NCT04501978) that will receive Moderna mRNA-1273 or the Pfizer BNT162b2 vaccine. It is expected to run until July 2022.

IMCOVAS is an ongoing phase 4, non-inferiority, randomized controlled trial (registered with the number 2021-001993-52 [University of Antwerp, 2021 ]) sponsored by University of Antwerp that is being conducted in Belgium. It was first registered in May 2021 and plans to enroll 840 healthy volunteer adults that will receive assess non-inferiority of the humoral immune response against SARS-Cov-2 infection of different vaccines and adapted vaccine schedules in comparison with the reference schedules (‘group a’ of each brand). End of study: Date not available.

Guerrerio PA et al is an ongoing phase 2, randomized, placebo-controlled crossover study (registered with the number NCT04977479 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases (NIAID) that is being conducted in United States. It was first registered in July 2021 and plans to enroll 100 people aged 18-69 that will receive a second dose of Pfizer-BioNTech COVID-19 vaccine or one dose of placebo on different days. It is expected to run until December 2022.

BECAME is an ongoing phase 4, a single-center, open-label, investigator-initiated randomized controlled, superiority trial (registered with the number NCT04961229 [dafna yahav, 2021 ]) sponsored by dafna yahav that is being conducted in Israel. It was first registered in July 2021 and plans to enroll 450 kidney transplant recipients that will receive a third booster dose of BNT162b2 with no change in immunosuppression or an immunosuppression reduction according to protocol. It is expected to run until July 2022.

C4591031 is an ongoing phase 3, randomized, controlled clinical trial (registered with the number NCT04955626 [BioNTech SE, 2021 ]) sponsored by BioNTech SE that is being conducted in United States, Brazil, Canada, and South Africa. It was first registered in July 2021 and plans to enroll 10000 participants ≥16 years of age that will receive a booster dose of BNT162b2 or placebo. It is expected to run until October 2022.

COVERALL is an ongoing phase 3, multicenter randomized controlled, open-label, 2-arm sub-study pilot trial (registered with the number NCT04805125 [University Hospital, Basel, Switzerland, 2021 ]) sponsored by University Hospital, Basel that is being conducted in Switzerland. It was first registered in March 2021 and plans to enroll 431 patients included in the Swiss HIV Cohort Study or the Swiss Transplant Cohort Study that will receive mRNA vaccine Comirnaty (Pfizer / BioNTech) or the Covid-19 mRNA Vaccine Moderna. It is expected to run until July 2022.

Boost-TX is an ongoing phase 2, randomized, single-blinded study (registered with the number 2021-002927-39 [Medical University of Vienna, 2021 ]) sponsored by Medical University of Vienna that is being conducted in Austria. It was first registered in May 2021 and plans to enroll 200 kidney transplant recipients that will receive BNT162b2 or mRNA-1273 (mRNA) vaccines. End of trial: Date not available.

CR109060 is an ongoing randomized, double-blind, phase 2 study (registered with the number NCT04999111 [Janssen Vaccines & Prevention B.V., 2021 ]) sponsored by Janssen Vaccines & Prevention B.V that is being conducted in United States. It was first registered in August 2021 and plans to enroll 660 adults 18 years of age and over that will receive Ad26.COV2.S administered as a booster vaccination. It is expected to run until 44,621.

Curumim is an ongoing phase 3 randomized study (registered with the number NCT05225285 [Federal University of Espirito Santo, 2022 ]) sponsored by Federal University of Espirito Santo that is being conducted in Brazil. It was first registered in February 2022 and plans to enroll 1120 healthy children and adults between 3 and 49 years old that will receive either the inactivated Coronavac/Butantan vaccine (VACC) or the immunizing BNT162b2 (Pfizer) (BNTC). The VACC group will also be compared to a group of adults aged 18 to 49 who received Coronavac (ADU). It is expected to run until March 2023.

Other studies providing efficacy or safety data

Dagan et al reported an observational study aimed to emulate a target trial [Dagan N, 2021 ] where vaccinated people from Israel’s largest health care organization were matched to unvaccinated controls in a 1:1 ratio) between December 2020 to February 2021.

BNT162-01 was a phase 1/2 non-randomized study (registered with the number NCT04380701 [Biontech RNA Pharmaceuticals GmbH, 2020 ]) sponsored by BioNTech SE that was conducted in Germany. It was first registered in May 2020 and enrolled 476 healthy adults, 19-55 years of age. The study evaluated four prophylactic SARS-CoV-2 RNA vaccines against COVID-19 using different dosing regimens [Ugur Sahin, 2020 ].

Bjork et al was a cohort study conducted in Sweden [Jonas Bjork, 2021 ]. The study included 805741 people aged 18-64 years. The study examined effectiveness of BNT162b2 vaccine against COVID-19.

Rossman et al conducted a retrospective analysis of data from the Israeli Ministry of Health conducted in Israel between August 28, 2020 and February 24, 2021 [Rossman H, 2021 ]. The study examined the temporal dynamics of the number of new COVID-19 cases and hospitalizations after the vaccination campaign, which was initiated on December 20, 2020.

Furer et al was an observational case series study monitoring post-vaccination adverse effects in people with autoimmune inflammatory rheumatic diseases conducted in Israel that included 590 patients [Furer V, 2021 ].

Golan et al conducted a prospective cohort study in 14 lactating individuals in the United States who received the Pfizer vaccine. The aim of the study was to determine whether anti-COVID-19 mRNA-based vaccines administered during lactation elicit an immune response or the transfer of anti-SARS-CoV2 antibodies into human milk. [Golan Y et al., 2021 ].

Shimabukuro et al. (CDC report) was a safety monitoring non-comparative study conducted in United States. The study enrolled 16,439 (pregnant persons) pregnant persons that received Moderna or Pfizer-BioNTech COVID-19 vaccine. Based on data from Vaccine Adverse Event Reporting System and the v-safe system from December 14 2020 to February 28, 2021.

Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324,033 participants that received Moderna or Pfizer-BioNTech 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.

Pawlowski C et al. was a retrospective cohort study conducted in United States. The study enrolled 266,094 participants (94,818 Pfizer doses). Based on data from the Mayo Clinic health system between January 1 2017 and March 15, 2021.

Zaqout A et al. was a retrospective cohort study (non-comparative) conducted in Qatar. The study enrolled 199,219 that received Pfizer-BioNTech COVID-19 vaccine. Based on data from the Communicable Disease Center, Hamad Medical Corporation on 16 March 2021.

Dagan N et al. was a cohort study conducted in Israel. The study enrolled 1,193,236 general population 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.

Barda N et al. was an observational study conducted in Israel. The study enrolled 1,736,832 general population 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 May 24, 2021 [Barda N, 2021 ].

Levy M et al is a 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 results. The authors suggest that COVID-19 mRNA vaccination was associated with a lower incidence of multisystem inflammatory syndrome in adolescents [Levy M, 2021 ].

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

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 ].

See I et al. was a non-comparative study conducted in the United States. The study enrolled 57 participants describes surveillance data and reports thrombosis rates with thrombocytopenia syndrome (TTS) cases after vaccination with Janssen, Moderna and Pfizer-BioTech COVID-19 vaccine [See I, 2022 ].

PRESTO was a cohort study conducted in the United States and Canada that assessed the association of female and male COVID-19 vaccination with fecundability from December 2020 to September 2021 [Wesselink AK, 2022 ]. 

Nakahara A et al. was a comparative cohort study conducted in United States [Nakahara A, 2022 ], evaluating safety results in pregnant individuals who received a dose of Moderna or Pfizer COVID-19 vaccine.

Levy M et al is a cohort study conducted in France [Levy M, 2021 ], evaluating the effect of vaccination on the multisystem inflammatory syndrome in children (MIS-C). In this study, the risk of MIS-C among adolescents by COVID-19 vaccination status during September 2021and October 2021 was estimated.

Huang HJ et al. was a comparative cohort study conducted in United States [Huang HJ, 2022 ], evaluating immunogenicity results from a cohort of solid organ transplant candidates and recipients who received two doses of Pfizer or Moderna COVID-19 vaccine.

Spensley K et al. was a cohort study conducted in United Kingdom [Katrina Spensley, 2022 ], evaluating vaccine effectiveness against the Omicron (B.1.1.529) variant in patients receiving haemodialysis.

The VIVALDI study was a cohort study conducted in United Kingdom [Oliver Stirrup, 2022 ], evaluating immunogenicity results from older adults residents of long-term care facilities who received two-dose of AstraZeneca or Pfizer COVID-19 vaccine. 

Muhsen K et al. was a non-randomized study conducted in Israel [Muhsen K, 2021 ], evaluating effects of Pfizer COVID-19 vaccine booster in long-care residents who were 60 years of age or older.

Tenforde MW et al. was a case-control study conducted in United States [Tenforde MW, 2022 ], evaluating vaccine effectiveness against  COVID-19  hospitalization in adults who had received two-dose of Pfizer o Moderna COVID-19 vaccine and had not received a third dose versus adults who had received the third dose

Li LL et al. was a comparative cohort study conducted in United States [Li LL, 2022 ], evaluating impact of prior SARS-CoV-2 infection on incidence of hospitalization and adverse events in veterans males after receiving Pfizer, Moderna or Janssen COVID-19 vaccines.

Aharon D et al. was a comparative cohort study conducted in United States [Aharon D, 2022 ], evaluating whether Pfizer or Moderna COVID-19 vaccine is associated with controlled ovarian hyperstimulation or early pregnancy outcomes in patients who undergo in vitro fertilization.

Accorsi EK et al. was a case-control study (Test-negative) conducted in United States [Accorsi EK, 2022 ], estimating the association between receipt of 3 doses of Pfizer or Moderna COVID-19 vaccine and symptomatic SARS-CoV-2 infection, stratified by variant.

McConeghy KW et al. was a comparative cohort study conducted in United States [Kevin W McConeghy, 2022 ], evaluating the effectiveness of a booster dose of Pfizer or Moderna COVID-19 vaccine in two nation-wide nursing home systems.

Buchan SA et al. was a Case-control study (Test-negative) conducted in Canada [Buchan, S. A., 2022 ], evaluating effectiveness among those who have received 2 doses of COVID-19 vaccines.

Johnson AG et al. was a comparative cohort study conducted in United States [Johnson AG, 2022 ], evaluating the effectiveness of a booster dose of Pfizer, Moderna, and Janssen COVID-19 vaccines in adults during periods of Delta and Omicron variant emergence.

The VISION Network study was a comparative cohort study conducted in United States [Thompson MG, 2022 ], evaluating effectiveness from adult individuals who had received Pfizer or Moderna COVID-19 vaccine during periods of Delta and Omicron variant predominance between august 2021 to January 2022.

Milano E et al. was a comparative cohort study conducted in Italy [Milano E, 2022 ], evaluating the immunogenicity and safety of the two doses of Pfizer COVID-19 vaccine.

Lytras T et al. was a comparative cohort study conducted in Greece [Theodore Lytras, 2022 ], evaluating vaccine effectiveness from individuals aged 15 years and over who had received two doses of Pfizer, Moderna, AstraZeneca COVID-19 vaccine or a single-dose of Janssen COVID-19 vaccine.

Perez-Then et al. was a comparative cohort study conducted in Dominican Republic [Pérez-Then E, 2022 ], evaluating immunogenicity results from adult individuals who had received two doses of Sinovac COVID-19 vaccine and a booster dose of Pfizer COVID-19 vaccine.

The ACCL21C2 is an ongoing prospective Cohort study (registered with the number NCT05228275 [Children's Oncology Group, 2022 ]) sponsored by Children's Oncology Group that is being conducted in United States. It was first registered in February 2022 and plans to enroll 532 individuals aged between 6 and 37 years old that will receive one of the FDA-EUA approved COVID-19 vaccines: Pfizer-BioNTech, Moderna or Janssen COVID-19 vaccines. It is expected to run until December 2024.

The 7 vaccines against COVID-19 study is an ongoing Prospective Cohort study (registered with the number NCT05228912 [Hospital Clinica Nova, 2021 ]) sponsored by Hospital Clinica Nova that is being conducted in Mexico. It was first registered in February 2022 and plans to enroll 1870 Children, Adult and Older Adult that will receive Pfizer-BioNTech, Moderna, Gamaleya, Cansino, Sinovac, Astrazeneca and Janssen COVID-19 vaccines. It is expected to run until October 2024.

Li et al. is a multicentre cross-sectional study conducted at rheumatology clinics in two major hospitals in Hong Kong [Li YK, 2022 ]. This study investigated the vaccination rate, reported side effects, and patient concerns for COVID‐19 vaccination in patients with rheumatic diseases who were interviewed between June 3, 2021 and October 8, 2021. 81.1% of vaccinated participants reported side effects, of which the most common were injection site pain or swelling, followed by fatigue, fever, and headache. Other side effects were uncommon and no serious side effects leading to hospitalization or death were found. In addition, younger age and messenger RNA (mRNA) vaccines were associated with more side effects and there was no difference in risk of side effects between specific rheumatic diseases or drug therapies. The authors suggest that COVID‐19 vaccination is associated with no increased risk of side effects in any particular disease or drug therapy, therefore vaccination should be encouraged in patients with rheumatic disease [Li YK, 2022 ].

 

Other ongoing registered studies 

COVAXID is an ongoing single group assignment study (registered with the number NCT04780659 [Karolinska University Hospital, 2021 ]) sponsored by Karolinska University Hospital that is being conducted in Sweden. It was first registered in March 2021 and plans to enroll 540 people with primary or secondary immunosuppressive disorders, as well as immunocompetent people, with the aim of investigating the immune response. Participants will receive the Comirnaty mRNA vaccine against COVID-19 administered two times, one at Day 0 and the second dose at Day 21. It is expected to run until December 2022.

900/24-12-2020 is an ongoing cohort study (registered with the number NCT04743388 [National and Kapodistrian University of Athens, 2021 ]) sponsored by the National and Kapodistrian University of Athens that is being conducted in Greece. It was first registered in February 2021 and plans to enroll 600 healthy volunteers ≥ 18 years old with the objective of determining both the degree and duration of the immunity provided after receiving Pfizer mRNA Vaccine. It is expected to run until April 2022.

SABREVAC is an ongoing observational study (registered with the number NCT04733807 [University of Roma La Sapienza, 2021 ]) sponsored by the University of Roma La Sapienza that is being conducted in Italy. It was first registered in February 2021 and plans to enroll 600 hospital health workers with the objective of monitoring IgM and IgG evolution after receiving BNT162b2 mRNA Vaccine to prevent COVID-19. It is expected to run until February 2022.

C4591007 is an ongoing non-randomized study (registered with the number NCT04816643 [BioNTech SE, 2021 ]) sponsored by BioNTech SE that is being conducted in the United States. It was first registered in March 2021 and plans to enroll 4644 healthy children <12 years of age with the objective of assessing the benefit-risk, safety, tolerability and immunogenicity of the BNT162b2 vaccine. It is expected to run until August 2023.

CoviCompareP is an ongoing non-randomized study (registered with the number NCT04824638 [ANRS, Emerging Infectious Diseases, 2021 ]) sponsored by ANRS, Emerging Infectious Diseases, that is being conducted in France. It was first registered in April 2021 and plans to enroll 300 participants with prior SARS-CoV-2 infection that will receive a single administration of the vaccine BNT162b2. It is expected to run until December 2023.

GREVAXIMO is an ongoing cohort study (registered with the number NCT04756817 [G.Gennimatas General Hospital, 2021 ]) sponsored by G.Gennimatas General Hospital, that is being conducted in Greece. It was first registered in February 2021 and plans to enroll 500 elderly people over 85 years of age, with the objective of evaluating the immunogenicity of the vaccine BNT162b2. It is expected to run until September 2021.

COVIVAC-ID is an ongoing single group assignment study (registered with the number NCT04844489 [Assistance Publique - Hôpitaux de Paris, 2021 ]) sponsored by Assistance Publique - Hôpitaux de Paris that is being conducted in France. It was first registered in April 2021 and 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 BNT162b2 vaccination and efficacy against SARS-CoV-2 variants. It is expected to run until December 2022.

C4591014 is an ongoing case-control study (registered with the number NCT04848584 [Pfizer, 2021 ]) sponsored by Pfizer that is being conducted in the United States. It was first registered in April 2021 and plans to enroll 999 participants 16 years and older that have received the 2 doses of the BNT162b2 vaccine. It is expected to run until July 2023.

REDU-VAC is an ongoing non-randomized phase 4 prospective study (registered with the number NCT04852861 [Sciensano, 2021 ]) sponsored by Sciensano that is being conducted in Belgium. It was first registered in April 2021 and plans to enroll 200 healthy adults up to 55 years old, to assess safety and immunogenicity of demi-doses of two COVID-19 mRNA vaccines, including Pfizer-BioNTech COVID‑19 Vaccine. It is expected to run for until September 2022.

COVATRANS is an ongoing cohort study (registered with the number NCT04828460 [University Hospital, Strasbourg, France, 2021 ]) sponsored by University Hospital, Strasbourg that is being conducted in France. It was first registered in April 2021 and plans to enroll 3,500 kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna, and Astra-Zeneca vaccines. It is expected to run until February 2023.

COVAC-IC is an ongoing non-randomized study (registered with the number NCT04805216) sponsored by University Hospitals of North Midlands NHS Trust that is being conducted in United Kingdom [University Hospitals of North Midlands NHS Trust, 2021 ]. It was first registered in March 2021 and plans to enroll 80 immunocompromised and immunocompetent haematology patients aged 18 years and older that will receive blood tests at baseline (15 - 30 days after 2nd dose of Covid-19 vaccine, +/- 5 days). It is expected to run for until November 2021.

COMBI is an ongoing non-randomized study (registered with the number 2021-000182-33) sponsored by Radboudumc that is being conducted in Netherlands
[Radboudumc, 2021 ]. It was first registered in January 2021 and plans to enroll 40 health care workers aged 18-64 years that will receive had received BCG-vaccination prior to BioNTech/Pfizer COVID-19 vaccine. 

HHCTC_COVID-19_VACCINE_Ab is an ongoing phase 4, non-randomized study (registered with the number NCT04775069 [Humanity & Health Medical Group Limited, 2021 ]) sponsored by Humanity & Health Medical Group Limited that is being conducted in Hong Kong, China. It was first registered in March 2021 and plans to enroll 900 adults with chronic liver disease or Underlying CLD, aged 18 years and older that will receive mRNA vaccine (Pfizer-Biontech), inactivated SARS-CoV-2 (Sinovac), or adenovirus-vector COVID-19 vaccine (Astrazeneca-Oxford). It is expected to run until March 2022.

ANTICOV is an ongoing monocentric observational study (registered with the number NCT04878796 [Azienda Socio Sanitaria Territoriale di Cremona, 2021 ]) sponsored by Azienda Socio Sanitaria Territoriale di Cremona that is being conducted in Italy. It was first registered in May 2021 and plans to enroll 300 cancer patients aged 18 years and older, to evaluate the effectiveness of BNT162b2 or mRNA-1273 vaccine. It is expected to run until May 2022.

COVA is an ongoing non-randomized study (registered with the number NCT04800133 [The University of Hong Kong, 2021 ]) sponsored by The University of Hong Kong that is being conducted in Hong Kong, China. It was first registered in March 2021 and plans to enroll 900 healthy or clinically stable participants aged 11 years and older that will receive BNT162b2 and CoronaVac. It is expected to run until March 2025.

UNICO is an ongoing non-randomized study (registered with the number NCT04932863 [Ente Ospedaliero Ospedali Galliera, 2021 ]) sponsored by Ente Ospedaliero Ospedali Galliera that is being conducted in Italy. It was first registered in June 2021 and plans to enroll 300 cancer patients aged 18 years and older that will receive BNT162b2 mRNA Covid-19 vaccine. It is expected to run until March 2023.

2021-04-30T1 is an ongoing non-randomized study (registered with the number NCT04895007 [Karamano?lu Mehmetbey University, 2021 ]) sponsored by Karamanoğlu Mehmetbey University that is being conducted in Turkey. It was first registered in May 2021 and plans to enroll 1,500 adults aged 18 years and older that will receive Sinovac, Sputnik V, or Pfizer / BionTEC vaccine. It is expected to run until June 2022.

COViNEPH-1 is an ongoing non-randomized study (registered with the number NCT04905862 [Medical University of Gdansk, 2021 ]) sponsored by Medical University of Gdansk that is being conducted in Poland. It was first registered in May 2021 and plans to enroll 180 patients on chronic dialysis vaccinated with BNT162b2. It is expected to run until May 2022.

BNT162-04 is an ongoing multi-site, phase 1/2, 2-part, dose-escalation, non-randomized study (registered with the number NCT04537949 [BioNTech RNA Pharmaceuticals GmbH, 2020 ]) sponsored by BioNTech SE that is being conducted in Germany. It was first registered in September 2020 and plans to enroll 96 healthy adults aged 18-85 years that will receive BNT162b3 administered as a prime or boost injection. It is expected to run until February 2022.

SHEBA is an ongoing non-randomized study (registered with the number NCT04778033 [Sheba Medical Center, 2021 ]) sponsored by Sheba Medical Center that is being conducted in Israel. It was first registered in March 2021 and plans to enroll 75 fertile men that received BNT162b2 COVID-19 Vaccine. It is expected to run until May 2021.

C4591019 is an ongoing multicenter cohort study (registered with the number NCT04880447 [Pfizer, 2021 ]) sponsored by Pfizer that is being conducted in Japan. It was first registered in May 2021 and plans to enroll 1000 patients aged 16 years and older with underlying disease considered to be at high risk of aggravation of COVID-19 that received BNT162b2 vaccine. It is expected to run until May 2022.

C4591006 is an ongoing non-randomized study (registered with the number NCT04815031 [Pfizer, 2021 ]) sponsored by Pfizer that is being conducted in Japan. It was first registered in March 2021 and plans to enroll 20000 healthcare professionals who are vaccinated at an early post-approval stage of COMIRNATY. It is expected to run until December 2022.

Gurbel PA et al is an ongoing non-randomized study (registered with the number NCT04910971 [LifeBridge Health, 2021 ]) sponsored by LifeBridge Health that is being conducted in United States. It was first registered in June 2021 and plans to enroll 60 health care workers that received Pfizer/BioNTech or Moderna vaccine. It is expected to run until July 2022.

Covid-19-Abs is an ongoing non-randomized study (registered with the number NCT04944095 [Dr. Sidney J. Stohs, 2021 ]) sponsored by Dr. Sidney J. Stohs that is being conducted in United States. It was first registered in June 2021 and plans to enroll 10,000 residents and staff associated with nursing homes, extended care facilities, and over 55 communities that will receive Pfizer, Moderna, or J &J COVID-19 vaccines. It is expected to run until December 2022.

CoVEHPI is an ongoing cohort study (registered with the number NCT04709003 [Clalit Health Services, 2020 ]) sponsored by Clalit Health Services that is being conducted in Israel. It was first registered in January 2021 and plans to enroll 4,504 healthcare workers aged 18 years and older that will receive Pfizer or Moderna COVID-19 vaccine. It is expected to run until June 2022.

ImmunoHaema-COVID-VAX-21 is an ongoing prospective, cohort, non-interventional, single-center clinical study (registered with the number NCT04878822 [Ospedale di Circolo - Fondazione Macchi, 2021 ]) sponsored by Ospedale di Circolo - Fondazione Macchi that is being conducted in Italy. It was first registered in May 2021 and plans to enroll 300 patients with hematological malignancies 18 years of age and over that received BNT162b2 vaccine, ChAdOx1 nCoV-19 vaccine, or Ad26.COV2.S vaccine. It is expected to run until April 2023.

McKelvey JL et al. is an ongoing non-randomized study (registered with the number NCT04852289 [National Institute on Aging (NIA), 2021 ]) sponsored by National Institute on Aging that is being conducted in United States. It was first registered in April 2021 and plans to enroll 160 healthy individuals over 18 years of age that will receive Pfizer and Moderna vaccines. It is expected to run until March 2024.

AssiutU21 is an ongoing prospective cohort (registered with the number NCT04706143 [Assiut University, 2021 ]) sponsored by Assiut University that is being conducted in Egypt. It was first registered in January 2021 and plans to enroll 100 healthy adults aged from 25-65 years old non immune-compromised or immune suppressed that received different available vaccines. It is expected to run until August 2021.

C4591024 is an ongoing phase 2, non-randomized study (registered with the number NCT04706143 [BioNTech SE, 2021 ]) sponsored by BioNTech SE that is being conducted in United States, Brazil and Germany. It was first registered in May 2021 and plans to enroll 360 immunocompromised participants ≥2 Years Of Age that will receive BNT162b2 vaccine. It is expected to run until January 2023.

Friis-Hansen L et al. is an ongoing non-randomized study (registered with the number NCT04842305 [Lenanrt Friis-Hansen, 2021 ]) sponsored by
Lenanrt Friis-Hansen that is being conducted in Denmark. It was first registered in April 2021 and plans to enroll 500 SARS-COV-2 Naïve persons, COVID-19 convalescents, and vaccinated with Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, or AstraZeneca ChAdOx1-S vaccine. It is expected to run until March 2024.

Pro00053511 is an ongoing non-randomized study (registered with the number NCT04883164 [Plexision, 2021 ]) sponsored by Plexision that is being conducted in United States. It was first registered in May 2021 and plans to enroll 300 adults aged 18 years or older that received Pfizer COVID-19 vaccine. It is expected to run until March 2023.

21-0012 is an ongoing phase 1/2, non-randomized study (registered with the number NCT04889209 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases that is being conducted in United States. It was first registered in May 2021 and plans to enroll 550 vaccinated healthy individuals 18 years of age and over that will receive a delayed booster dose of Ad26.COV2.S or mRNA-1273 vaccine. It is expected to run until May 2025.

IROC is an ongoing non-randomized study (registered with the number NCT04930055 [Indiana University, 2021 ]) sponsored by Indiana University that is being conducted in United States. It was first registered in June 2021 and plans to enroll 240 cancer patients 18 years of age and over receiving BTN162b2, mRNA-1273, or Ad26.COV2.S. It is expected to run until August 2023.

GREVACIM is an ongoing phase 4, non-randomized study (registered with the number ISRCTN61884303 [Georgios Gennimatas General Hospital, 2021 ]) sponsored by Georgios Gennimatas General Hospital that is being conducted in Greece. It was first registered in December 2020 and plans to enroll 450 health professionals 18-69 years of age that will receive BNT162b2 mRNA Covid-19 vaccine. It is expected to run until March 2022.

LymphVAX is an ongoing non-randomized study (registered with the number NCT04872738 [Massachusetts General Hospital, 2021 ]) sponsored by Massachusetts General Hospital that is being conducted in United States. It was first registered in May 2021 and plans to enroll 2000 women with a history of breast cancer that will receive Moderna or Pfizer COVID-19 vaccines. It is expected to run until December 2022.

VIOLA is an ongoing non-randomized study (registered with the number NCT04843774 [NYU Langone Health, 2021 ]) sponsored by NYU Langone Health that is being conducted in United States. It was first registered in April 2021 and plans to enroll 60 COVID-negative Multiple Sclerosis patients treated with ocrelizumab that received Moderna or Pfizer COVID-19 vaccines. End of study: Date not available.

Covid Vaccin Allo is an ongoing phase 4, non-randomized study (registered with the number NCT04951323 [University of Liege, 2021 ]) sponsored by University of Liege that is being conducted in Belgium. It was first registered in July 2021 and plans to enroll 50 patients allo-hematopoietic cell transplantation recipients that will receive BNT162b2 vaccine. It is expected to run until January 2023.

Bahl A et al. is an ongoing non-randomized study (registered with the number NCT04912700 [William Beaumont Hospitals, 2021 ]) sponsored by William Beaumont Hospitals that is being conducted in United States. It was first registered in June 2021 and plans to enroll 11834 unvaccinated individuals, partially or fully vaccinated with Pfizer, Moderna or Johnson & Johnson COVID-19 vaccines. It is expected to run until June 2021.

VAX4FRAIL is an ongoing non-randomized study (registered with the number NCT04848493 [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ]) sponsored by Azienda Unità Sanitaria Locale Reggio Emilia that is being conducted in Italy. It was first registered in April 2021 and plans to enroll 1300 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. It is expected to run until April 2022.

UMIN000043851 is an ongoing non-randomized study (registered with the number UMIN000043851 [St. Marianna University School of Medicine, Dept. of Gastroenterology and Hepatology, 2021 ]) sponsored by St. Marianna University School of Medicine that is being conducted in Japan. It was first registered in April 2021 and plans to enroll 100 medical workers 18 years of age and over that will receive BNT162b2 mRNA COVID-19 vaccine. End of study: Date not available.

UMIN000044261 is an ongoing non-randomized study (registered with the number UMIN000044261 [Kamagaya General Hospital, 2021 ]) sponsored by Kamagaya General Hospital that is being conducted in Japan. It was first registered in June 2021 and plans to enroll 551 Kamagaya general hospital staff 20 years of age and older that received a COMIRNATY intramuscular injection. End of study: Date not available.

EREVA is an ongoing phase 4, non-randomized study (registered with the number NCT04952766 [Centre Hospitalier Régional d'Orléans, 2021 ]) sponsored by Centre Hospitalier Régional d'Orléans that is being conducted in France. It was first registered in July 2021 and plans to enroll 240 adults immunocompromised or non-immunocompromised volunteers that will receive Comirnaty COVID-19 vaccine. It is expected to run until March 2022.

2021-000175-37 is an ongoing phase 4, open, non-randomized, multicenter study (registered with the number 2021-000175-37 [Karolinska Universitetssjukhuset, 2021 ]) sponsored by Karolinska Universitetssjukhuset that is being conducted in Sweden. It was first registered in February 2021 and plans to enroll 540 adults aged 18 years and older with/without immunosuppressive disease that will receive Comirnaty COVID-19 vaccine. End of study: Date not available.

Bauernfeind S et al. is an ongoing phase 4, non-randomized study (registered with the number DRKS00025271 [Uniklinik Regensburg Abteilung für Hygiene und Infektiologie, 2021 ]) sponsored by Uniklinik Regensburg Abteilung für Hygiene und Infektiologie that is being conducted in Germany. It was first registered in May 2021 and plans to enroll 154 Universitätsklinikum Regensburg staff aged 18-60 years vaccinated with ChAdOx1-S that will receive a second dose with BNT162b2 vaccine. End of study: Date not available.

NL73618.100.20 is an ongoing phase 4, non-randomized study (registered with the number 2021-001202-30 [Diakonessenhuis, 2021 ]) sponsored by Diakonessenhuis that is being conducted in Netherlands. It was first registered in April 2021 and plans to enroll 400 healthy volunteers aged 18 years and older that will receive Pfizer, Moderna, Janssen or AstraZeneca COVID-19 vaccine. End of study: Date not available.

Shieldvacc2 is an ongoing phase 4, non-randomized study (registered with the number 2021-002030-16 [Medizinische Universität Innsbruck, Institut für Virologie, 2021 ]) sponsored by Medizinische Universität Innsbruck, Institut für Virologie that is being conducted in Austria. It was first registered in April 2021 and plans to enroll 3,340 women of child-bearing potential using contraception, 12 years of age and older, vaccinated with two-doses of Comirnaty. End of study: Date not available.

PACIFIC is an ongoing phase 1 and 2, interventional, non-randomized study (registered with the number NCT04969601 [Assistance Publique - Hôpitaux de Paris, 2021 ]) sponsored by Assistance Publique - Hôpitaux de Paris that is being conducted in France. It was first registered in July 2021 and plans to enroll 150 children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old) that will receive BNT162b2 vaccine. It is expected to run until February 2023.

CPAT is an ongoing non-randomized study (registered with the number NCT04969263 [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]) sponsored by National Institute of Allergy and Infectious Diseases (NIAID) that is being conducted in United States. It was first registered in July 2021 and plans to enroll 200 kidney transplant recipients that will receive a third dose of Moderna COVID-19 vaccine or Pfizer-BioNTech COVID-19 vaccine. It is expected to run until October 2022.

COGEVAX-BIO is an ongoing interventional, non-randomized study (registered with the number NCT04961502 [Gérond'if, 2021 ]) sponsored by Gérond'if that is being conducted in France. It was first registered in July 2021 and plans to enroll 40 people over age 75 institutionalized in the long-term care units that received BNT162b2 vaccine. It is expected to run until September 2021.

O'Connor DL et al. is an ongoing cohort (registered with the number NCT05004740 [Deborah O'Connor, 2021 ]) sponsored by Deborah O'Connor that is being conducted in Canada. It was first registered in August 2021 and plans to enroll 700 lactating mothers that will receive Pfizer-BioNTech and Moderna COVID-19 vaccines. It is expected to run until 44,621.

Stupica D et al. is an ongoing observational study (registered with the number NCT05198453) sponsored by University Medical Centre Ljubljana that is being conducted in Slovenia [University Medical Centre Ljubljana, 2021 ]. It was first registered in January 2022 and plans to enroll 529 participants 18 years and over that received Pfizer, Moderna, AstraZeneca, or Janssen COVID-19 vaccine. It is expected to run for until January 2022.

HUM00206480 is an ongoing phase 4, non-randomized study (registered with the number NCT05212610 [University of Michigan, 2022 ]) sponsored by University of Michigan that is being conducted in United States. It was first registered in January 2022 and plans to enroll 200 individuals aged 18 years and older that had adverse reactions to the first dose of a mRNA COVID-19 vaccine. The participants will receive a second dose of the Pfizer-BioNTech COVID-19 vaccine. It is expected to run until December 2024.

STOPCoV is an ongoing cohort study (registered with the number NCT05208983 [University Health Network, Toronto, 2021 ]) sponsored by University Health Network, Toronto that is being conducted in Canada. It was first registered in January 2022 and plans to enroll 1286 individuals aged 30-50 years and individuals aged 70 years and over that will receive Pfizer, Moderna, Janssen, or AstraZeneca COVID-19 vaccines. It is expected to run until March 2024.

As-Vac-CoV is an ongoing non-randomized study (registered with the number EudraCT 2021-006832-24 [Ziekenhuis Oost-Limburg A.V., 2021 ]) sponsored by Ziekenhuis Oost-Limburg A.V. that is being conducted in Belgium. It was first registered in December 2021 and plans to enroll 2600 individuals aged 18 years and older that will receive a second dose or booster dose of AstraZeneca, Moderna, or Pfizer COVID-19 vaccine. End of study: date not available.

Sheba HCW Cohort is an ongoing phase 4, non-randomized study (registered with the number NCT05231005 [Sheba Medical Center, 2021 ]) sponsored by Sheba Medical Center that is being conducted in Israel. It was first registered in February 2022 and plans to enroll 1000 individuals aged 18 years and older that received Pfizer-BioNTech COVID-19 vaccine. The participants will receive a fourth dose of Pfizer COVID-19 vaccine 4 months after the third dose. It is expected to run until June 2022.

 

 

 

Methods used to assess efficacy

In the C4591001 trial [Polack, Fernando P., 2020 ], the primary endpoint was specified as efficacy against confirmed COVID-19, with onset at least 7 days after the second dose in participants who had been without serologic or virologic evidence of SARS-CoV-2 infection, up to 7 days after the second dose.

Confirmed COVID-19 was defined according to the FDA criteria for clinical symptoms and a positive for SARS-CoV-2 by nucleic acid amplification–based testing, either at the central laboratory or at a local testing facility.

Safety evaluation methods

C4591001 trial [Polack, Fernando P., 2020 ]

Primary safety endpoints

Solicited, specific local or systemic adverse events and use of antipyretic or pain medication within 7 days after the receipt of each dose of vaccine or placebo, and unsolicited adverse events through 1 month after the second dose and unsolicited serious adverse events through 6 months after the second dose. 

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 (40 per 1000) versus 77 out of 20998 in the group that did receive it (4 per 1000). In other words, 36 less people per 1000 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 28. Which means that 28 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 COVID-19 after the first dose (median follow-up time of 2 months)

The relative risk of contracting COVID-19 after the first dose in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.18 (95% CI 0.13 to 0.25). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 after the first dose in 82%, compared with placebo vaccine.

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

In the trials identified in this review, 275 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21686 presented this outcome (13 per 1000) versus 50 out of 21669 in the group that did receive it (2 per 1000). In other words, 11 less people per 1000 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 82%, or that the intervention reduced the risk of contracting COVID-19 after the first dose by 82 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 is 91. Which means that 91 people need to receive the vaccine for one of them to not contracting COVID-19 after the first dose.

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


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 (1 per 1000) versus 1 out of 23040 in the group that did receive it (0 per 1000). In other words, 1 less people per 1000 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.



Contracting COVID-19 (16-64y) (measured at least 7 days after the second injection)

The relative risk of contracting COVID-19 (16-64y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.06 (95% CI 0.02 to 0.16). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 (16-64y) by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (16-64y). Comparison: Pfizer-BioNTech COVID-19 vaccine versus placebo vaccine

In the trials identified in this review, 69 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 18325 presented this outcome (4 per 1000) versus 4 out of 18198 in the group that did receive it (0 per 1000). In other words, 4 less people per 1000 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 (16-64y) 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 250. Which means that 250 people need to receive the vaccine for one of them to not contracting COVID-19 (16-64y).

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

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 (6 per 1000) versus 7 out of 20998 in the group that did receive it (0 per 1000). In other words, 6 less people per 1000 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 167. Which means that 167 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 (18 per 1000) versus 3 out of 2636 in the group that did receive it (1 per 1000). In other words, 17 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% (15,921 out of 37,706 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% (2,260 out of 3,358 participants) [Frenck RW, 2021 ].

The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1,098 out of 3,358 participants) [Frenck RW, 2021 ].

In the group that included 1,983 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 2,229 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 to 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 ].

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 ].

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 ].

 
Sex

Randomized trials

The proportion of females in the C4591001 trial was 49.4% (18,631 out of 37,706 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, 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% (2,260 out of 3,358 participants) [Frenck RW, 2021 ].

The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1,098 out of 3,358 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 2,229 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% to 100%) [Frenck RW, 2021 ].


Other comparative studies

C4591007 is an ongoing non-randomized study evaluating the efficacy of the vaccine in children and adolescents [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 ].

Levy M et al is a 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 results. The authors suggest that COVID-19 mRNA vaccination was associated with a lower incidence of multisystem inflammatory syndrome in adolescents [Levy M, 2021 ].

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 ]

 

Pregnancy

Randomized trials

Pregnant females of 18 years of age and over 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 ].

 

Breast-feeding

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 ].

 

Immunocompromised people

Randomized trials

Immunocompromised participants were excluded from the C4591001 trial, so 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 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 hematological malignancies 18 years of age and over [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 over [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 ].

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 ].

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 hemodialysis. 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%) [Katrina Spensley, 2022 ].

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, 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 it was 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, and the rate of severe infections was significantly reduced in all the disease-modifying therapies excluding ocrelizumab [Irene Schiavetti, 2022 ].

 

Persons with recent COVID-19

Randomized trials

Available data are currently insufficient to assess efficacy in persons with recent COVID-19.

Other data on vaccine efficacy and effectiveness

Main effectiveness outcomes of Pfizer COVID-19 vaccine (Other 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 the 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. The outcome was 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 vaccine group ; 302,909 Control group. Based on retrospective surveillance data from the nationwide vaccination program in people aged ≥ 16 years in Maccabi HealthCare services, Israel, between January 18 to April 25, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness of 93.0% (95% CI 92.6 to 93.4) [Yaki Saciuk, 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 healthcare 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 and 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 the 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 28 December 2020 and 19 May 19 2021. Outcomes were 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. The outcome was measured starting at ≥ 8 days after the 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 with health care personnel from the Alicante-Hospital-General health department between January 25 and June 6, 2021. Results showed 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 the Pfizer vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing an 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 the United Kingdom. The study included 82,959 health care workers. Based on data from a national cohort of health care workers to describe the uptake of COVID-19 vaccines and effectiveness of the Pfizer COVID-19 vaccine against PCR-confirmed infection following first and second doses, between 7 December 2020 to 30 September 2021. The study results showed that the effectiveness of the Pfizer COVID-19 vaccine was found to be strong and consistent across the different dose groups; 52% in the first dose group and 86% in the second dose group. The effectiveness of the vaccine declined to 53% when measured 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 responsible for more than 90% of severe SARS-CoV-2 infections nationwide in Japan, the study results showed 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 the 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 vaccine effectiveness against documented infection of 68.9% (95% CI.:61.9,74.7)( Outcome measured 14 days after the 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 ]

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 individuals. The 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 vaccine effectiveness against infection after 26 weeks from 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 positive to COVID-19, 8,817 were 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 were 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 the Pfizer vaccine and 150,423 received the 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 was 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 ]

 

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 the 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 vaccine group; 302,909 Control group. Based on retrospective surveillance data from the nationwide vaccination program in people aged ≥ 16 years in Maccabi HealthCare services, Israel, between January 18 to April 25, 2021. Outcomes were measured starting 7 days after the second dose. Results showed vaccine effectiveness against hospitalization of 93.4% (95% CI 91.9 to 94.7) and deaths of 91.1% (95% CI 86.5 to 94.1) [Yaki Saciuk, 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 cases line 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. The 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 ].

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 the Pfizer vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing an 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 ].  

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 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 ].

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, 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 ].

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 was 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 ].

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 individuals. The 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 vaccine effectiveness against infection after 26 weeks from the second dose was 45% (95% CI 44 to 47) for the Pfizer-BioNTech vaccine. [Drawz PE, 2022  

Whittaker R et al was a cohort study conducted in Norway. The study enrolled 3,203 hospitalized participants: 716 were fully vaccinated with mRNA vaccines, 2,487 were unvaccinated. Based on data from the Norwegian national emergency preparedness registry for COVID-19, patients 18 years and older were hospitalized between February 1 and November 30, 2021, with a positive SARS-CoV-2 test up to 2 days prior to their hospitalization, with a minimum of 13 days follow-up. The effectiveness of Pfizer-BioNTech for hospitalization outcomes expressed as adjusted hazard ratio compared to unvaccinated was: overall length of stay 1.61 (95%CI: 1.24 to 2.0), length of stay without ICU 1.27 (95%CI: 1.07 to 1.52) and ICU Admission 0.50 (95%CI: 0.37 to 0.69). [Whittaker R, 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 against severe infection of 87.1% (95% CI 80.3 to 91.6) [Emily Roberts, 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 healthcare 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 wanned 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 for 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 BNT162b2 vaccine. Rates of COVID-19 hospitalization and COVID-19 death at week 26 showed  HRs <0.20 (>80% vaccine effectiveness) for BNT162b vaccine.

 

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 cohorts 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 ].

 

 

SARS-CoV-2 variants

Immunogenicity outcomes

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. A 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 ].

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 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 ].

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 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 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 was 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.[ ].

Xia H et al. was a non-comparative study conducted in the United States. The study included serum panels that contain 22 specimens collected on the day of the third 30 µg Pfizer dose administered 7.9 to 8.8 months after the second dose and 1 and 4 months after the third dose. The study results showed that three doses of Pfizer elicited substantial neutralization activity against Omicron-spike SARS-CoV-2, while two doses showed significantly reduced [Hongjie Xia, 2022 ].

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 ].

Cohen et al. was a non-comparative study conducted in Israel. The study recruited 8 healthy individuals 4 to 5 months after the third dose of Pfizer vaccine. The study measured T cell response on donor PBMCs stimulated with a peptide pool derived from Wuhan or Omicron spike protein. The results showed a similar Th1 based response to both lineages with only a small, insignificantly decreased response to Omicron compared to Wuhan [Hila Cohen, 2022 ]. 

Biyan Zhang et al. was a cohort study conducted in Singapore. The study enrolled 52 participants and evaluated the levels of antibodies for the 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 ].

Benning et al. was a longitudinal cohort study conducted in Germany, which evaluated the humoral response generated by two doses of the Pfizer vaccine in adult participants over a prolonged period. The study reports data results from 60 healthcare workers who received two doses of the Pfizer COVID-19 vaccine. The study evaluated the antibody response against wild-type and Delta variants over a period of time. The results showed a similar neutralizing activity for both variants that decreases over time, with some individuals showing no neutralizing activity for both variants 8 months after the first dose [Benning L, 2022 ].

Lu et al, recruited 135 COVID-19 recovered individuals who were scheduled to receive either a Sinovac or Pfizer vaccine. The study compared the neutralizing response against the Beta, Delta and Omicron variants of the vaccinated individuals to the unvaccinated ones. The study found 1 dose of the Pfizer vaccine greatly increased the neutralizing titers against all three variants as well as the seropositivity rate. Neutralizing titers against the Delta and Beta variants were not significantly different than against the ancestral lineage [Lu Lu, 2022 ].

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 in adults older than 65 years old. Alidjinou et al, included 106 adults older than 65 years old who received a booster dose of the Pfizer COVID-19 vaccine. 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 amount 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 ].

Nickel et al. was a prospective cohort study conducted in Germany. The study followed two groups of vaccine recipients who either received a homologous Pfizer regimen plus a booster dose or an AstraZeneca/Pfizer regimen. The study measured mucosal and systemic antibody responses to wildtype, Beta and Delta variants.
Nickel et al. recruited 172 participants who received two doses of Pfizer vaccine plus a booster dose or one dose of AstraZeneca vaccine and one dose of Pfizer vaccine or had COVID-19. The study found the heterologous regimen induced higher neutralizing titers than the homologous regimen prior to a booster dose. All cohorts had decreased neutralizing titers against the Beta and Delta variants compared to wildtype virus. The booster dose increased neutralizing titers against wildtype, Beta and Delta variants when compared to 8 months after the second dose [Olaf Nickel, 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. At day 28 the GMT of neutralizing antibodies against the Delta variant increased to 1 505 and 2 088 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups, GMTs against Omicron variant reached 343.3 and 541.2 for the same vaccine groups  [Sitthichai Kanokudom, 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 ].

 

Efficacy outcomes

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 [Thomas SJ, 2021 ].

 

Effectiveness outcomes

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 efficacy 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% efficacy 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 the 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 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 ].

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 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 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 ].

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 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 ].

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 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 the 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 ].

Spensley K et al. included 1121 patients on hemodialysis. 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%) [Katrina Spensley, 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-negativecontrols= 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 againts 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 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 the presentation date. Pooled effectiveness against developing severe COVID-19 during 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. The effectiveness against the 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. [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 the 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 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 ].

 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 results 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 the United States. The study included 14,137 admissions. Based on data from members of Kaiser Permanente Southern California (KPSC), which contains a large integrated healthcare 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=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-negativecontrols= 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 againts 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 ].

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 ]

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 were 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 ]

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 ]

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 ].

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, hospitalizations 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 Brasil. It was a nationwide study of adults who were tested for SARS-CoV-2 infection. We evaluated vaccine effectiveness against symptomatic Covid-19 and severe Covid-19 (hospital admission or deaths) for the primary series of CoronaVac and homologous and heterologous (BNT162b2) booster doses. Vaccine effectiveness against Symptomatic COVID-19 after Two doses > 180 days was 3.7% (95% CI 2.5 to 5.0). Vaccine effectiveness after the third dose of CoronaVac (8-59 days) was 13.8% (95% CI 10.3 to 17.2) and after the third dose of Pfizer (8-59 days) was 57.2% (95% CI 56.6 to 57.8). Vaccine effectiveness against hospitalization or death after Third dose of CoronaVac (8-59 days) was 71.9% (95% CI 41.9 to 86.4) and after Third dose of Pfizer (8-59 days) was 90.8% (95% CI 88.5 to 92.7) [Otavio T. Ranzani, 2022 ].


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 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 ].

Eliakim-Raz N et al. was a before-after study conducted in Israel, assessing anti-spike (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 the SARS-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, from a median of 440 AU/mL (IQR, 294-923) to 25 468 AU/mL (IQR,14 203-36 618) [Eliakim-Raz N, 2021 ].

Xia H et al. was a non-comparative study conducted in the United States. The study included serum panels that contain 22 specimens collected on the day of the third 30 µg Pfizer dose administered 7.9 to 8.8 months after the second dose and 1 and 4 months after the third dose. The study results showed that three doses of Pfizer elicited substantial neutralization activity against Omicron-spike SARS-CoV-2, while two doses showed significantly reduced [Hongjie Xia, 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 8680 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 ].


Efficacy outcomes

C4591031was 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 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; 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 6, 2021 and September 29, 2021. Outcome was 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 the 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 the 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 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 or 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-negativecontrols= 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 againts 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. 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. The study showed that rates of COVID-19 cases were lowest among fully vaccinated persons with a booster dose of Pfizer COVID-19 vaccine, compared with fully vaccinated persons without a booster dose, and much lower than rates among unvaccinated persons. During October - November (Delta predominance period), average weekly incidence rate ratios were 3.7 (95% CI 3.4 to 4.1) among fully vaccine persons without booster dose and 12.9 (95% CI 11.4 to 14.5) among fully vaccinated persons with a booster dose. During December (Omicron Emergence period), average weekly incidence rate ratios were 2.6 (95% CI 1.4 to 4.7) among fully vaccine persons without booster dose and 4.5 (95% CI 2.4 to 8.3) among fully vaccinated persons with a booster dose
[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). 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 data from RT-PCR SARS-CoV-2 positive cases were 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 ].

 

Heterologous vaccine regimens

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 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 schedule [Liu X, 2021 ]. 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 ].

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 preserves antibody responses [Lazarus R, 2021 ].

Hollstein et al. 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. Hollstein et al, 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 on neutralizing antibodies titers that was 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 ].

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 ].

ISIDB-H was a phase 1, randomized controlled trial. The trial included 91 participants who had previously received 2 doses of CoronaVac, and were assigned to receive Pfizer-BioNTech boosters: 30 received a full intramuscular dose, 30 received half of an intramuscular dose and 31 received an intradermal booster of one sixth of the full dose. Results show that all boosters increased anti-Spike IgG levels, intramuscular boosters provided significantly higher neutralization against delta, and intramuscular doses were superior levels of IFN-γ SFCs to the intradermal route [Intapiboon P, 2021 ].

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 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 ].
 

Heterologous-booster regimens

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, hearafter 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 neutralising 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 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 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.[ ].

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 the 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 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 8680 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 [Sitthichai Kanokudom, 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 titer 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 ].


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 the 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)

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 ].

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 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 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 ].

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 ].

 

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

Incidence of any adverse events (measured at 2 months )

The relative risk of incidence 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 incidence of any adverse events in 119%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: incidence of 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 (122 per 1000) versus 5770 out of 21621 in the group that did receive it (267 per 1000). In other words, 145 more people per 1000 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 (5 per 1000), versus 126 out of 21621 in the group that did receive it (6 per 1000). 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 1000.

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

Incidence of any adverse events (5-15y) (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 1.12 (95% CI 0.91 to 1.37). This means Pfizer-BioNTech COVID-19 vaccine increased the risk of any adverse events by 12%, 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 trials identified in this review, 136 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 1879 presented this outcome (72 per 1000) versus 234 out of 2649 in the group that did receive it (80 per 1000). In other words, 8 more people per 1000 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 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 125. Which means that 125 people need to receive the vaccine for one of them to not any adverse events.

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% (18,631 out of 37,706 participants) [Polack, Fernando P., 2020 ].

The proportion of females that experienced adverse effects with the 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 studies

The phase 4, non-randomized study Shieldvacc2 is currently evaluating the effectiveness/safety of the vaccine in women of childbearing 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) [Li LL, 2022 ].

Barda et al. is a prospective cohort study conducted in Israel at the Institute for the study of fertility at a tertiary, university-affiliated medical center. The study included healthy participants, and elective sperm donors that had the SARS-CoV-2 vaccine administered according to the local national vaccination program between December 2020 to March 2021. The Pfizer-BioNTech COVID-19 vaccine did not negatively affect any of the fresh sperm quality parameters. The total sperm count and the total motile count significantly increased after the second vaccine, with no change in the percent movement. Moreover, the Pfizer-BioNTech COVID-19 vaccine did not negatively affect sperm quality after freezing. The authors suggest that the Pfizer-BioNTech COVID-19 vaccine has no deleterious effect on sperm samples, and can be administered safely [Barda S, 2022 ].

 

Age

Randomized trials

The proportion of participants >55 years of age in the C4591001 trial was 42.2% (15,921 out 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 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) [Li LL, 2022 ].

Children and adolescents

Randomized trials

In the phase 2/3 components of the C4591001 trial, reactogenicity was measured in a subset that included 8,183 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% (2,260 out of 3,358 participants) [Frenck RW, 2021 ].

The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1,098 out of 3,358 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 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 ].

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 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 were: 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 the 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 ].

Goldshtein et al. is a population-based cohort study conducted in Israel, which analyzed data from the database of the Maccabi Healthcare Services. The study included all singleton live births at any time from March 1, 2021, through September 31, 2021. There were no substantial differences between groups in the proportion of newborns with preterm birth (RR = 0.95; 95% CI, 0.83-1.10) or small birth weight for gestational age (SGA) (RR = 0.97; 95% CI, 0.87-1.08). The risk of hospitalizations in exposed as compared with unexposed newborns was similar for neonatal (RR = 0.99; 95% CI, 0.88-1.12) and for postneonatal (RR = 0.95; 95% CI, 0.84-1.07) hospitalizations. No significant difference was observed in the rate of phototherapy (RR = 1.24, 95% CI, 0.95-1.63). However, a sensitivity analysis was performed to exclude mothers who had SARS-CoV-2 infection before they gave birth and an increased risk of jaundice requiring phototherapy (RR = 1.46; 95% CI, 1.06-2.06) was associated with exposure. Overall infant mortality rates were low in both groups, with crude counts of n = 8 death cases (0.1%) among unexposed newborns and n = 22 (0.1%) in the exposed group. The authors suggest that there is no evident differences between newborns of women who received the Pfizer-BioNTech COVID-19 vaccine during pregnancy vs those of women who were not vaccinated [Goldshtein I, 2022 ].


Breast-feeding

Randomized trials

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

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 ].

 

Persons/ individuals with comorbidities

Randomized trials

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

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 ]. Available data are currently insufficient to assess safety in individuals with comorbidities.

Other studies

Li et al. is a multicentre cross-sectional study conducted at rheumatology clinics in two major hospitals in Hong Kong [Li YK, 2022 ]. This study investigated the vaccination rate, reported side effects, and patient concerns for COVID‐19 vaccination in patients with rheumatic diseases who were interviewed between June 3, 2021 and October 8, 2021. 81.1% of vaccinated participants reported side effects, of which the most common were injection site pain or swelling, followed by fatigue, fever, and headache. Other side effects were uncommon and no serious side effects leading to hospitalization or death were found. In addition, younger age and messenger RNA (mRNA) vaccines were associated with more side effects and there was no difference in risk of side effects between specific rheumatic diseases or drug therapies. The authors suggest that COVID‐19 vaccination is associated with no increased risk of side effects in any particular disease or drug therapy, therefore vaccination should be encouraged in patients with rheumatic disease [Li YK, 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 ].

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 hematology 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 hematological malignancies 18 years of age and over [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 over [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 ].  

Persons living with HIV

Randomized trials

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

Other studies

Milano E et al. is a comparative cohort study conducted in Italy. The study included people living with HIV infection aged 18 years and over who received vaccination between April 14 and May 14, 2021. No serious adverse events were reported. 47.3% of the cases had an adverse reaction after the first dose, while 47.0% occurred after the second dose. The authors suggest that Pfizer COVID-19 vaccination is safe in people living with HIV infection [Milano E, 2022 ].

Safety of the vaccine post-authorization

Post-authorization studies

Comparative post-authorization studies

Omar M Albalawi et al. was a study conducted in the United States. The study enrolled the general population that received Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S vaccines. Based on data from Vaccine Adverse Event Reporting System (VAERS) between 15 December 2020 to 19 March 2021. Results of the study showed that the Moderna group had more deaths than the Pfizer group (7% 95% CI-14% to 33%). [Omar M Albalawi, 2021 ].

Maxime Taquet et al. is a comparative cohort study conducted in the United States. The study enrolled 537,913 patients with a confirmed diagnosis of COVID-19. Based on data from ​a federated electronic health records network recording anonymized data from 59 healthcare organizations from January 20, 2020, and March 25, 2021. The authors compared the adverse events between Moderna or Pfizer and Influenza vaccine groups. Results of the study showed that the Moderna/Pfizer group had more cerebral sinus and venous thrombosis (567%, 95% IC 98% to 2,134%), and portal vein thrombosis 640% (95% CI 387% to 1,024%) than the Influenza group [Maxime Taquet, 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, it included clinical and laboratory records from December 20 2020, until May 31, 2021. Among the 9,289,765 participants registered in the database; 5,442,696 received the first dose of the 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 at 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 the Pfizer-BioNTech vaccine and was based on data from electronic health 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 vaccinated 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 the 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 [Magnus MC, 2021 ].

Kharbanda EO et al. was a case-control study conducted in the 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 records 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 the 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 the 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 receiving the 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 ].

PRESTO study showed no association between vaccines and fecundability in 2,126 participants vaccinated with Pfizer, Moderna or Janssen COVID-19 vaccine. The fecundability rate in vaccinated versus non-vaccinated individuals was 1.08 in females (95% CI 0.95 to 1.23) and 0.95 in males (95% CI 0.83 to 1.10) [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 was 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 Sinovac COVID-19 vaccine and Pfizer COVID-19 vaccine 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 Inflammatory Bowel Disease flare, showing an incidence rate ratio (IRR) for unplanned IBD-related hospitalization 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 inflammatory 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 ].

Hviid A et al. was a cohort study conducted in Denmark. The study enrolled 355,209 participants: 222,364 vaccine group; 130,640 control group and was based on data from Danish linkable registers on vaccinations, hospitalizations, occupation, and other covariates, between 27 December 2020 to 13 April 2021. The study results showed a risk difference (RD) of 1.32 (95%CI -2.55 to 5.19) for pulmonary embolism and of 2.05 (95% CI -2.49 to 6.69) for deep vain thrombosis in vaccinated individuals [Hviid A, 2022 ].

TU TM et al. was a comparative cohort study conducted in Singapore. The study enrolled 62,447 individuals diagnosed with SARS-CoV-2 and 3,006,662 individuals with at least one dose of mRNA-based SARS-CoV-2 vaccine. It was conducted between January 23, 2020, and August 3, 2021,  at all public acute hospitals in Singapore, where patients hospitalized with cerebral venous thrombosis (CVT) within 6 weeks of SARS-CoV-2 infection or after mRNA-based SARS-CoV-2 vaccination (Pfizer-BioNTech or Moderna) were identified. Annualized incidence rate of hospitalized CVT cases per 100,000 person-years for Pfizer-BioNTech Vaccine was 1.58 (95% CI 0.04 to 8.79) for individuals who received only one dose and 2.50 (95% CI 0.81 to 5.83) for individuals who received 2 doses [Tu TM, 2022 ].

Gallo K et al. was a comparative study conducted in the United State. The study evaluated 580.000 cases from the Vaccination Adverse Event Reporting System. Data for vaccination associated side effects were obtained from VAERS, between 1 January and 24 September 2021. The prevalence of adverse events in the general population was assessed based on previously published studies concerning each condition. The OR for Pfizer-BioNTech adverse events compared to the general population was: 0.9 for cerebral thrombosis, 2.0 for Guillán-Barre syndrome, 0.7 for myocarditis and 0.7 for pericarditis [Gallo K, 2022 ]. 

Shapiro B et al was a retrospective cohort study. The study investigated self-reported systemic vaccine side-effects using electronic surveys sent to vaccinated individuals between 20 December 2020 and 11 March 2021, within 3 days following administration of the first and second dose. The main reported side effects after the first dose were fatigue (11.1%), headaches (9.8%) and myalgia (8.8%). The main reported side effects after the second dose were fatigue (36.3%), headaches (9.8%) and myalgia (8.8%) [Shapiro Ben David S, 2022 ].

 

 

Non-comparative studies

Omar M Albalawi et al. was a study conducted in the United States. The study enrolled general population that received Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S vaccines. Based on data from Vaccine Adverse Event Reporting System (VAERS) between 15 December 2020 to 19 March 2021. Results of the study showed that the Moderna group had more deaths than the Pfizer group (7% 95% CI-14% to 33%). [Omar M Albalawi, 2021 ].

Schulz, J. B et al. was a non-comparative study carried out in Germany, which included 7,126,424 first doses (Pfizer-BioNTech, Moderna, AstraZeneca vaccines) and sought to estimate the incidence of cerebral venous thrombosis (CVT) within a month after administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as an underlying mechanism after vaccination. Given an incidence of 0.22-1.75 per 100,000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after ChAdOx1 vaccination, especially for women [Schulz, J. B., 2021 ].

David Presby et al. is a retrospective cohort conducted in United States. The study enrolled 50,977 (AstraZeneca (AZ, n=2,093), Janssen/Johnson & Johnson (J&J&J, n=3 888), Moderna (n=23,776; M1, 14,553 first dose; M2, 9,223 second dose), or Pfizer/BioNTech (n=35,929; P&B1, 22,387 first dose; P&B2, 13,542 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 ].

ACP et al. was a retrospective cohort study conducted in the United Kingdom. The study recruited 373 participants who received the Pfizer-BioNTech, Moderna, and AstraZeneca vaccines. Based on data from the London Cancer Center from December 8, 2020 to February 28, 2021. Of the patients, 88.5% were receiving cancer treatment (36.2% parenteral chemotherapy and 15.3% immunotherapy), 76.1% developed some degree of vaccine-related adverse events (VRAE's) of which 2.1% were grade 3. No grades 4/5 or anaphylaxis were observed. The most common VRAE within 7 days after vaccination were arm pain (61.7%), fatigue (18.2%), and headaches (12.1%). The most common grade 3 VRAE's was fatigue (1.1%). Our results demonstrate that COVID-19 vaccines in cancer patients have mild reactogenicity [So ACP, 2021 ].

Català A et al. Was a non-comparative study carried out in Spain, which included 405 skin reactions to the Pfizer-BioNTech, Moderna and AstraZeneca vaccines. The most-reported reactions in each vaccine group were COVID-ARM (injection site; mRNA-1273, Moderna, 61.9%), varicella-zoster virus reactivation (BNT162b2, Pfizer-BioNTech, 17.2%), and urticaria (AZD1222, AstraZeneca, 21.1%). Most reactions to the mRNA-1273 (Moderna) vaccine are described in women (90.5%). Eighty reactions (21%) were classified as serious / very serious and 81% required treatment [Català A, 2021 ].

Kaur RJ et al. was a non-comparative study that reported 4,863 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 ].

William Whiteley et al. it was a non-comparative study conducted in England. The study enrolled 46,162,942 (8,712,477 BNT162b2; 12,481,337 ChAdOx1-S) adults registered with a general NHS practice in England and alive on December 8, 2020 who received the first dose of vaccination with ChAdOx1-S and BNT162b2. Based on data from electronic questionnaires during weeks 11-13, 2021. Increases in intracranial venous thrombosis (ICVT) and thrombocytopenia after ChAdOx1-S vaccination in adults <70 years are small compared to their effect on reduction in morbidity and mortality from COVID-19, although more precise estimates are needed for adults <40 years. For people [≥] 70 years old, arterial or venous thrombotic event rates were generally lower after either vaccine [William Whiteley, 2021 ].

Pawlowsky C et al. conducted a non-comparative study in the United States, which included 266,094 participants. The frequencies of cerebral venous sinus thrombosis (CVST) observed among people who received FDA-cleared COVID-19 vaccines from Pfizer-BioNTech (n = 94,818 doses), Moderna (n = 36,350 doses), and Johnson & Johnson were studied. Johnson - J&J (n = 1,745 doses), and among people who received one of the 10 FDA-approved non-COVID-19 vaccines (n = 771,805 doses). When comparing CVST incidence rates in 30-day time windows before and after vaccination, no statistically significant differences were found for COVID-19 vaccines or any other vaccine studied in this population. In total, 3 cases of CVST were observed within 30 days of vaccination with Pfizer-BioNTech (2 female, 1 male; Ages (years): [79, 80, 84]), including one individual with a history of thrombosis and another individual with recent trauma in the past 30 days. No cases of CVST are believed among patients who received the Moderna or J&J vaccines in this study population. Overall, this real-world evidence-based study highlights that TSVC is rare and not significantly associated with the COVID-19 vaccine [Colin Pawlowski, 2021 ].

Pushkar Aggarwal conducted a non-comparative study in the United States, in which he reported 68,123 adverse events (Pfizer, Moderna or Janssen vaccines). A statistically significant signal was found between cerebrovascular accidents (CVA) events and each of the three COVID-19 vaccines (Pfizer / BioNTech's, Moderna's, and Janssen's) in the vaccine adverse event reporting system (VAERS). Women and people 65 and older had a higher number of case reports of stroke events with COVID-19 vaccines. Women also had more reports of COVID-19 adverse events in which stroke was reported and resulted in the patient having permanent disability or death [Pushkar Aggarwal, 2021 ].

Zhao H et al. was a cross-sectional conducted in the United States. The study enrolled 15,785 adverse event reports (0.7% (113) urologic symptoms) from participants that received Pfizer-BioNTech and Moderna vaccines. Based on data from FDA Vaccine Adverse Event Reporting System (VAERS) as of February 12th, 2021.

Witberg G et al. was a non-comparative study conducted in Israel. The study assessed the incidence of myocarditis after the administration of at least one dose of the BNT162b2 mRNA vaccine in a single health care organization. Out of 2,558,421 vaccinated participants, 54 cases met the criteria for myocarditis and the estimated incidence was 2.13 cases per 100,000 people (95% CI, 1.56 to 2.70) who received at least one dose of the vaccine. The highest incidence was among male patients between 16 and 29 years of age (10.69 cases per 100,000 people; 95% CI, 6.93 to 14.46) [Witberg G, 2021 ].

Lacy J et al. was a non-comparative study conducted in England. The study enrolled 40 participants and assessed the risk of a second Covid-19 vaccine dose in patients with vaccine-induced immune thrombotic thrombocytopenia [Lacy J, 2021 ].

Menni C et al. was a non-comparative study conducted in the United Kingdom. The study enrolled 627,383 participants and examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine [Menni C, 2021 ].

See I et al. was a non-comparative study conducted in the United States. The study enrolled 57 participants describes surveillance data and reports thrombosis rates with thrombocytopenia syndrome (TTS) cases after vaccination with Janssen, Moderna and Pfizer-BioTech COVID-19 vaccine [See I, 2022 ].

Lotan I et al. was a non-comparative study conducted in Israel. The study enrolled 56 participants and described adverse events in patients with myasthenia gravis who received at least 1 dose of Pfizer-BioNTech. [Lotan I, 2022 ]

Yap J et al. was a non-comparative study conducted in Singapore The study enrolled 7,183,889 participants and reported the incidence of pericarditis and myocarditis following Pfizer-BioNTech and Moderna Vaccination. [Yap J, 2022 ]

Zhang B et al. was a non-comparative study conducted in the United States. The study included 14.431 reports of menstrual disorders, analyzing the relationship between COVID-19 vaccines and menstrual disorders in females. [Zhang B, 2022 ]

Kant et al. was a non-comparative study conducted in the Netherlands. The study included 27,554 participants and assessed systemic adverse events following immunization and adverse events of special interest following immunization for Pfizer-BioNTech, Moderna, Janssen and AstraZeneca vaccines. [Kant A, 2022 ]


Naim Ouldali et al. was a non-comparative study conducted in France. The study enrolled 4,079,234 12-17-year-old children and assessed the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines [Naim Ouldali, 2022 ].

Oster ME et al. was a non-comparative study conducted in the United States. The study enrolled 192,405,448 persons aged 12 year or older receiving a total of 354,100,845 mRNA-based COVID-19 vaccines between December 2020 and August 2021, using data from the Vaccine Adverse Event Reporting System (VAERS) with the objective of describing reports of myocarditis and reporting rates after mRNA-based COVID-19 vaccination in the US. [Oster ME, 2022 ]

Kitagawa H et al. was a non-comparative study conducted in Japan. The study enrolled 12,214 participants receiving Pfizer or Moderna COVID-19 vaccines and reporting adverse reactions an online survey of self-reported adverse reactions after mass vaccination. The study results showed that adverse reactions were more frequently reported in females, younger individuals, and after the mRNA-1273 vaccine [Kitagawa H, 2022 ].

Rolfes L et al. was a cohort study conducted in the Netherlands. The study enrolled 22,184 participants and explored factors that were associated with reactogenicity in general and systemic after the first dose of COVID-19 vaccine through a web-based design using patient-reported outcomes between February 1st 2021 and May 9th 2021 [Rolfes L, 2022 ].

Mevorach D et al. was a descriptive study conducted in Israel. The study enrolled 404,407 adolescents receiving the first dose of vaccine and 326,463 adolescents receiving the second dose and reported the incidence of hospitalization for myocarditis between June 2 and October 20, 2021, among adolescents in this age group within 21 days after receipt of the first vaccine dose and within 30 days after receipt of the second dose, using an active nationwide surveillance system administered by the Israeli Ministry of Health [Mevorach D, 2022 ].

Fronza M et al. was a descriptive cohort study conducted in Canada. The study enrolled 92 participants with myocarditis with at least one T1-based and at least one T2-based abnormality on cardiac MRI performed at a tertiary referral hospital between 2019-2021 and found that 21 participants (22%) had myocarditis following COVID-19 vaccination [Fronza M, 2022 ].

Krug A et al. was a cohort study conducted in the United States. The study used the Vaccine Adverse Event Reporting System (VAERS) and identified Pfizer COVID-19 vaccine-associated myo/pericarditis occurrence in adolescents aged 12-15 and 16-17 according to CDC criteria. The study reported 253 cases of myo/pericarditis, 129 after first dose and 124 after second dose, with an incidence per million after dose two in males aged 12-15 and 16-17 of 162.2 and 93.0, respectively [Krug A, 2022 ].

Sharff KA et al. was a cohort study conducted in the United States. The study included 65,785 participants and assessed the risk of myopericarditis following COVID-19 booster vaccination in individuals age 18-39 years from an integrated health system. The study reported 6 patients who met the confirmed or probable CDC case definition for acute myocarditis or pericarditis within 21 days of COVID-19 booster dose, with an estimated incidence of 9.1 cases (95% CI 3.4 to 19.9) of post-booster myopericarditis per 100,000 booster doses given [Katie A Sharff, 2022 ].

Marco Massari et al. was a self-controlled case series study conducted in Italy. The study included 2,861,809 participants and investigated the association between SARS-CoV-2 mRNA vaccines and myocarditis/pericarditis, using national data on COVID-19 vaccination and emergency care/hospital admissions. The study reported 441 participants aged 12-39 years developing myocarditis/pericarditis (346 received Pfizer COVID-19 vaccine and 95 received Moderna COVID-19 vaccine)[Marco Massari, 2022 ].

Sharon Walmsley et al. was a cohort study conducted in Canada. The study enrolled 1,286 participants and compared the safety and antibody responses to COVID-19 vaccines in an older community-dwelling cohort relative to a younger cohort using self-administered electronic questionnaires to collect local and systemic adverse events for 7-days after each vaccine dose. The study results showed that the most commonly reported events were pain near the injection site, fatigue, muscle aches or pains, malaise, and headaches. Adverse events after the second dose were more likely for participants receiving Moderna COVID-19 vaccine compared to Pfizer COVID-19 vaccine [Sharon Walmsley, 2022 ]

Lee K.M et al. was a non-comparative study conducted in the United States. The study enrolled 39,129 participants aged 18 to 80 years old and investigated unexpected menstrual bleeding after SARS-CoV-2 vaccination using an exploratory, mixed-methods survey instrument intended to capture a wide range of responses from current and formerly menstruating adults, between April 7, 2021 and June 29, 2021. The study reported that 42% of people with regular menstrual cycles bled more heavily than usual, while 44% reported no change after being vaccinated [Lee, K. M., 2022 ].

Kim JE et al. was a case series conducted in South Korea. The study enrolled 13 participants diagnosed with Guillain-Barré Syndrome and its variants following COVID-19 vaccination at four referral hospitals during the period of the mass vaccination program between February and October 2021. Eight cases were reported after AstraZeneca vaccine and 5 cases after Pfizer vaccine [Kim JE, 2021 ]

Keh RYS et al. was a cohort study conducted in the United Kingdom. The study enrolled 996 Guillain-Barré syndrome cases considered for immunoglobulin treatment in the National Immunoglobulin Database, between 8 December 2021 and 8 July 2021. The study results showed that 198 Guillain-Barré syndrome cases occurred within 6 weeks of the first dose of COVID-19 vaccination, with an incidence of 0.618 cases per 100,000 vaccinations. A total of 176 were seen after AstraZeneca COVID-19 vaccine, 21 after Pfizer COVID-19 vaccine and 1 after Moderna COVID-19 vaccine [Keh RYS, 2022 ].

Orfanoudaki E et al. was a cross-sectional study conducted in Greece. The study included 1,007 inflammatory bowel disease (IBD) patients and aimed to investigate the real-world use and adverse events (AEs) of COVID-19 vaccines. The study results showed that adverse events were reported by 81% after first dose and 76% after second dose. Systemic adverse events were more common after the second dose (51% vs. 44%). Very few patients reported new onset abdominal symptoms, mainly abdominal pain in 4% after first dose, 6% after second dose and diarrhea in 5% after first dose, 7% after second dose. There were no serious adverse events leading to emergency room visit or hospitalization [Orfanoudaki E, 2022 ].

 

Monitoring

WHO recommends the following research and post-authorization monitoring activities:

Safety surveillance and monitoring
- Serious adverse events, anaphylaxis and other serious allergic reactions, Bell’s palsy, cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death.

Vaccine effectiveness
− Vaccine effectiveness over time and whether protection can be prolonged by booster doses.
− Studies to investigate whether this vaccine reduces SARS-CoV-2 transmission and viral shedding.
− Assessment and reporting of vaccination failures and virus sequence information.

Subgroups
− Prospective studies on the safety of COVID-19 vaccine in pregnant and lactating females.
− Randomized controlled trials on efficacy and safety of vaccination in children below the age of 18 years.
− Safety data on vaccination in immunocompromised people, including patients living with HIV and autoimmune disease.

Vaccination logistics
− Immunogenicity and safety studies of co-administration with other vaccines, including influenza and pneumococcal vaccines, to adults and older persons.
− Safety, immunogenicity, and impact of a delayed second dose, as currently implemented by certain countries.
− Stability of the vaccine under alternative cold-chain distribution and storage conditions.
− Effectiveness of the proposed strategies for the prevention and management of anaphylactic reactions.
− Interchangeability studies within and across COVID-19 vaccine platforms.

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