Moderna COVID-19 vaccines

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Extended version of the vaccine

Moderna COVID-19 vaccines

Authorization

Moderna COVID-19 vaccine (original strain)

World Health Organization Emergency Use Listing Procedure

Listed for emergency use on 30 April 2021 [WHO, 2021 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Recommended for individuals 6 months of age and older [WHO, 2022 ].

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

Authorized for emergency use (Conditional Marketing Authorization).
6 January 2021: For individuals 18 years of age and older [EMA , 2021 ].
23 July 2021: For individuals from 12 to 17 years of age [EMA, 2021 ].
24 February 2022: For individuals from 6 to 11 years of age [EMA, 2022 ]

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
4 October 2021: Authorized for emergency use in individuals 12 years of age and older [MINISTERIO DE SALUD DE ARGENTINA, 2021 ].

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

Health Canada [Government of Canada, 2022 ]
Authorized for emergency use on 23 December 2020.
17 March 2022: Authorized for emergency use in individuals 6 years of age and older.
14 July 2022: For individuals 6 months of age and older.

Public Health Institute (ISP, Chile) [Instituto de Salud Pública de Chile, 2022 ].
Authorized for emergency use on 03 February 2022.
06 April 2022: For individuals 6 years of age and older.
08 July 2022: For individuals 2 years of age and older.
23 August 2022: For individuals 6 months of age and older [Instituo de Salud Pública, 2022 ].

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use on 25 June 2021 [INVIMA, 2021 ].
20 September 2021: For individuals from 12 years of age and older [INVIMA, 2021 ].


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

U.S. Food and Drug Administration [FDA, 2022 ].
Authorized for emergency use.
18 December 2020: Emergency Use Authorization (EUA) in individuals 18 years of age and older [FDA, 2022 ].
17 June 2022: Emergency Use Authorization (EUA) for individuals from 6 months to 17 years of age [FDA, 2022 ].


Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use on 18 August 2021 [Gobierno de México, 2021 ].

Authorization in jurisdictions in Latin America and the Caribbean
Curaçao
Bolivia
Guadeloupe
Guatemala
Guyana
Haiti
Honduras
Paraguay
Peru
Puerto Rico
Saint Vincent and the Grenadines
San Martin
Sint Eustatius
Suriname
Trinidad and Tobago

Authorization in other jurisdictions
Listed by alphabetical order
Andorra
Australia
Austria
Bangladesh
Belgium
Bhutan
Botswana
Brunei
Bulgaria
Congo
Croatia
Cyprus
Czechia
Denmark
Egypt
Estonia
Faroe Islands
Fiji
Finland
France
Germany
Ghana
Greece
Greenland
Hungary
Iceland
India
Indonesia
Israel
Italy
Japan
Kenya
Kuwait
Latvia
Libya
Liechtenstein
Lithuania
Luxembourg
Malawi
Malaysia
Maldives
Malta
Micronesia
Moldova
Mongolia
Nepal
Netherlands
Nigeria
Norway
Oman
Pakistan
Philippines
Poland
Portugal
Qatar
Romania
Rwanda
Saba
Saudi Arabia
Seychelles
Singapore
Slovakia
Slovenia
South Korea
Spain
Sri Lanka
Sweden
Switzerland
Taiwan
Thailand
Ukraine
United Arab Emirates
United Kingdom
Vietnam
West Bank

Adapted Moderna COVID-19 vaccines

Spikevax bivalent (original + omicron BA.1)

World Health Organization Emergency Use Listing Procedure
Not authorized.

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

Regulatory Authorities of Regional Reference in the Americas

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

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

Health Canada
Authorized for emergency use on 01 September 2022 for individuals 18 years of age and older [Health Canada, 2022 ].

Public Health Institute (ISP, Chile)
29 September 2022: Authorized for emergency use in individuals 18 years of age and older [ISP, 2022 ].

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

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

U.S. Food and Drug Administration
Not authorized.

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

Authorization in jurisdictions in Latin America and the Caribbean
Chile

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

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

World Health Organization Emergency Use Listing Procedure
Not authorized.

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

Regulatory Authorities of Regional Reference in the Americas

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

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

Health Canada
03 November 2022: Authorized for emergency use in individuals 18 years of age and older [Health Canada, 2022 ].

Public Health Institute (ISP, Chile)
Not authorized.

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

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

U.S. Food and Drug Administration
Authorized for emergency use [FDA, 2022 ].
31 August 2022: Emergency Use Authorization (EUA) for individuals 18 years of age and older.
12 October 2022: Emergency Use Authorization (EUA) for individuals 6 years of age and older.

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

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

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

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

Manufacturing

Manufacturer

Drug substance [World Health Organization, 2020 ]
Lonza Group. Visp, Switzerland. [MODERNA TX INC. & LONZA SALES LTD, 2020 ].
Moderna TX Inc. Norwoord, MA, USA.
Lonza Biologics, Inc. Portsmouth, NH, USA.


Other manufacturers

Drug Product [World Health Organization, 2020 ]
Rovi Pharma Industrial Services, S.A. Spain. Principal manufacturers of Moderna COVID-19 vaccine.

Catalent Indiana, USA, provides vial filling and packaging [Rick Mullin, 2021 ].

Baxter Pharmaceutical Solutions (United States) produces the drug product of the vaccine.

Samsung Biologics 300, Republic of Korea.

Adapted Moderna COVID-19 vaccines

Spikevax bivalent (original + omicron BA.1)

Manufacturers
Moderna Biotech Spain, S.L. Madrid, Spain [EMA, 2022 ].

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

Manufacturers
Moderna Biotech Spain, S.L. Madrid, Spain [EMA, 2022 ].
Moderna TX Inc., USA [FDA, 2022 ].

General characteristics

The Moderna is an RNA vaccine composed of nucleoside-modified mRNA (modRNA). The synthetic mRNA is a single-stranded, 5'-capped messenger RNA encoding the SARS-CoV-2 spike (S) glycoprotein of SARS-CoV-2 virus stabilized in its prefusion conformation (S-2P antigen). S-2P consists of the SARS-CoV-2 glycoprotein (S glycoprotein) with a transmembrane anchor and an intact S1-S2 cleavage site. S-2P is stabilized in its prefusion conformation by two consecutive proline substitutions at amino acid positions 986 and 987, at the top of the central helix in the S2 subunit [Wrapp D, 2020 ]. The S glycoprotein mediates host cell attachment and is required for viral entry [Corbett KS, 2020 ].

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 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 [Corbett KS, 2020 ]. 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 [Corbett KS, 2020 ].

Assembling mRNA using pseudouridine, a nucleoside variant naturally occurring in the body, reduces the response of dendritic cells, interferon-associated genes and other components of the immune system to trigger an inflammatory response. [Karikó K, 2008 ].

One way a vaccine mRNA molecule can be modified is by placing it between two RNA untranslated regions which stabilize the mRNA and optimize it for translation. The ends of the mRNA, known as 5‘ and 3‘ ends, can be modified by the addition of a cap and a poly(A) tail. The cap serves as a recognition signal for the cellular ribosome to bind and translate the mRNA and the poly(A) tail stabilizes the protein and further enhances translation of the protein [Schlake T, 2012 ].

The mRNA is encapsulated in lipid nanoparticles through a modified ethanol-drop nanoprecipitation process [Hassett KJ, 2019 ].

The modification of the lipid nanoparticles improves the immune response and improves tolerability [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 membrane-bound spike protein of SARS-CoV-2 is expressed and 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.

 

Ingredients

The vaccine contains the following ingredients:

Active ingredient

One dose (0.5 mL) contains 100 micrograms of nucleoside-modified messenger RNA encoding the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion configuration.

Excipients

Lipids
SM-102 (proprietary to Moderna)
Polyethylene glycol (PEG) 2000-dimyristoyl glycerol (DMG)
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
Cholesterol
Salts, sugars and buffers
Tromethamine (Synonyms: trometamol,tromethamin,Tris, tris(hydroxymethyl)aminomethane)
Tromethamine hydrochloride (Synonyms: Tris hydrochloride; Tris chloride; Tris(hydroxymethyl)aminomethane hydrochloride)
Acetic acid
Sodium acetate trihydrate
Sucrose
Water for injections
Moderna COVID-19 vaccine is preservative-free.

Risk considerations

Risk of insertional mutagenesis
Unlike DNA vaccines, which might carry a small risk of insertional mutagenesis and integration, mRNA does not have the potential to integrate into the host genome and is degraded naturally during the process of antigen expression [Stenler S, 2014 ].

Risk of infection
Moderna COVID-19 vaccine is a non-replicating platform. This means the delivered mRNA does not carry an intrinsic risk for infection [GAVI,2020 ]. Additionally, contaminating microorganisms in mRNA vaccines are unlikely because the manufacturer does not need bacterial cell culture [Pardi N, 2018 ].

Inflammatory reactions
mRNA vaccines have a more pronounced proinflammatory nature. This feature might provide a self-adjuvant property but also can result in local and systemic reactions
[Liu MA, 2019 ]. However, a proposed mechanism for possible autoimmune responses is via the induction of type I interferon, which has been observed in preclinical studies [Pepini T, 2017 ].

Allergic reactions
Most immediate allergic reactions associated with vaccines are related 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 Moderna COVID-19 vaccine. Therefore, PEG constitutes the main candidate for explaining the cause of allergic reactions to this vaccine [Stone CA, 2019 ].
PEG itself has not previously used in other vaccines but polysorbate, a closely related compound, has been implicated in allergic reactions to other vaccines [Stone CA, 2019 ].

Dosing and schedule

Moderna COVID-19 vaccine (original strain)

The recommended schedule for the Moderna COVID-19 vaccine is: [WHO, 2022 ]
For children aged 6 months to 5 years: a series of two doses (25 μg, 0.25 ml each) 4 weeks apart.
For children aged 6 to 11 years: a series of two doses (50 μg each) 4 weeks apart.
For persons 12 years of age and older: a series of two doses (100 μg, 0.5 ml each) 4 weeks apart.
WHO recommends an interval between the first and second dose of 4 to 8 weeks, preferably extending it up to 8 weeks.

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


This vaccine is presented as:*
Suspension for intramuscular injection provided in a multidose vial (each 0.5 mL dose containing 100 μg) indicated for persons aged 12 and older [WHO, 2021 ].
Suspension for intramuscular injection provided in a multidose vial with the label "BOOSTER DOSE ONLY" (each 0.5 mL dose containing 50 μg) [FDA, 2022 ]
Pediatric formulation: suspension for intramuscular injection provided in a multidose vial (doses of 25 μg in 0.25 mL per vial) indicated for persons aged 6 months to 5 years (dark blue cap vial with magenta border label) [FDA, 2022 ].
Pediatric formulation: suspension for intramuscular injection provided in a multidose vial (doses of 50 μg in 0.5 mL per vial) indicated for persons aged 6 to 11 years (dark blue cap vial with teal border label) [FDA, 2022 ].
*labeling depends on the availability of supply for each country [WHO, 2021 ], [FDA, 2022 ].


Booster dose [WHO, 2022 ]
A booster dose (50 µg for adults) is recommended for the highest priority-use groups (i.e. older adults, health workers, persons with comorbidities) 4-6 months after the completion of the primary series. If more than 6 months have elapsed since the completion of the primary series, the booster dose should be given at the earliest opportunity.
Once high booster dose coverage has been achieved in the highest priority-use group, countries may also consider a booster for other lower priority-use groups.

WHO has not yet determined the need for and timing of booster doses for persons below 12 years of age, except for immunocompromised children.

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

FDA recommends a second booster dose for persons 50 years of age and older and immunocompromised individuals from 18 years of age, provided at least after 4 months of the first booster dose [FDA, 2022 ].
EMA recommends second booster dose for persons 60 years of age and older and medically vulnerable individuals provided at least after 4 months of the first booster dose [EMA, 2022 ].


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

For persons aged 12 and older, a 50 μg dose of the Moderna COVID-19 vaccine may be used as a booster dose following a completed primary series from any other EUL COVID-19 vaccine platform.

Heterologous vaccination should only be implemented with careful consideration of current vaccine supply, vaccine supply projections, and other access considerations, along with the potential benefits and risks of the specific products being used.


Vaccination schedule for immunocompromised persons [WHO, 2022 ]
WHO recommends an extended primary series including an additional (third) full 100 µg dose for immunocompromised persons.

An additional (third) dose should be given 1-3 months after the second dose in the standard primary series in order to increase protection as quickly as possible in immunocompromised persons.

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

Adapted Moderna COVID-19 vaccines

Spikevax bivalent (original + omicron BA.1)

Spikevax bivalent (original + omicron BA.1) is administered as a single booster dose (0.5 mL) for persons aged 12 and older [EMA, 2022 ] after three months of the primary series or monovalent booster.

The pharmaceutical form is a dispersion for intramuscular injection provided in a multidose vial (each 0.5 mL dose containing 25 μg of elasomeran and 25 μg of imelasomeran)
The preferred site of injection is the deltoid muscle of the upper arm.

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

EMA recommends to administer Spikevax bivalent (original + omicron BA.4/BA.5) as a single booster dose (0.5 mL) for persons aged 12 years and older after three months of the primary series or monovalent booster [EMA, 2022 ].
FDA recommends to administer Spikevax bivalent (original + omicron BA.4/BA.5) as a single booster dose (0.25 mL for persons aged 6-11 years, and 0.5 mL for persons aged ≥12 years) after two months of the primary series or monovalent booster [FDA, 2022 ].

The pharmaceutical form is a dispersion for intramuscular injection provided in a multidose vial (each 0.5 mL dose containing 50 μg)
The preferred site of injection is the deltoid muscle of the upper arm.

Indications and contraindications

Moderna COVID-19 vaccine (original strain)

Indications

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

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

WHO recommends the use of Moderna COVID-19 vaccine in pregnant individuals.
WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2022 ].


Contraindications

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

Adapted Moderna COVID-19 vaccines

Spikevax bivalent (original + omicron BA.1)

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

Contraindications

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

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

Indications
EMA recommends to administer Spikevax bivalent (original + omicron BA.4/BA.5) as a booster dose for individuals 12 years of age and older [EMA, 2022 ].
FDA recommends to administer Spikevax bivalent (original + omicron BA.4/BA.5) as a booster dose for individuals 6 years of age and older [FDA, 2022 ].

Contraindications

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

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

Precautions

Moderna COVID-19 vaccine (original strain)

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

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

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 Moderna COVID-19 vaccine does not contain eggs or gelatine, there is no contraindication or precaution to vaccination for persons with allergies to any food substances.

Myocarditis [WHO, 2022 ].
Myocarditis is a rare adverse event that has been reported after receipt of mRNA COVID-19 vaccines. The observed risk is highest in males aged 18–39 years (with the highest risk in males aged 18–24 years), and highest within a few days after the second dose.
Vaccinated individuals should be instructed to seek immediate medical attention if they develop symptoms indicative of myocarditis or pericarditis, such as new onset and persisting chest pain, shortness of breath, or palpitations following vaccination. It is important to rule out other potential causes of myocarditis and pericarditis, including COVID-19 infection and other viral aetiologies.
Individuals who develop myocarditis or pericarditis after a dose of Moderna COVID-19 vaccine should generally not receive additional doses of any COVID-19 vaccine, unless recommended after review by a health professional with specialist expertise [WHO, 2022 ].

Pregnancy [WHO, 2022 ]
WHO recommends the use of Moderna COVID-19 vaccine in pregnant individuals.
WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination.

Breastfeeding [WHO, 2022 ].
Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults. As Moderna COVID-19 vaccine is not a live virus vaccine and the mRNA does not enter the nucleus of the cell and is degraded quickly, it is biologically and clinically unlikely to pose a risk to the nursing infant. Several small studies show that mRNA vaccine-elicited antibodies are found in breast milk, which might help protect breastfeeding infants.
On the basis of these considerations, WHO recommends the use of Moderna COVID-19 vaccine in breastfeeding women.
WHO does not recommend discontinuing breastfeeding because of vaccination.

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

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

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

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

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

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

Other precautions
Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5 °C) or acute infection [WHO, 2022 ].

A few cases of capillary leak syndrome (CLS) flare-ups have been reported within the first days after the vaccination with Spikevax (original). In individuals with a history of CLS, vaccination should be assessed by appropriate medical experts [EMA, 2022 ].

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

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

Adapted Moderna COVID-19 vaccines

Spikevax bivalent (original + omicron BA.1)


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

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

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

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

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

Other precautions
Vaccination should be postponed in individuals with an acute febrile illness or acute infection [EMA, 2022 ].
A few cases of capillary leak syndrome (CLS) flare-ups have been reported within the first days after the vaccination with Spikevax (original). In individuals with a history of CLS, vaccination should be assessed by appropriate medical experts [EMA, 2022 ].
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [EMA, 2022 ].
Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions may occur in association with the vaccination process itself [EMA, 2022 ].

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


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

Myocarditis and pericarditis [FDA, 2022 ].
There is an increased risk of myocarditis and pericarditis after vaccination with Spikevax (original), observed more often after the second dose or first booster, and in younger males (18 through 24 years of age).

Pregnancy [FDA, 2022 ]
There are no available data regarding the use of Spikevax bivalent (original + omicron BA.4/BA.5) during pregnancy.

Breastfeeding [FDA, 2022 ].
There are no available data regarding the use of Spikevax bivalent (original + omicron BA.4/BA.5) during breastfeeding.

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

Other precautions
Anxiety-related reactions, including vasovagal reactions (syncope) may occur in association with the vaccination process itself [FDA, 2022 ].

Storage and logistics

Moderna COVID-19 vaccine (original strain)

Storage
The Moderna COVID-19 vaccine is presented as 1. Spikevax 100 mcg (light blue border label), 2. Spikevax 50 mcg (purple border label), 3. Spikevax 25 mcg (magenta border label) [WHO, 2021 ], [FDA, 2022 ].
All presentations are provided frozen and stored at -50°C to -15°C (-58°F to 5°F) for up to 9 months [FDA, 2022 ].

Within the 9 months of shelf life, the vaccine can be stored 30 days at 2°-8°C [WHO, 2022 ].

Do not refreeze once thawed.
Keep vaccine vials in their box and place them in the storage unit.
Store in the original carton to protect from light.

Administration logistics [WHO, 2021 ]
Remove the required number of the vial(s) from storage and thaw each vial before use.

Keep the vial for 2 hours and 30 minutes in the refrigerator from 2°C to 8°C (36°F and 46°F), after, let vial sits for 15 minutes before administering, or, maintained 1 hour at room temperature from 15°C to 25°C [Moderna Inc., 2020 ].

The vaccine should be inspected visually for particulate matter and discoloration prior to administration.
The vial should be inspected visually for cracks or any abnormalities, such as evidence of tampering prior to administration. If any of these should exist, do not administer the vaccine.

Swirl the vial gently after thawing and before each withdrawal. Do not shake or dilute.

Use a sterile needle and syringe to extract a single dose from the multidose vial.

Administration
1. Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 ml reuse prevention syringe (RUP) or a 5 mL RUP syringe, and a 21G or narrower needle.
3. Gently invert the vial to mix, and withdraw the dose according to the targeted group. If the amount of vaccine remaining in the vial cannot provide a full dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Storage after first puncture
After taking the first dose from the multidose vial, the vial should be used within a maximum of 6 hours (stored at 2°C to 8°C [36°F to 46°F]) or discarded at the end of the immunization session, whichever comes first [WHO, 2022 ].

Record the date and time the vial should be discarded.

To improve traceability, the name and batch number of the administered product should be clearly recorded [WHO, 2021 ].

Disposal
Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of 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, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Adapted Moderna COVID-19 vaccines

Spikevax bivalent (original + omicron BA.1)

Storage [EMA, 2022 ].
Spikevax bivalent (original + omicron BA.1) is provided as a frozen dispersion for intramuscular injection stored at -50°C to -15°C (-58°F to 5°F) for up to 9 months [EMA, 2022 ]
Unopened vials can be stored for up to 30 days refrigerated at 2° to 8°C.

Do not refreeze once thawed.
Keep vaccine vials in their box and place them in the storage unit.
Store in the original carton to protect from light.


Administration logistics [EMA, 2022 ]
Remove the required number of the vial(s) from storage and thaw each vial before use.

Keep the vial for 2 hours and 30 minutes in the refrigerator from 2°C to 8°C (36°F and 46°F), after let vial sits at room temperature for 15 minutes before administering, or, maintained 1 hour at room temperature from 15° to 25°C.

The vaccine should be inspected visually for particulate matter and discoloration prior to administration.
The vial should be inspected visually for cracks or any abnormalities, such as evidence of tampering prior to administration. If any of these should exist, do not administer the vaccine.

Swirl the vial gently after thawing and before each withdrawal. Do not shake or dilute.

Use a sterile needle and syringe to extract a single dose from the multidose vial.

Administration [EMA, 2022 ]
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 21G or narrower needle.
3. Gently invert the vial to mix, and withdraw the dose according to the targeted group. If the amount of vaccine remaining in the vial cannot provide a full dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Storage after first puncture [EMA, 2022 ]
After taking the first dose from the multidose vial, the vial should be used within a maximum of 19 hours (stored at 2°C to 8°C [36°F to 46°F]).

Record the date and time the vial should be discarded.

To improve traceability, the name and batch number of the administered product should be clearly recorded.

Disposal
Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of 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, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

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

Storage [EMA, 2022 ].
Spikevax bivalent (original + omicron BA.4/BA.5) is provided as a frozen dispersion for intramuscular injection stored at -50°C to -15°C (-58°F to 5°F) for up to 9 months [EMA, 2022 ]
Unopened vials can be stored for up to 30 days refrigerated at 2° to 8°C.

Do not refreeze once thawed.
Keep vaccine vials in their box and place them in the storage unit.
Store in the original carton to protect from light.

Administration logistics [EMA, 2022 ]
Remove the required number of the vial(s) from storage and thaw each vial before use.

Keep the vial for 2 hours and 30 minutes in the refrigerator from 2°C to 8°C (36°F and 46°F), after, let vial sits for 15 minutes before administering, or, maintained 1 hour at room temperature from 15°C to 25°C.

The vaccine should be inspected visually for particulate matter and discoloration prior to administration.
The vial should be inspected visually for cracks or any abnormalities, such as evidence of tampering prior to administration. If any of these should exist, do not administer the vaccine.

Swirl the vial gently after thawing and before each withdrawal. Do not shake or dilute.

Use a sterile needle and syringe to extract a single dose from the multidose vial.

Administration [EMA, 2022 ]
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 21G or narrower needle.
3. Gently invert the vial to mix, and withdraw the dose according to the targeted group. If the amount of vaccine remaining in the vial cannot provide a full dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.

Storage after first puncture [EMA, 2022 ]
After taking the first dose from the multidose vial, the vial should be used within a maximum of 19 hours (stored at 2°C to 8°C [36°F to 46°F]).

Record the date and time the vial should be discarded.

To improve traceability, the name and batch number of the administered product should be clearly recorded.

Disposal
Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of 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, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Clinical studies - general characteristics

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

Phase 1:
The 20-0003 trial, (NCT04283461, [National Institute of Allergy and Infectious Diseases (NIAID), 2020 ]), conducted in the United States, initiated in April 2020, included 45 healthy adults, 18 to 55 years of age, who received two Moderna vaccines, 28 days apart, in doses of 25 μg, 100 μg, or 250 μg with 15 participants in each dose group. The trial was expanded to include 40 older adults, who were stratified by age (56 to 70 years or ≥71 years). All participants were sequentially assigned to receive two 25-μg or 100-μg doses of vaccine administered 28 days apart [Jackson LA, 2020 ], [Widge AT, 2021 ], [Greaney AJ, 2021 ], [Kai Wu, 2021 ], [Anderson EJ, 2020 ].

The 21-0002 trial (NCT04785144, [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ]), conducted in the United States, started in March 2021, included 135 participants 18 years of age and older. Three mRNA booster vaccines were evaluated in participants who received their primary two-dose series as part of trial 20–0003. Participants were matched by age (18 to 55 years, 56 to 70 years, and ≥71 years) and received a primary series of two mRNA-1273 vaccines 28 days apart at doses of 25, 50, 100, or 250 mcg [Anderson E, 2022 ].

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

The COVAIL trial (NCT05289037, [National Institute of Allergy and Infectious Diseases (NIAID), 2022 ]), conducted in the United States, started in March 2022, included 597 healthy adults previously vaccinated with a SARS-CoV-2 primary series and a single booster. Participants were randomized to one of six Moderna COVID-19 mRNA vaccine arms (50 mcg dose): Prototype (mRNA-1273), Omicron BA.1+Beta (1 or 2 doses), Omicron BA.1+ Delta, Omicron BA.1 monovalent and Omicron BA.1+Prototype [Angela R Branche, 2022 ].

Phase 2:
The mRNA-1273-P201 trial (NCT04405076, [ModernaTX, Inc., 2020 ]) conducted in the United States, initiated in May 2020, included 600 participants 18 years of age and older. Participants were stratified into two age cohorts (≥18-<55 and ≥55 years; 300 in each group) and randomly assigned (1:1:1) to 50 or 100 µg of the Moderna vaccine, or placebo given as two intramuscular injections 28 days apart [Chu L, 2021 ].

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

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

Phase 2/3:
The TeenCove trial (NCT04649151, [ModernaTX, Inc., 2020 ]), conducted in the United States and started in November 2020, included 3,732 adolescent participants between the ages of 12 and 17 who were randomized in a 2:1 ratio to receive two injections of the Moderna vaccine ( 100 μg each) or placebo, administered 28 days apart. [Ali K, 2021 ].

The KidCOVE trial (NCT04796896 [ModernaTX, Inc., 2021 ]), conducted in the United States, initiated in March 2021, included 13,574 children between 6 months and 11 years of age. Part 1 of the trial was conducted for dose selection. In part 2 children were randomly assigned in a 3:1 ratio to receive two injections of Moderna (50 μg each) or placebo, given 28 days apart. [Creech CB, 2022 ].

The mRNA-1273-P205 trial (NCT04927065 [ModernaTX, Inc., 2021 ]) conducted in the United States, initiated in June 2021, included 896 adults fully vaccinated with Moderna who received a single booster dose of Moderna Bivalent (mRNA-1273.211) 50 g (mRNA-1273.211) vaccine (n = 300) or 100µg (n = 595) between 8.7 and 9.7 months after the primary regimen [Chalkias S, 2022 ], [Chalkias S, 2022 ].

Phase 3:
The COVE trial (NCT04470427, [ModernaTX, Inc., 2020 ]) conducted in the United States, initiated in July 2020, included 30,420 participants aged 18 years and older. Participants received either two doses of the Moderna vaccine (100 μg) or the placebo vaccine, administered 28 days apart [Pajon R, 2022 ], [Rojas C, 2022 ], [Gilbert PB, 2021 ], [El Sahly HM, 2021 ], [Baden LR, 2021 ], [Baden LR, 2021 ], [El Sahly HM, 2022 ].

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

Phase 4:
The trial by Hall VG et al (NCT04885907, [University Health Network, Toronto, 2021 ]) conducted in Canada, started in May 2021, included 120 transplant patients who had received two doses of the Moderna vaccine at 0 and 1 month. Participants were randomized 1:1 to receive a third dose of  Moderna COVID-19 vaccine or placebo 3 months after the primary vaccination schedule. [Kumar D, 2021 ], [Hall VG, 2021 ].

The RECOVAC trial (NCT05030974, [University Medical Center Groningen, 2021 ]) conducted in the Netherlands started in October 2021 and enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after an initial mRNA vaccine schedule: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. [Kho MML, 2022 ]

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

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 ]

Direct preclinical evidence of immune response induced by Moderna 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 challenge with SARS-CoV-2 and active viral replication and viral genomes in bronchoalveolar-lavage fluid and nasal swab specimens were assessed by polymerase chain reaction, and 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.

Mutations of mRNA sequence of SARS-CoV-2, such as E484K, N501Y or K417N, can potentially reduce vaccine-elicited response. The evidence on these and other variants is still evolving but mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy [Wang Z, 2021 ].

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

mRNA-1273-P201 (NCT04405076) was a phase 2 trial sponsored by ModernaTX, Inc. and conducted in the United States. The trial included healthy participants ≥18 years of age. The sample size was 600 (2 cohorts of 300). Participants were randomized 1: 1 to receive Moderna COVID-19 vaccine in doses of 50 µg, 100 µg or placebo. The results showed that in both vaccination schemes of mRNA-1273 vaccine, the geometric mean titers increased 28 days after the first dose. Furthermore, 14 days after the second dose (day 43), the geometric mean titers improved significantly, 1733 (1611-1865) µg/ml in the 50 µg group and 1909 (1849-1971) µg/ml in 100 µg group in young adults, while in older adults, mean titers were 1827 (1722 -1938) µg/ml in the 50 µg group and 1686 [1521-1869] µg/ml in the 100 µg group of mRNA-1273 vaccine [Chu L, 2021 ].

In the preliminary report of the phase 1 study [Jackson LA, 2020 ], it was reported that the vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. In this dose-escalation trial, in 45 adults 18 to 55 years of age antibody responses were higher with higher doses after a first vaccination, and serum neutralizing activity was detected after second vaccination.

Main efficacy outcomes of Moderna COVID-19 vaccine

Key messages

Moderna COVID-19 vaccine reduces the risk of contracting COVID-19

Moderna COVID-19 vaccine reduces the risk of contracting severe COVID-19

Contracting COVID-19 (measured at least 14 days after the second injection, with a median follow-up of 5.3 months after 2nd dose)

The relative risk of contracting COVID-19 in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.07 (95% CI 0.06 to 0.1). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 by 93%, compared with placebo vaccine.

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

In the trial identified in this review, 751 people not receiving Moderna COVID-19 vaccine out of 14164 presented this outcome (49 per 1000) versus 55 out of 14287 in the group that did receive it (4 per 1000). In other words, 45 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 4.5%, or that the intervention reduced the risk of contracting COVID-19 by 4.5 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 22. Which means that 22 people need to receive the vaccine for one of them to not contract COVID-19.

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 14 days after the second injection, with a median follow-up of 5.3 months after 2nd dose)

The relative risk of contracting severe COVID-19 in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.02 (95% CI 0 to 0.08). This means Moderna COVID-19 vaccine reduced the risk of contracting severe COVID-19 by 98%, compared with placebo vaccine.

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

In the trial identified in this review, 106 people not receiving Moderna COVID-19 vaccine out of 14164 presented this outcome (7 per 1000) versus 2 out of 14287 in the group that did receive it (0 per 1000). In other words, 7 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 0.7%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.7 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 143. Which means that 143 people need to receive the vaccine for one of them to not contract severe COVID-19.

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









Mortality

The existing evidence does not allow to assess the impact of Moderna COVID-19 vaccine on the risk of death attributable to COVID-19. 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 Moderna COVID-19 vaccine would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (6-11y) (measured at least 14 days after the first injection)

The relative risk of contracting COVID-19 (6-11y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.12 (95% CI 0.05 to 0.28). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 (6-11y) by 88%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 (6-11y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine


In the trial identified in this review, 7 people not receiving Moderna COVID-19 vaccine out of 2887 presented this outcome (20 per 1000) versus 18 out of 880 in the group that did receive it (2 per 1000). In other words, 18 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 1.8%, or that the intervention reduced the risk of contracting COVID-19 (6-11y) by 1.8 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 NNT is 56. Which means that 250 people need to receive the vaccine for one of them to not contract COVID-19.

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

Contracting COVID-19 after second dose (12-17y) (measured at least 14 days after the second injection)

The relative risk of Contracting COVID-19 after second dose (12-17y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.06 (95% CI 0 to 1.03). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 after second dose (12-17y) by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: Contracting COVID-19 after second dose (12-17y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, people not receiving Moderna COVID-19 vaccine out of presented this outcome (3 per 1000) versus out of in the group that did receive it (0 per 1000). In other words, 3 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 0.3%, or that the intervention reduced the risk of Contracting COVID-19 after second dose (12-17y) by 0.3 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 333. Which means that 250 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (>65y) (measured at least 14 days after the second injection)

The relative risk of Contracting COVID-19 (>65y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.11 (95% CI 0.05 to 0.21). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>65y) by 89%, compared with placebo vaccine.

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

In the trial identified in this review, 81 people not receiving Moderna COVID-19 vaccine out of 2898 presented this outcome (8 per 1000) versus 9 out of 2990 in the group that did receive it (1 per 1000). In other words, 7 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 0.7%, or that the intervention reduced the risk of Contracting COVID-19 (>65y) by 0.7 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 143. Which means that 143 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (>75y) (measured at least 14 days after the second injection)

The relative risk of Contracting COVID-19 (>75y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.03 (95% CI 0 to 0.46). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>75y) by 97%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: Contracting COVID-19 (>75y). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 19 people not receiving Moderna COVID-19 vaccine out of 697 presented this outcome (8 per 1000) versus 0 out of 636 in the group that did receive it (0 per 1000). In other words, 8 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 0.8%, or that the intervention reduced the risk of Contracting COVID-19 (>75y) by 0.8 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 125. Which means that 125 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (men subgroup) (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 in men in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.08 (95% CI 0.06 to 0.12). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in men by 92%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 in men. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 378 people not receiving Moderna COVID-19 vaccine out of 7494 presented this outcome (50 per 1000) versus 30 out of 7439 in the group that did receive it (4 per 1000). In other words, 46 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 4.6%, or that the intervention reduced the risk of contracting COVID-19 in men by 4.6 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 22. Which means that 22 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Contracting COVID-19 (women subgroup) (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 in women in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.07 (95% CI 0.04 to 0.1). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in women by 93%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 in women. Comparison: Moderna COVID-19 vaccine versus

In the trial identified in this review, 366 people not receiving Moderna COVID-19 vaccine out of 6670 presented this outcome (55 per 1000) versus 25 out of 6848 in the group that did receive it (4 per 1000). In other words, 51 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 5.1%, or that the intervention reduced the risk of contracting COVID-19 in women by 5.1 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 20. Which means that 20 people need to receive the vaccine for one of them to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Summary of findings (iSoF) Table

Efficacy and effectiveness of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the COVE trial was 43% (14372 out of 30346 participants) [El Sahly HM, 2021 ].
The relative risk of contracting COVID-19 in men in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.08 (95% CI 0.06 to 0.12). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in men by 92%, compared with placebo vaccine.
The relative risk of contracting COVID-19 in women in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.07 (95% CI 0.04 to 0.1). This means Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in women by 93%, compared with placebo vaccine.
The magnitude of the effect was similar between the subgroups, and there was no statistical evidence of a subgroup effect by sex
   
Age
Randomized trials
The proportion of patients ≥65 years of age in the COVE trial was 25% (7512 out of 30351 participants) [El Sahly HM, 2021 ].
The relative risk of contracting COVID-19 (>65y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.11 (95% CI 0.05 to 0.21). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>65y) by 89%, compared with placebo vaccine.
The relative risk of contracting COVID-19 (>75y) in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.03 (95% CI 0 to 0.46). This means Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>75y) by 97%, compared with placebo vaccine.
    
The phase 2, open-label study QHD00028 is currently evaluating the efficacy/safety of the vaccine in fully vaccinated adults with mRNA-1273 65 years of age and older [Sanofi Pasteur, a Sanofi Company, 2021 ].
The phase 4, randomized controlled trial mRNA-1273-D3-2021 is currently evaluating the efficacy/safety of the vaccine in vaccinated residents ≥65 years that received  [Mark Loeb, 2021 ].
           
Other comparative studies
The phase 1 study 20-0003 [Anderson EJ, 2020 ], NCT04283461 number, was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). This study showed that binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients. A follow-up of this study at 119 days after the first vaccination [Widge AT, 2021 ] showed that despite a slight expected decline in titers of binding and neutralizing antibodies, the vaccine provided durable humoral immunity and elicited primarily CD4 type 1 helper T responses. There is no evidence that indicates a lower efficacy in older adults. It is important to notice that very few patients >80 years old were included.
           
Children and adolescents
Randomized trials
The TeenCove or study P203 (NCT04649151) was a phase 2/3 trial sponsored by Moderna evaluating vaccine efficacy in adolescents from 12 to 17 years of age. Results of the study showed an efficacy of the vaccine of 95% after the second dose [Ali K, 2021 ].

The KidCOVE trial or study P204 (NCT04796896) is an ongoing phase 2/3 randomized trial sponsored by Moderna evaluating vaccine efficacy in children from 6 to 11 years of age. Preliminary results showed an efficacy of 88% after the second dose [Creech CB, 2022 ].

Other comparative studies
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 Hazard ratio 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 ].

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

Pregnancy
Randomized trials
The available data are insufficient to assess vaccine efficacy since no clinical trial has included this group.
    
Breast-feeding
Randomized trials
The available data are insufficient to assess vaccine efficacy since no clinical trial has included this group.

Other comparative studies
Golan et al. was a prospective cohort study that enrolled 50 lactating women 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 ].
    
Alisa Fox et al. was a cohort study that enrolled 50 lactating women (23 participants had received Pfizer vaccine, 14 had received Moderna vaccine, and 13 had received Janssen Vaccine). 50 pairs of milk samples were obtained from vaccine recipients within 1 week before vaccination and 14 days (Pfizer/Moderna) or 28 days (Janssen) after completion of the vaccine regimen. Results showed that Moderna milk samples exhibited significantly greater relative IgA than Pfizer and Janssen recipients. It was found that 100% and 87% of Moderna and Pfizer recipient post-vaccine milk samples contained positive levels of Spike-specific IgG [ ].

Immunocompromised persons 
Randomized trials
The proportion of participants with HIV in the COVE trial was 0.6% (179 out of 30351 participants) [Baden LR, 2021 ].
In a post hoc analysis, the relative risk of contracting COVID-19 in participants living with HIV that received Moderna COVID-19 vaccine versus those that received placebo vaccine was 0.32 (95% CI 0.01 to 7.67) [FDA, 2020 ].
           
COVERALL was a phase 3 randomized trial conducted in Switzerland. The study enrolled 430 patients (412 included in the intention to treat analysis): 341 patients living with HIV and 71 solid organ transplant recipients. Patients were randomized to Moderna or Pfizer–BioNTech. The primary endpoint was antibody response to the SARS-CoV-2 spike (S1) protein receptor binding domain 8 weeks after the second vaccination. The percentage of patients showing an immune response to Moderna was 92.1%  (95% CI 88.4 to 95.8)  and 94.3% (95% CI 91.2 to 97.4) for Pfizer–BioNTech fulfilling the non-inferiority of Moderna. With the ABCORA 2 test, 89.1% (95% CI 84.8 to 93.4) had an immune response to mRNA-1273 and 89.5% (95% CI 85.4 to 93.7) to BNT162b2. Based on the Elecsys test, all patients living with HIV had an antibody response while for solid organ transplant recipients only 60.6% (95% CI 49.2 to 71.9%) had titres above the cut-off [Speich B, 2022 ].
           
The Hall VG et al was a phase 4, randomized, placebo-controlled trial evaluating vaccine efficacy in organ-transplant recipients. Results showed that at month 4 post-vaccination, an anti-RBD antibody level of at least 100 U per milliliter was present in 33 of 60 patients (55%) in the mRNA-1273 group and in 10 of 57 patients (18%) in the placebo group (relative risk, 3.1; 95% CI: 1.7 to 5.8; P<0.001) [Hall VG, 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 ]

RECOVAC was a randomized trial conducted in the Netherlands that enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after an initial mRNA vaccine schedule: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination. The seroreponse rates were 68% (95% CI, 56% to 79%) for the 2 × mRNA-1273 group, 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group and 68% (95% CI, 57% to 79%) for the single mRNA-1273 group. The seroresponse rate in mycophenolate mofetil- was 80% (95% CI, 66% to 91%) and 67% (95% CI, 52% to 80%) in mycophenolate mofetil+. [Kho MML, 2022 ]

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

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 ].

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 ].

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 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.
           
Lombardi A et al. was a cohort study conducted in Italy. The study enrolled 71 participants living with HIV, mostly male (84·5%), with a mean age of 47 years, a median CD4+ T cell count of 747·0 cells per µL and a median HIV viral load <50 copies/mL. The study results showed that inoculation with mRNA-1273 vaccine given 4 weeks apart produced detectable humoral immune response, similar to individuals without HIV infection [Lombardi A, 2021 ].

Lin et al conducted a sub-analysis of a previous study [Sheng WH, 2022 ] wich compare the immunogenicity of heterologous ChAdOx1/mRNA-1273 versus standar homologous ChAdOx1 and mRNA-1273m vaccination. 399 participants were enrolled, there were 100, 100, 100, and 99 participants undergoing ChAdOx1/ChAdOx1 8 weeks apart (Group 1), ChAdOx1/mRNA-1273 8 weeks apart (Group 2), ChAdOx1/mRNA-1273 4 weeks apart (Group 3), and mRNA-1273/mRNA-1273 4 weeks apart (Group 4), respectively. The majority of the enrolled participants were ≤50 years with 74.7% being women. Among participants undergoing boost vaccination with mRNA-1273, compared with healthy participants aged ≤50 years, participants with immunocompromising conditions had similar anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination (geometric means, 1769.66 vs. 1946.41 BAU/mL; P = 0.255). Only participants with autoimmune diseases and receiving hydroxychloroquine, low-dose steroid, methotrexate, and/or sulfasalazine had numerically lower anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination compared to those without (geometric means, 1474.34 vs. 1923.23 and 1590.61 vs. 1918.38 BAU/mL; both P > 0.05). While anti-SARS-CoV-2 spike IgG titers 4 weeks after booster vaccination were comparable between participants receiving and not receiving NSAIDs (geometric means, 1894.94 vs. 1903.09 BAU/mL, P = 0.981), those receiving COX-2 selective NSAIDs had numerically lower titers (geometric means, 1362.55 vs. 1915.86 BAU/mL, P = 0.179). [Lin KY, 2022 ]

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

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine health-care system, the Michigan State Registry and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA based COVID-19 vaccines. During the Omicron dominant period December 2021 to March 2022. The effectiveness of the Moderna vaccine during the Omicron period in immunocompromised participants the effectiveness was 57% (95%CI 29 to 74) for two doses and 60% (95%CI 42 to 73) for three doses. [Risk M, 2022 ]

Embi P et al. conducted a case-control study with a test-negative design among eight VISION Network sites in the United States during the Delta variant predominance period. Persons aged 18 years and older with ≥1 immunocompromising conditions were included and compared with non-immunocompromised individuals. It included 8,848 emergency department/urgent care (ED/UC) events and 18,843 hospitalizations among immunocompromised (IC) patients; and 200,071 ED/UC events and 70,882 hospitalizations among non-IC patients. In the IC population, adjusted vaccine effectiveness (VE) for the Moderna vaccine was 69% (95% CI, 62% to 76%) for ED/UC events, and 76% (95% CI, 72% to 80%) for hospitalization, measured 14 days after the second dose. After a third dose, VE was 77% (95% CI, 58% to 87%), and 87% (95% CI, 79% to 92%) for ED/UC events and hospitalization, respectively. Preprint. [Peter J. Embi, 2022 ]

Wagner A et al was an open-label phase 4 randomized trial conducted in Austria, including 263 patients: 63 with solid tumors, 70 with multiple myeloma, 130 with inflammatory bowel disease and 66 controls. The seronegativity rate 6 months after the primary schedule was 8% in the solid tumors group and 21,1% in the multiple myeloma group. [Furer V, 2022 ]

Persons with recent COVID-19
Most guidelines recommend that individuals who have had COVID-19 should receive an identical vaccine regimen as those who have not had the infection. 
Randomized trials
Participants with a known history of COVID-19 were excluded from the COVE trial [Baden LR, 2021 ],[FDA, 2020 ] and there was only one case of COVID-19 among study participants with positive SARS-COV-2 infection status at baseline. Thus, this trial does not offer information to assess the benefit in individuals with recent infection.
           
Other comparative studies
Saadat S et al [Saman Saadat, 2021 ] assessed 59 health care workers with and without history of SARS-CoV-2 infection prior to vaccine. After a single dose of the SARS-CoV-2 vaccine (30/59 vaccinated with Moderna vaccine and the other half received Pfizer vaccine), individuals that had prior SARS-CoV-2 infection had higher titers of binding and functional antibodies than individuals that had no history of infection. 

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Chung H 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. The effectiveness of the vaccine in symptomatic infections, observed 14 days after the first dose, was 60%, and increases to 75% between 35-71 days. The effectiveness at 7 days of the second dose was 91%. The effectiveness of the vaccine against hospitalization or death was 70% with the first dose and 91% with the second dose. In adults ≥70 years, the effectiveness was comparable to that in younger people for all intervals after 28 days. [Chung H, 2021 ]

Flacco M et al. conducted a retrospective cohort study conducted in Italy. The study enrolled 245,226 participants: 69,539 Vaccine; 175,687 Control. Based on data from an interim analysis of COVID-19 vaccines effectiveness in the entire population of an Italian Province between 2 January to 21 May 2021. Results showed vaccine effectiveness of 99 to 100% (n = 0 infections)[Flacco ME, 2021 ].

Pawlowski C et al. was a retrospective cohort study conducted in the United States. The study enrolled 136,532 participants: 68,266 vaccine (16,471 Moderna COVID-19 vaccine); 68,266 Control. Based on data from the Mayo Clinic health system between December 1 2020 and April 20, 2021. Results showed vaccine effectiveness of 92.3% (95% CI 82.4% to 9.3%) and infection rate 0.014%/ 0.19% (vaccinated/unvaccinated) [Pawlowski C, 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 7,368,289 receiving the Moderna vaccine. Based on claims and laboratory data from vaccinated individuals between January 1 and September 7, 2021. Odds ratios (OR) for developing incident breakthrough infection, hospitalization or ICU admission in months two through six following full vaccination were estimated relative to the first month after full vaccination. The study results showed evidence of waning protection against infections starting in month 2 from vaccination for both BNT162b2 and mRNA-1273 and in month 4 for Ad26.COV2.S. Evidence of waning protection against hospitalization started in month 2 for BNT162b2 and in month 3 for mRNA-1273. There was no evidence of waning protection against hospitalization for Ad26.COV2.S. No waning of protection was observed at any time for ICU admissions for all three vaccines [Amanda Zheutlin, 2022 ].

Molani S et al. was a comparative cohort study conducted in the United States. The study included 7,620,084 records: 2,627,914 vaccine-induced immunity cohorts (Pfizer-BioNTech, Moderna or Janssen) and 191,722 infection-induced immunity cohorts. The study was based on data from Providence-St. Joseph Health electronic health records. The vaccine-induced cohort period data were collected from December 12, 2020, and the infection-induced cohort data were collected from the beginning of the pandemic. Data collection ended on May 11, 2021. Survival against breakthrough infection for Moderna was 99,7% in 180 days [Sevda Molani, 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 vaccine effectiveness of 75.1% (95%CI 22.7 to 92.0) against infection in vaccinated individuals [Chadeau-Hyam M, 2022 ].

Draws 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–BioNTech and 1,066,645 were fully vaccinated with Moderna. A Pfizer–BioNTech 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 after 26 weeks from the second dose was 65% (95% CI 65 to 66) for the Moderna COVID-19 Vaccine. [Drawz PE, 2022 ]

Roberts E et al. was a case-control study conducted in the United States. The study analyzed data from 170,487 positive COVID-19 adult patients: 74,060 fully vaccinated, 18,425 partially vaccinated and 7,187 fully vaccinated, and 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 vaccine effectiveness for contracting COVID-19 of 88.1% (95% CI 85.5 to 90.2). [Emily Roberts, 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 66% (95% CI 65 to 67) and 69% (95% CI 67 to 71) for adults ≥ 65 years [Winkelman TNA, 2022 ].

Oren Miron et al was a secondary analysis of a phase 3 randomized clinical trial conduct in United States. The study reunited data from 30,420 participants aged 18 to 95 years that were enrolled to receive two doses of Pfizer-BioNTech vaccine on days 0 and 28 (n= 15,181) or were enrolled to the placebo group (n= 15,170). Vaccine effectiveness (VE) was defined by the ratio between the COVID-19 cumulative rate in vaccinated participants and in the placebo group participants. The study results showed that  the cumulative incidence at day 111 of COVID-19 increased by 0.19% in the intervention group and 2.84% in the placebo group.The mRNA-1273 effectiveness at days 7, 14, and 21 was 33%, 62% and 90% respectively, followed by a mean of 95% effectiveness until day 112 [Oren Miron, 2021 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. Based on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of 2 doses of Moderna against infection was 76.5% (95% CI 75.7 to 77.2) and 48.4% (95% CI 47.5 to 49.3), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ].

Chung et al. conducted a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1, between January 11th and November 21st 2021 in Ontario, Canada. They included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for a homologous mRNA-1273 schedule 7 to 59 days after the second dose was 92% (95% CI, 91% to 92%) against any infection and 95% (95% CI, 94% to 96%) against symptomatic infection. VE >240 days after the second dose was 80% (95% CI, 71% to 86%) against any infection and 87% (95% CI, 78% to 92%) against symptomatic infection [Chung H, 2022 ].

Contracting severe COVID-19
Pawlowski C et al. was a retrospective cohort study conducted in the United States. The study enrolled 136,532 participants: 68,266 vaccine (16 471 Moderna COVID-19 vaccine); 68,266 Control. Based on data from the Mayo Clinic health system between December 1,2020 and April 20, 2021. Results showed vaccine effectiveness 90.6% (95% CI 76.5% to 97.1%) infection rate 0.006%/0.064% (vaccinated/unvaccinated) [Pawlowski C, 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 7,368,289 receiving the Moderna 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 ].

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

Draws 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–BioNTech and 1,066,645 were fully vaccinated with Moderna. A Pfizer–BioNTech 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 after 26 weeks from the second dose was 65% (95% CI 65 to 66) for the Moderna COVID-19 Vaccine. [Drawz PE, 2022 ]

Roberts E et al. was a case-control study conducted in the United States. The study analyzed data from 170,487 positive COVID-19 adult patients: 74,060 fully vaccinated, 18,425 partially vaccinated and 7,187 fully vaccinated, and 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 vaccine effectiveness for contracting COVID-19 of 88.1% (95% CI 85.5 to 90.2). [Emily Roberts, 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 69% (95% CI 65 to 72) [Winkelman TNA, 2022 ].

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. IBased on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of 2 doses of Moderna against hospitalization was 77.2% (95% CI 63.8  to 72.2) and 72.7% (95% CI 67.8 to 77), 1 and 10 months after vaccination respectively. [Lin DY, 2022 ]

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

Chung et al. conducted a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1, between January 11th and November 21st 2021 in Ontario, Canada. They included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for a homologous mRNA-1273 schedule 7 to 59 days after the second dose was 96% (95% CI, 95% to 97%) against severe outcomes (hospitalization or death) and 98% (95% CI, 88% to 100%), >240 days after the second dose [Chung H, 2022 ].

Transmission
Abu-Raddad LJ et al. was a retrospective cohort study conducted in Qatar. The study enrolled 384,246 participants: 192,123 received Moderna vaccine; 192,123 received Pfizer vaccine. Based on data from national Covid-19 electronic health databases of the two matched 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 ].

Efficacy and effectiveness against SARS-CoV-2 variants

Immunogenicity outcomes
Alpha (B.1.1.7) 
Lafon et al. used data from samples of 116 patients who had been vaccinated with AstraZeneca, Pfizer, or Moderna COVID-19 vaccines or had recovered from COVID-19. The study found that all the vaccines induced a neutralizing response against the Alpha variant that was higher than the wild-type virus. The mRNA vaccines generated an 82% increase in neutralizing activity, while the AstraZeneca vaccine induced a 13% increase.  Responses against the Beta and Delta variants were lower for all vaccines than for wild-type viruses. Neutralizing activity against the Beta variant was 42 and 47% lower in AstraZeneca and Pfizer recipients while only 25% lower for Moderna recipients. The AstraZeneca vaccine had an 82% reduction in neutralizing activity against the Delta variant, and the Pfizer and Moderna vaccines had a decrease of 2% and 14% respectively [Lafon E, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901.The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that the neutralizing activity increased significantly post boost (P < 0.0001) and the fold-rise ranged from 23.0 in MCV-COV1901 to 118.1 in mRNA1273 against the Alpha variant. After each booster vaccine, the neutralization titers against the Alpha variant were compatible with those of the wild type [Chih-Hsien Chuang, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received an mRNA vaccine first dose and a second dose of Pfizer-BioNTech or Moderna after 28 days. Measurement of neutralizing antibodies against the specific variants (Alpha, Beta, Delta) was performed on a representative population of 30 subjects randomly selected after stratification on vaccine schedule group, age (<40 years, ≥40 years, and <55 years, ≥55 years), and level of anti-spike IgG against the wild-type viral strains at D28 (<1000 BAU/mL, ≥1000 BAU/mL, and <5000 BAU/ml, ≥ 5000 BAU/mL). The study showed that the neutralizing antibodies titers against SARS-CoV-2 variants were not different between the homologous and heterologous vaccine groups [Janssen C, 2022 ].

Beta (B.1.351) 
Lafon et al. used data from samples of 116 patients who had been vaccinated with AstraZeneca, Pfizer, or Moderna COVID-19 vaccines or had recovered from COVID-19. The study found that all the vaccines induced a neutralizing response against the Alpha variant that was higher than the wild-type virus. The mRNA vaccines generated an 82% increase in neutralizing activity, while the AstraZeneca vaccine induced a 13% increase.  Responses against the Beta and Delta variants were lower for all vaccines than for wild-type viruses. Neutralizing activity against the Beta variant was 42 and 47% lower in AstraZeneca and Pfizer recipients while only 25% lower for Moderna recipients. The AstraZeneca vaccine had an 82% reduction in neutralizing activity against the Delta variant, and the Pfizer and Moderna vaccines had a decrease of 2% and 14% respectively [Lafon E, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received an mRNA vaccine first dose and a second dose of Pfizer-BioNTech or Moderna after 28 days. Measurement of neutralizing antibodies against the specific variants (Alpha, Beta, Delta) was performed on a representative population of 30 subjects randomly selected after stratification on vaccine schedule group, age (<40 years, ≥40 years, and <55 years, ≥55 years), and level of anti-spike IgG against the wild-type viral strains at D28 (<1000 BAU/mL, ≥1000 BAU/mL, and <5000 BAU/ml, ≥ 5000 BAU/mL). The study showed that the neutralizing antibodies titers against SARS-CoV-2 variants were not different between the homologous and heterologous vaccine groups [Janssen C, 2022 ].

Anderson et al. was a phase 2 randomized controlled trial conducted in the United States that included 96 participants with a primary schedule of Moderna: 48 with Monovalent prototype boost (100 mcg) of mRNA-1273, 25 with Monovalent variant boost of mRNA-1273.351 (50 mcg) and 23 with a bivalent boost of mRNA1273.351 (25 mcg ) and bivalent mRNA-1273 (25 mcg). This study assessed the immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary schedule approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA1273.351 that encodes Beta variant spike protein, and a bivalent vaccine of 25 mcg each mRNA-1273 and mRNA-1273.351. The results showed that following booster vaccination, a robust response to similar titers was observed in all three groups to 614D S-2P at Day 15 [monovalent prototype 62,272 AUC (95% CI 59,973, 64,659); monovalent variant 61,373 (95% CI 58,622, 64,254); bivalent 62,025 (95% CI 59,468, 64,691). In all groups, the third dose of mRNA vaccine induced similar responses against B.1.351 [monovalent prototype 47,733 AUC (95% CI 44,932, 50,710); monovalent variant 49,768 (95% CI 46,282, 53,517); bivalent 48,126 (95% 44,728, 51,781)] that were only 20% lower than the Day 15 responses to 614D . Spike-specific CD4+ and CD8+ T cells increased to similar levels to that after the second dose.

Chalkias et al. was a phase 2/3 non-randomized trial conducted in the United States as part of a larger study registered as NCT04927065. Its aim was to evaluate the safety, reactogenicity and immunogenicity of a single booster dose of the bivalent beta-containing mRNA candidate vaccine mRNA-1273.211, in adults who received a primary schedule of mRNA-1273. The study included 300 participants who received 50 µg of mRNA-1273.211 booster, 595 participants who received 100 µg of mRNA-1273.211 booster, a historical cohort of 584 participants who received the 100 µg primary schedule and 171 participants who received a mRNA-1273 50 µg booster dose. Geometric Mean Titers (GMT) of neutralizing antibodies against the Beta variant were 953.9 (95% CI, 844.1–1,078.0) for the mRNA-1273.211 (50 µg) group and 1,574.6 (95% CI, 1,439.4–1,722.5) for the mRNA-1273.211 (100 µg) group. [Chalkias S, 2022 ]

Delta (B.1.617.2) 
Lafon et al. used data from samples of 116 patients who had been vaccinated with AstraZeneca, Pfizer, or Moderna COVID-19 vaccines or had recovered from COVID-19. The study found that all the vaccines induced a neutralizing response against the Alpha variant that was higher than the wild-type virus. The mRNA vaccines generated an 82% increase in neutralizing activity, while the AstraZeneca vaccine induced a 13% increase.  Responses against the Beta and Delta variants were lower for all vaccines than for wild-type viruses. Neutralizing activity against the Beta variant was 42 and 47% lower in AstraZeneca and Pfizer recipients while only 25% lower for Moderna recipients. The AstraZeneca vaccine had an 82% reduction in neutralizing activity against the Delta variant, and the Pfizer and Moderna vaccines had a decrease of 2% and 14% respectively [Lafon E, 2022 ].

Kanokudom S et al. recruited 222 adults with a complete CoronaVac regimen who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), and 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54)or standard Moderna vaccine (n=58). The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that were not affected by dosage. On 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. [Kanokudom S, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901.The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that the neutralizing activity increased significantly post boost (P < 0.0001) and the fold-rise ranged from 23.8 in MCV-COV1901 to 97.8 in mRNA1273 against the Delta variant. After each booster vaccine, the neutralization titers against the Delta variant were compatible with those of the wild type [Chih-Hsien Chuang, 2022 ].

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received an mRNA vaccine first dose and a second dose of Pfizer-BioNTech or Moderna after 28 days. Measurement of neutralizing antibodies against the specific variants (Alpha, Beta, Delta) was performed on a representative population of 30 subjects randomly selected after stratification on vaccine schedule group, age (<40 years, ≥40 years, and <55 years, ≥55 years), and level of anti-spike IgG against the wild-type viral strains at D28 (<1000 BAU/mL, ≥1000 BAU/mL, and <5000 BAU/ml, ≥ 5000 BAU/mL). The study showed that the neutralizing antibodies titers against SARS-CoV-2 variants were not different between the homologous and heterologous vaccine groups [Janssen C, 2022 ].

Anderson et al. was a phase 2 randomized controlled trial conducted in the United States that included 96 participants with a primary schedule of Moderna: 48 with Monovalent prototype boost (100 mcg) of mRNA-1273, 25 with Monovalent variant boost of mRNA-1273.351 (50 mcg) and 23 with a bivalent boost of mRNA1273.351 (25 mcg ) and bivalent mRNA-1273 (25 mcg). This study assessed the immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary schedule approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA1273.351 that encodes Beta variant spike protein, and a bivalent vaccine of 25 mcg each mRNA-1273 and mRNA-1273.351. The results showed that following booster vaccination, a robust response to similar titers was observed in all three groups to 614D S-2P at Day 15 [monovalent prototype 62,272 AUC (95% CI 59,973, 64,659); monovalent variant 61,373 (95% CI 58,622, 64,254); bivalent 62,025 (95% CI 59,468, 64,691). In all groups, the third dose of mRNA vaccine induced similar responses against B.1.351 [monovalent prototype 47,733 AUC (95% CI 44,932, 50,710); monovalent variant 49,768 (95% CI 46,282, 53,517); bivalent 48,126 (95% 44,728, 51,781)] that were only 20% lower than the Day 15 responses to 614D . Spike-specific CD4+ and CD8+ T cells increased to similar levels to that after the second dose.

Suntronwong N et al was a cohort study conducted in Thailand. 167 participants primed with heterologous CoronaVac/Oxford-AstraZeneca vaccination were enrolled to receive a booster dose of Oxford-AstraZeneca (n= 60), Pfizer-BioNTech (n= 55) of Moderna (n= 52) vaccines. This study assessed the capability of the booster vaccination to induce an increase in neutralizing antibodies and T-cell responses against SARS-CoV-2, Omicron (BA.1 and BA.2), and Delta variants. The study showed that, following the booster dose, individuals boosted with mRNA vaccines demonstrated a higher level of neutralizing activity than those boosted with Oxford-AstraZeneca [Suntronwong N, 2022 ].

Omicron (B.1.1.529.1) 
Kanokudom S et al. recruited 222 adults with a complete CoronaVac regimen who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), and 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54) or standard Moderna vaccine (n=58). The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that were not affected by dosage. On day 28 the GMTs against the Omicron variant reached 343.3 and 541.2 in the reduced dose Pfizer-BioNTech and Moderna vaccine groups. [Kanokudom S, 2022 ].

Branche A et al. recruited 602 adults with primary schedules and a single homologous or heterologous boost. The participants were randomized to six Moderna vaccine arms (50µg dose): 99 received prototype Moderna vaccine, 100 received 1 dose of Beta and Omicron BA.1 bivalent vaccine, 102 received 2 doses of Beta and Omicron BA.1 bivalent vaccine, 101 received 1 dose of Delta and Omicron BA.1 bivalent vaccine, 100 received 1 dose of Omicron BA.1 monovalent vaccine and 100 received 1 dose of Omicron BA.1 Moderna bivalent vaccine. Neutralization antibody titers (ID50) were assessed for D614G, Delta, Beta, and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. The study found that the Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218- 4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907) [Angela R Branche, 2022 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901. The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that the neutralizing activity increased significantly post boost (P < 0.0001) and the fold-rise ranged from 2.1 in MCV-COV1901 to 14.4 in Pfizer against the omicron variant. The neutralization titers against the omicron variant were 6.4 to 13.5 times lower than those against the wild type. All except one participant who received mRNA vaccines as a booster had detectable neutralizing antibodies against the Omicron variant [Chih-Hsien Chuang, 2022 ].

Chalkias S et al was an open-label, ongoing phase 2–3 study conducted in United States. The study included 819 participants with primary schedule of Moderna: 377 included in the mRNA-1273 (50 µg) booster group and 437 included in the mRNA-1273.24 (50 µg) booster omicron-containing bivalent group. This study assessed the immunogenicity, safety, and reactogenicity of bivalent booster vaccine mRNA-1273.214 as compared with the previously authorized mRNA-1273 booster vaccine in adults who had received a two-dose primary series (100 μg) and first booster dose (50 μg) of mRNA-1273. Geometric mean titers of neutralizing antibodies against Ancestral SARS-CoV-2 (D614G) were 5977.3 (95% CI 5321.9 to 6713.3) in the mRNA-1273.214 (50 µg) group and 5649.3 (95% CI 5056.8 to 6311.2) in the mRNA-1273 (50 µg) group. Adjusted geometric mean titer ratio against wild type was 1.22 (97.5% CI 1.08 to 1.37) wich met the prespecified criterion for noninferiority. Geometric mean titers of neutralizing antibodies against Omicron were 2372.4 (95% CI 2070.6 to 2718.2) in the mRNA-1273.214 (50 µg) group and 1473.5 (95% CI 1270.8 to 1708.4) in the mRNA-1273 (50 µg) group. Adjusted geometric mean titer ratio against Omicron was 1.75 (97.5% CI 1.49 to 2.04) wich met the prespecified criterion for noninferiority. The percentages of participants with a seroresponse against ancestral SARS-CoV-2 (D614G) were 100% (95% CI, 98.9 to 100) for mRNA1273.214 and 100% (95% CI, 98.6 to 100) for mRNA-1273 at 28 days after the booster doses, with an estimated difference of 0, which met the noninferiority criterion. [Chalkias S, 2022 ]

Effectiveness outcomes
Alpha (B.1.1.7) 
Nasreen et al. was a case-control study (test-negative) conducted in Canada. The study included 421,073 SARS-CoV-2-positive symptomatic cases (707 with Alpha variant receive 1 or 2 doses of Moderna) and 351,540 SARS-CoV-2-negative symptomatic controls. The study evaluates the effectiveness of mRNA-1273 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes caused by the Alpha (B.1.1.7) variant, from December 2020 to May 2021. Effectiveness against symptomatic infection was 92% (95% CI, 86–96%) and effectiveness against hospitalization or death was 94% (95% CI, 89–97%). [Nasreen, S., 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 the 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 ].

Delta (B.1.617.2) 
Nasreen et al. was a case-control study (test-negative) conducted in Canada. The study included 421,073 SARS-CoV-2 positive symptomatic cases (participants ≤61 years of age with Delta variant infection receive 1 or 2 doses of Moderna) and 351,540 SARS-CoV- 2 negative symptomatic controls. The study evaluates the efficacy of the Moderna COVID-19 vaccine against the symptomatic infection of SARS-CoV-2 and the serious outcomes caused by the Delta variant (B.1.617.2) during December 2020 to May 2021. Effectiveness against symptomatic infection was 72% (95% CI, 57–82%) and effectiveness against hospitalization or death was 96% (95% CI, 72 to 99%) [Nasreen, S., 2021 ].

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 Moderna 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 0.28 (95% CI 0.26 to 0.31) and for Delta variant OR 0.045 (95% CI 0.038 to 0.053). Comparison of 3 doses versus 2 doses showed for Omicron variant OR 0.31 (95% CI 0.28 to 0.34) and for Delta variant OR 0.13 (95% CI 0.11 to 0.15) [Accorsi EK, 2022 ].

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination and health administration in Ontario (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435, 4261 were Delta-positive cases, and 114 087 were test-negative controls. VE against Delta symptomatic infection: 97% (95% CI 95-98). VE against Delta severe outcome:100% (95% CI 98-100). [Buchan SA, 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. Data were collected between April  4, 2021, and 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 4.6 (95% CI 4.2 to 5.1)  for the group without a booster and IRR 17.4 (95% CI 14.5 to 21.1) for the booster group.[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 2021 to and 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 ]

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 the Delta variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 69% (95% CI 66.7 to 71.2), >14 days after the second dose. Furthermore,Vaccine effectiveness against severe infection during Delta variant predominance period (aggregated data from 2 mRNA vaccines: Pfizer and Moderna) was 91.1% (95% CI 89.7 to 92.2), > 14 days after second dose ​​[Fabiani M, 2022 ].

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 or Moderna. 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 the Delta variant was 62.5% (95% CI: 61 to 63.9) for the primary scheme and 94% (95% CI: 93.4 to 94.6) for the booster [Irina Kislaya, 2022 ].

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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 2022 ].

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

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination and health administration in Ontario (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 4261 were Delta-positive cases (mean [SD] age, 44.2 [16.8] years; 2199 [51.6%] female), and 114 087 were test-negative controls (mean [SD] age, 42.0 [16.5] years; 7 884 [59.5%] female). Symptomatic Infection DELTA (VE %, 95% CI) BNT16b2: 97 (96-98) and mRNA-1273: 97 (95-98). Severe Outcome DELTA (VE %, 95% CI) BNT16b2: 99 (98-99) and mRNA-1273: 100 (98-100). [Buchan SA, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Delta-predominant period for Moderna vaccine was 98% (95% CI, 97-99) (less than two months after the second dose) and 97% (95% CI, 96-98) with the third booster dose. [Ferdinands JM, 2022 ]

Rennert L. was an observational study conducted in the United States that included 21,261 university students undergoing repeated surveillance testing during which Delta was the dominant SARS-CoV-2 variant. The estimated Moderna vaccine effectiveness against any SARS-CoV-2 infection was 75.4% (95% CI, 70.5-79.5). Between 0 and 6 months post-vaccination, the estimated protection decreased from 88.9% to 58.3% for mRNA-1273 vaccine. [Rennert L, 2022 ].

Omicron (B.1.1.529.1) 
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 Moderna 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 0.28 (95% CI 0.26 to 0.31) and for Delta variant OR 0.045 (95% CI 0.038 to 0.053). Comparison of 3 doses versus 2 doses showed for Omicron variant OR 0.31 (95% CI 0.28 to 0.34) and for Delta variant OR 0.13 (95% CI 0.11 to 0.15) [Accorsi EK, 2022 ].

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination and health administration in Ontario (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 16,087 were Omicron-positive cases , and 114 087 were test-negative controls. VE against Omicron symptomatic infection: 65% (95% CI 55-72). VE against Omicron severe outcome: 93% (95% CI 74-98). [Buchan SA, 2022 ]

Chemaitelly H et al was a case-control study conducted in Qatar, based on data from a test-negative design study that seeks to assess the duration of protection of Pfizer-BioNTech after the 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.  Vaccine effectiveness was 53.1% (95% CI 40.7 to 62.8) 2 to 3 weeks after receiving the booster dose [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. Data were collected between April  4, 2021, and 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 4.6 (95% CI 4.2 to 5.1)  for the group without a booster and IRR 17.4 (95% CI 14.5 to 21.1) for the booster group.[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 and 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 ].

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 ].

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 or Moderna. 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 the Delta variant was 62.5% (95% CI: 61 to 63.9) for the primary scheme and 94% (95% CI: 93.4 to 94.6) for the booster [Irina Kislaya, 2022 ].

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna. The study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Omicron variant of the booster dose compared to the two-dose regimen was 47.3% (95% CI 40.7  to 53.3) 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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 2022 ].

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

Ng OT et al was cohort study conducted in Singapore. The study included 2,441,581 eligible individuals. It was based on data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27th 2021 to March 10th 2022. Risk Infeccion (Incidence Rate Ratios) was 0.67% (95% CI 0.62 to 0.72) and 1.16% (95% CI 0.82 to 1.65) against Severe COVID Infeccion (Aggregated data from Moderna  and Pfizer COVID-19 vaccines). [Ng OT, 2022 ]

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination and health administration in Ontario (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 16,087 were Omicron-positive cases (mean [SD] age, 36.0 [14.1] years; 8249 [51.3%] female), and 114 087 were test-negative controls (mean [SD] age, 42.0 [16.5] years; 7 884 [59.5%] female). Symptomatic Infection OMICRON (VE %, 95% CI) BNT16b2: 60 (55-65) and mRNA-1273: 65 (55-72). Severe Outcome OMICRON (VE %, 95% CI) BNT16b2: 95 (87-98) and mRNA-1273: 93 (74-98). [Buchan SA, 2022 ]

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. IBased on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of 2 doses of Moderna was 59% (95% CI 57.7% to 60.3%], when the Omicron variant emerged. [Lin DY, 2022 ].

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

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine health-care system, the Michigan State Registry and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA based COVID-19 vaccines. During the Omicron dominant period December 2021 to March 2022. The effectiveness of the Moderna vaccine during the Omicron period in immunocompetent participants was 16% (95%CI 5 to 26) for two doses and 57% (95%CI 51 to 62) for three doses. In immunocompromised participants the effectiveness was 57% (95%CI 29 to 74) for two doses and 60% (95%CI 42 to 73) for three doses. [Risk M, 2022 ]

Monge S et al,  was a nationwide Cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no booster group. The aim of this study was to  estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. Vaccine effectiveness with Moderna booster and AstraZeneca, JAnssen, Moderna or Pfizer primary schedule was 52,5% (95% CI, 51,3–53,7). Vaccine effectiveness of Moderna primary schedule and ARNm booster was 55.3% (95% CI, 52.3–58.2) (Moderna or Pfizer booster dose). [Monge S, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Omicron-predominant period for Moderna vaccine was 87% (95% CI, 75-93) (less than two months after the second dose) and 91% (95% CI, 89-92)
with the third booster dose. [Ferdinands JM, 2022 ]

Ioannu et al. was a retrospective matched-cohort study conducted in the United States. The study included 981,676 participants: 490,838 boosted individuals and 490,838 non-boosted individuals. Based on data from the Veterans Association's (VA) Corporate Data Warehouse, a database of VA enrollees' comprehensive electronic health records, and the VA COVID-19 Shared Data Resource. It included patients 18 years old and above, who received mRNA based COVID-19 boosters and a matched cohort of participants that did not, during the Omicron dominant period between December 2021 and March 2022. The effectiveness of the Moderna vaccine booster during the Omicron dominance period was 44.6% (95% CI, 42.5-46.6) against infection and 52.9% (95% CI, 45.6-59.2) against hospitalization. [Ioannou GN, 2022 ]

Grewal R et al. was a case-control study (test negative design) conducted in the United States. The aim of this study was to estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of the mRNA COVID-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the Omicron variant. Vaccine effectiveness of three doses of the Moderna vaccine against the Omicron variant to any infection was 44% (95% CI, 38% to 49%), against symptomatic infection was 61% (95% CI, 50% to 69%) and against severe outcomes 81% (95% CI, 74% to 86%). [Grewal R, 2022 ].

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that included 16,208,600 participants, of which 7,589,080 received a Pfizer-BioNTech primary schedule and 8,619,520 received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform, during the Omicron period, between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group, and 0.41 (95% CI, 0.33-0.50) for the ChAdOx1 primary schedule and Moderna booster group. [Agrawal U, 2022 ]

Hung FT et al was a case-control study conducted in the United States that included 123,236 participants, 30,809 cases and 92,427 controls. Based on data from KPSC electronic health records, California Immunizations Registry (CAIR) and Care Everywhere, during the Omicron predominance period (between January and June 2022). The study assessed the effectiveness of 3 and 4 doses of the mRNA-1273 vaccine against SARS-CoV-2 Omicron variants. The adjusted vaccine effectiveness against infection 14-30 days after the third dose against the BA.4 variant was 72.6% (95% CI, -54.7% to 96.6%) and against the BA.5 variant was 90.6% (95% CI, 30.6% to 98.7%). Vaccine effectiveness after the fourth dose against BA.4: 75.7% (95% CI, 44.7% to 91%) and 30.8% (95% CI, -9.2% to 56.5%) against BA.5. The adjusted effectiveness against hospitalization after the third dose against BA.4/BA.5 was 72.4% (95% CI, 23.9% to 90%), and 88.5% (95% CI, 51.8% to 97.2%) after the fourth dose. [Hung Fu Tseng, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness (VE) against hospital admission during the Omicron period was 79% (95% CI, 43% to 92%) for the primary schedule, 96% (95% CI, 91% to 98%) for the Moderna schedule+Moderna booster, 91% (95% CI, 87% to 94%) for the Pfizer schedule + Moderna booster, 92% (95% CI, 80% to 97%) for the Moderna schedule + Pfizer Booster, and 94% (95% CI, 81% to 98%) for the AstraZeneca schedule + Moderna booster [Baum U, 2022 ].

Vaccine efficacy and effectiveness for booster dose

Immunogenicity results
Benotmane I et al. was a non-comparative study conducted in France. The study included 159 participants (kidney transplant). This study found that a third dose of Moderna vaccine induced a serologic response in 49% of kidney transplant recipients who did not respond after 2 doses. ​Based on data from the French National Authority for Health that assesses the administration of a third vaccine dose in immunosuppressed patients who did not respond after two doses. [Benotmane I, 2021 ].
              
Hall VG et al was a phase 4, randomized, placebo-controlled trial sponsored by University Health Network, Toronto and conducted Canada May 2021 to August 2021. It was registered with trial registry number NCT04885907. The trial included organ-transplant recipients who had received two doses of mRNA-1273. The sample size was 120. The mean age of the participants was 66.6 years. The proportion of women in the mRNA-1273 group was 38.3% and in the placebo group was 30%. Participants were randomly assigned in a 1:1 ratio to receive a third dose of mRNA-1273 or a placebo. The intervention was administered as a third dose of mRNA-1273 vaccine or saline placebo 2 months after the second dose of mRNA-1273 (dosing schedule: 0, 1, and 3 months). [Hall VG, 2021 ]
          
Branche A et al. recruited 602 adults with primary schedules and a single homologous or heterologous boost. The participants were randomized to six Moderna vaccine arms (50µg dose): 99 received prototype Moderna vaccine, 100 received 1 dose of Beta and Omicron BA.1 bivalent vaccine, 102 received 2 doses of Beta and Omicron BA.1 bivalent vaccine, 101 received 1 dose of Delta and Omicron BA.1 bivalent vaccine, 100 received 1 dose of Omicron BA.1 monovalent vaccine and 100 received 1 dose of Omicron BA.1 Moderna bivalent vaccine. Neutralization antibody titers (ID50) were assessed for D614G, Delta, Beta, and Omicron BA.1 variants and Omicron BA.2.12.1 and BA.4/BA.5 subvariants 15 days after vaccination. The study found that the Omicron BA.1 monovalent and Omicron BA.1+Prototype vaccines induced a geometric mean ratio (GMR) to Prototype for Omicron BA.1 of 2.03 (97.5%CI:1.37-3.00) and 1.56 (97.5%CI:1.06-2.31), respectively. Omicron BA.4/BA.5 GMTs were approximately one third BA.1 GMTs (Prototype 517 [95%CI:324-826] vs. 1503 [95%CI:949-2381]; Omicron BA.1+Beta 628 [95%CI:367-1,074] vs. 2125 [95%CI:1139-3965]; Omicron BA.1+Delta 765 [95%CI:443-1,322] vs. 2242 [95%CI:1218- 4128] and Omicron BA.1+Prototype 635 [95%CI:447-903] vs. 1972 [95%CI:1337-2907) [Angela R Branche, 2022 ].

Anderson et al was a phase 2 randomized controlled trial conducted in the United States that included 96 participants with a primary schedule of Moderna: 48 with Monovalent prototype boost (100 mcg) of mRNA-1273, 25 with Monovalent variant boost of mRNA-1273.351 (50 mcg) and 23 with a bivalent boost of mRNA1273.351 (25 mcg ) and bivalent mRNA-1273 (25 mcg). This study assessed the immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary schedule approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA1273.351 that encodes Beta variant spike protein, and a bivalent vaccine of 25 mcg each mRNA-1273 and mRNA-1273.351. The results showed that following booster vaccination, a robust response to similar titers was observed in all three groups to 614D S-2P at Day 15 [monovalent prototype 62,272 AUC (95% CI 59,973, 64,659); monovalent variant 61,373 (95% CI 58,622, 64,254); bivalent 62,025 (95% CI 59,468, 64,691). In all groups, the third dose of mRNA vaccine induced similar responses against B.1.351 [monovalent prototype 47,733 AUC (95% CI 44,932, 50,710); monovalent variant 49,768 (95% CI 46,282, 53,517); bivalent 48,126 (95% 44,728, 51,781)] that were only 20% lower than the Day 15 responses to 614D . Spike-specific CD4+ and CD8+ T cells increased to similar levels to those after the second dose. [Anderson E, 2022 ]

Chalkias S et al was an open-label, ongoing phase 2–3 study conducted in United States. The study included 819 participants with primary schedule of Moderna: 377 included in the mRNA-1273 (50 µg) booster group and 437 included in the mRNA-1273.24 (50 µg) booster omicron-containing bivalent group. This study assessed the immunogenicity, safety, and reactogenicity of bivalent booster vaccine mRNA-1273.214 as compared with the previously authorized mRNA-1273 booster vaccine in adults who had received a two-dose primary series (100 μg) and first booster dose (50 μg) of mRNA-1273. Geometric mean titers of neutralizing antibodies against Ancestral SARS-CoV-2 (D614G) were 5977.3 (95% CI 5321.9 to 6713.3) in the mRNA-1273.214 (50 µg) group and 5649.3 (95% CI 5056.8 to 6311.2) in the mRNA-1273 (50 µg) group. Adjusted geometric mean titer ratio against wild type was 1.22 (97.5% CI 1.08 to 1.37) wich met the prespecified criterion for noninferiority. Geometric mean titers of neutralizing antibodies against Omicron were 2372.4 (95% CI 2070.6 to 2718.2) in the mRNA-1273.214 (50 µg) group and 1473.5 (95% CI 1270.8 to 1708.4) in the mRNA-1273 (50 µg) group. Adjusted geometric mean titer ratio against Omicron was 1.75 (97.5% CI 1.49 to 2.04) wich met the prespecified criterion for noninferiority. The percentages of participants with a seroresponse against ancestral SARS-CoV-2 (D614G) were 100% (95% CI, 98.9 to 100) for mRNA1273.214 and 100% (95% CI, 98.6 to 100) for mRNA-1273 at 28 days after the booster doses, with an estimated difference of 0, which met the noninferiority criterion. [Chalkias S, 2022 ]

Haggenburg S et al was a cohort study conducted in Netherlands. The study included 584  immunocompromised patients with hematologic cancers. The aim of this study was to assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. A third mRNA-1273 vaccination was associated with a significant increase in S1-IgG concentration. Seroconversion rates improved from 68.9% (399 of 579) to 78.8% (443 of 562), and 378 of 562 (67.3%) patients obtained S1-IgG concentration of 300 BAU/mL or greater. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. [Haggenburg S, 2022 ]

Chalkias et al, was a phase 2/3 non-randomized trial conducted in the United States as part of a larger study registered as NCT04927065. Its aim was to evaluate the safety, reactogenicity and immunogenicity of a single booster dose of the bivalent beta-containing mRNA candidate vaccine mRNA-1273.211, in adults who received a primary schedule of mRNA-1273. The study included 300 participants who received 50 µg of mRNA-1273.211 booster, 595 participants who received 100 µg of mRNA-1273.211 booster, a historical cohort of 584 participants who received the 100 µg primary schedule and 171 participants who received a mRNA-1273 50 µg booster dose. The Geometric Mean Titers (GMT) of neutralizing antibodies against the ancestral strain were 1,996.2 (95% CI, 1,777.9–2,241.4) for the mRNA-1273.211 (50 µg) group and 4,324.7 (95% CI, 3,974.6–4,705.6) for the mRNA-1273.211 (100 µg) group. The GMT of neutralizing antibodies against the Beta variant were 953.9 (95% CI, 844.1–1,078.0) for the mRNA-1273.211 (50 µg) group and 1,574.6 (95% CI, 1,439.4–1,722.5) for the mRNA-1273.211 (100 µg) group. [Chalkias S, 2022 ]

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

Effectiveness results
 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 doses of Moderna 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 50.8% (95% CI: 43.4-57.3%)[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 Moderna 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 0.28 (95% CI 0.26 to 0.31) and for Delta variant OR 0.045 (95% CI 0.038 to 0.053). Comparison of 3 Doses vs 2 Doses showed for Omicron variant OR 0.31 (95% CI 0.28 to 0.34) and for Delta variant OR 0.13 (95% CI 0.11 to 0.15)[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 Pfizer or Moderna COVID-19 vaccine booster dose reduced infections by 50.4% (95% CI 29.4% to 64.7%) in nursing home 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 S et al. included 134,435 tests (Omicron-positive cases=16,087; Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021. The study showed that 2 doses of COVID-19 vaccines only offer modest and short-term protection against symptomatic Omicron infection. A third dose improves protection against symptomatic infection and provides excellent protection against severe outcomes for Delta and Omicron variants. Vaccine efficacy against Delta variant was 97% (95% CI 95 to 98) and 65% (95% CI 55 to 72) 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. Data were collected between April  4, 2021, and 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 4.6 (95% CI 4.2 to 5.1)  for the group without a booster and IRR 17.4 (95% CI 14.5 to 21.1) for the booster group.[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 and 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 ].

Chemaitelly H et al.was a case-control study conducted in Qatar based on data from a test-negative design study that seeks to assess the duration of protection of Pfizer-BioNTech after the second dose and after the third/booster dose against symptomatic Omicron infection and against COVID-19 hospitalization and death, between December 23, 2021, and February 2, 2022.  Vaccine effectiveness was 53.1% (95% CI 40.7 to 62.8) 2 to 3 weeks after receiving the booster dose. [Hiam Chemaitelly, 2022 ].

Draws 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–BioNTech and 1,066,645 were fully vaccinated with Moderna. A Pfizer–BioNTech 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 after 26 weeks from the second dose was 65% (95% CI 65 to 66) for the Moderna COVID-19 Vaccine. [Drawz PE, 2022 ]

Shrestha NK et al. was a cohort study conducted in the United States, Based on data from the Cleveland Clinic Health System in Ohio, United States, all employees vaccinated (with both Pfizer-BioNTech and Moderna) or who have a history of prior COVID-19 infection until November 26, 2021 were included, with a follow-up period of 90 days. Vaccine effectiveness during the Omicron variant boost was 57% (95% CI: 54% to 59%) for the full schedule and a boost with mRNA [Nabin K Shrestha, 2022 ] vaccines.

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 mRNA-1273) for individuals with PCR–confirmed infections was 0.198 (95% CI 0.144 to 0.271) [Tan SHX, 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 ].

Abu-Raddad LJ et al. was a study conducted in Qatar including data from 2,239,193 vaccinated individuals: 1,299,010 with Pfizer-BioNTech and 890,619 with Moderna, the study also included matched unvaccinated controls. The study analyzed information from national, federated databases regarding Covid-19 vaccination, laboratory testing, hospitalization, and death from December 19, 2021, through January 26, 2022. The vaccine effectiveness against the Omicron variant of the booster dose compared to the two-dose regimen was 47.3% (95% CI 40.7  to 53.3) 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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 2022 ].

Ng OT et al was cohort study conducted in Singapore. The study included 2,441,581 eligible individuals. It was based on data from the Singapore Ministry of Health’s (MOH) official COVID-19 database, including individuals who had received 2 or 3 doses of mRNA vaccines (by Pfizer-BioNTech or Moderna) or inactivated vaccines (by Sinovac or Sinopharm) and notified infections from December 27th 2021 to March 10th 2022. Effectiveness of booster dose against COVID-19 Infeccion was 35.6% (95%CI 32.8-38.3) and 97.5% (95% CI 89.7 -  99.4) against Severe COVID Infeccion. [Ng OT, 2022 ]

Lin DY et al, was a comparative cohort study conducted in the USA. The study included 10,600,823 individuals, among which were 2,771,364 cases of COVID-19. IBased on data from the North Carolina COVID-19 Surveillance System and the Covid-19 Vaccine Management System, including data from residents of North Carolina from December 11, 2020, to September 8, 2021. Vaccine effectiveness of Moderna homologous booster was 62.1% (95%CI 60.7 to 63.5) after 1 month. [Lin DY, 2022 ].

Risk M et al was a retrospective cohort study conducted in the United States including 168,414 participants: 133,238 vaccinated with mRNA vaccines and 35,176 unvaccinated. Based on data from the Michigan Medicine health-care system, the Michigan State Registry and chart-reviewed COVID-19 hospitalization data. Including patients 18 years old and above, who received mRNA based COVID-19 vaccines. During the Omicron dominant period December 2021 to March 2022. The effectiveness of the Moderna vaccine during the Omicron period was 16% (95%CI 5 to 26) for two doses and 57% (95%CI 51 to 62) for three doses. [Risk M, 2022 ]

Monge S et al,  was a nationwide Cohort study conducted in Spain. This study included 7,036,433 participants older than 40 years: 3,111,159 in the booster group and 3,111,159 in the no booster group. The aim of this study was to  estimate the effectiveness of mRNA-based vaccine boosters against infection during the period of the predominance of the omicron variant in Spain. Vaccine effectiveness with Moderna booster and AstraZeneca, JAnssen, Moderna or Pfizer primary schedule was 52,5% (95% CI, 51,3–53,7). Vaccine effectiveness of Moderna primary schedule and ARNm booster was 55.3% (95% CI, 52.3–58.2) (Moderna or Pfizer booster dose). [Monge S, 2022 ]

Ferdinands JM et al was a test-negative case-control study conducted in United States. The study included data from 259,006 hospital admissions: 213,103 with SARS-CoV-2 negative test and 45,903 with SARS-CoV-2 positive test. The main outcome was waning of vaccine effectiveness with BNT162b2 or mRNA-1273 vaccine during the omicron and delta periods. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Omicron-predominant period for Moderna vaccine was 87% (95% CI, 75-93) (less than two months after the second dose) and 91% (95% CI, 89-92) with the third booster dose. Vaccine effectiveness (VE) against COVID-19-associated hospitalizations during the Delta-predominant period for Moderna vaccine was 98% (95% CI, 97-99) (less than two months after the second dose) and 97% (95% CI, 96-98) with the third booster dose.[Ferdinands JM, 2022 ]

Grewal R et al. was a case-control study (test negative design) conducted in the United States. The aim of this study was to estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of mRNA COVID-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the Omicron variant. Vaccine effectiveness of three doses of Moderna vaccine against the Omicron variant to any infection was 44% (95% CI, 38% to 49%), against symptomatic infection was 61% (95% CI, 50% to 69%) and against severe outcomes 81% (95% CI, 74% to 86%).[Grewal R, 2022 ].

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

Hung FT et al fue un estudio de casos y controles conducido en Estados Unidos que incluyó 123.236 participantes, 30.809 casos y 92.427 controles. Basado en datos de KPSC, registros electrónicos, el registro de inmunización de California (CAIR) y el servicio Care Everywhere, durante el período de predominancia de Ómicron (entre enero y junio de 2022). El estudio evaluó la efectividad de una tercera y cuarta dosis de Moderna. La efectividad ajustada contra la infección 14-30 días después de la tercera dosis fue de 72,6% (IC 95%, -54,7% a 96,6%) contra BA.4 y 90,6% (IC 95%, 30,6% a 98,7%) contra BA.5. Luego de la cuarta dosis la efectividad de la vacuna fue de 75,7% (IC 95%, 44,7% a 91%) contra BA.4 y 30,8% (IC 95%, -9,2% a 56,5%) contra BA.5. La efectividad ajustada contra la hospitalización luego de la tercera dosis fue de 72,4% (IC 95%, 23,9% a 90%) contra BA.4/BA.5 y luego de la cuarta dosis fue de 88,5% (IC 95%, 51,8% a 97,2%). [Hung Fu Tseng, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and over. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness of the booster against hospital admission was 97% (95% CI, 93% to 98%). [Baum U, 2022 ]

Vaccine efficacy and effectiveness for heterologous schedule

Immunogenicity results
Macchia et al, was a randomized noninferiority clinical trial conducted in Argentina. The study compared the immune response generated by the homologous Sputnik V regimen to heterologous Sputnik V vaccine regimens with Moderna, Sinopharm BIBP, or AstraZeneca vaccines. The study showed that all but the Moderna regimen were statistically inferior to the standard Sputnik V regimen (rAd26/rAd5). The Moderna regimen showed a 3.53-fold increase in antibody concentrations compared to the standard Sputnik V regimen. [Macchia A, 2022 ]

ARNCOMBI was a randomized controlled trial conducted in France. The study included 414 individuals who received a first dose mRNA vaccine and a second dose of Pfizer-BioNTech or Moderna after 28 days. The primary outcome was to compare the immune response generated by the homologous Pfizer-BioNTech schedule to Pfizer-BioNtech/Moderna schedule. The study showed that the GMT antibodies were higher with the heterologous schedule compared to the Pfizer-BioNTech homologous regimen. [Janssen C, 2022 ]

Pascuale CA et al was a comparative cohort sutdy conducted in Argentina. The study enrolled 1,314 participants who had received the first dose of Sputnik V C1 (n = 669), AstraZeneca (n = 448), or BBIBPCorV (n = 197): 148 with Moderna second dose and Sputnik first dose, 67 Moderna second dose and AstraZeneca first dose, and 42 Moderna second dose and BBIBPCorV first dose. The study assessed the immunogenicity and reactogenicity by comparing homologous vaccination programs using either Sputnik V, ChAdOx1-S, or BBIBP-CorV with different heterologous schemes to define strategies to accelerate vaccination plans. A second dose of mRNA-1273 induced the highest antibody response in all cohorts. The levels of IgG anti-spike antibodies and the serum neutralizing capacity of the heterologous combinations with mRNA-1273 in all arms were similar to those obtained with the homologous two-dose schedule with mRNA1273, used as the reference. In all three cohorts, heterologous vaccination with mRNA-1273 resulted in a significant (p < 0.01) increase in the serum neutralizing titers compared with the homologous schemes. [Pascuale CA, 2022 ]

RECOVAC was a randomized trial conducted in the Netherlands that enrolled 333 kidney transplant recipients (KTR) who did not seroconvert after an initial mRNA vaccine schedule: 230 KTRs were randomly assigned in a 1:1:1 manner to receive 100 μg mRNA-1273, 2 × 100 μg mRNA-1273, or Ad26.COV2-S vaccination. In addition, 103 KTRs receiving 100 μg mRNA-1273, were randomly assigned 1:1 to continue (mycophenolate mofetil+) or discontinue (mycophenolate mofetil-) mycophenolate mofetil or mycophenolic acid treatment for 2 weeks. The primary outcome was the percentage of participants with a spike protein (S1)-specific IgG concentration of at least 10 binding antibody units per mL at 28 days after vaccination. The seroreponse rates were 68% (95% CI, 56% to 79%) for the 2 × mRNA-1273 group, 63% (95% CI, 51% to 74%) for the Ad26.COV2-S group and 68% (95% CI, 57% to 79%) for the single mRNA-1273 group. The seroresponse rate in mycophenolate mofetil- was 80% (95% CI, 66% to 91%) and 67% (95% CI, 52% to 80%) in mycophenolate mofetil+. [Kho MML, 2022 ]

Effectiveness results
Chung et al. conducted a case-control study with a test-negative design to estimate vaccine effectiveness (VE) against SARS-CoV-2 infection after the primary schedule of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11th and November 21st 2021 in Ontario, Canada. They included 261,360 test-positive cases (of any SARS-CoV-2 lineage) and 2,783,699 individuals as test-negative controls. VE for ChAdOx1/mRNA-1273 7-59 days after second dose was 91% (95% CI, 89% to 93%) against any infection, 96% (95% CI, 93% to 97%) against symptomatic infection and 99% (95% CI, 95% to 100%) against severe outcomes. VE for ChAdOx1/mRNA-1273 60-119 days after second dose was 87% (95% CI, 85% to 89%) against any infection, 93% (95% CI, 91% to 94%) against symptomatic infection and 99% (95% CI, 98% to 100%) against severe outcomes. [Chung H, 2022 ]

Vaccine efficacy and effectiveness for heterologous booster schedule

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

COV-BOOST 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 the 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 ].

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 the 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 ].

Kanokudom S et al. recruited 222 adults with a complete CoronaVac regimen who received a booster dose of 15μg Pfizer-BioNTech vaccine (n=59), and 50μg Moderna vaccine (n=51), standard Pfizer-BioNTech vaccine (n=54)or standard Moderna vaccine (n=58). The study found no significant differences in binding antibody levels between standard and reduced doses. 28 days after the booster dose binding antibody levels were 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. [Kanokudom S, 2022 ].

Poh X 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 on 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 ].

Chuang et al. was a randomized controlled study made in Taiwan. It included data from samples of 340 health care workers (HCW) with prior Oxford-AstraZeneca homologous vaccination and that received one of the four vaccines as booster doses: Pfizer–BioNTech, half-dose Moderna, full dose Moderna or MVC-COV1901. The primary outcomes were humoral and cellular immunogenicity and the secondary outcomes safety and reactogenicity 28 days post-booster. The study found that, compared with pre-boost, all study vaccines elicited significantly higher anti-spike IgG at 28 days post-boost (P < 0.0001). The mRNA vaccines had more reactogenicity than the protein vaccine [Chih-Hsien Chuang, 2022 ].

COV-BOOST  was a phase 2 randomized clinical trial conducted in the United Kingdom. This study enrolled 166 participants who had received Pfizer-BioNTech as their third dose and randomly assigned them to receive a fourth dose of either Pfizer-BioNTech (30 µg in 0.30 mL; full dose) or Moderna  (50 µg in 0.25 mL; half dose). It was compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. The results showed a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25,317 ELU/mL, 95% CI 20,996–30,528) to 14 days after a fourth dose of Moderna (54 936 ELU/mL, 46,826–64,452), with a geometric mean fold change of 2,19 (1,90–2,52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12,19 (95% CI 10,37–14,32) and 15,90 (12,92–19,58) in the Pfizer–BioNTech and Moderna groups, respectively. T-cell responses were also boosted after the fourth dose (the fold changes for the wild-type variant from before to after the fourth dose were 7,32 [95% CI 3,24–16,54] in the Pfizer–BioNTech group and 6,22 [3,90–9,92] in the Moderna group) [Munro APS, 2022 ].

Suntronwong N et al. was a cohort study conducted in Thailand. One hundred and sixty-seven participants primed with heterologous CoronaVac/Oxford-AstraZeneca vaccination were enrolled to receive a booster dose of Oxford-AstraZeneca (n= 60), Pfizer-BioNTech (n= 55) of Moderna (n= 52) vaccines. This study assessed the capability of the booster vaccination to induce an increase in neutralizing antibodies and T-cell responses against SARS-CoV-2, Omicron (BA.1 and BA.2), and Delta variants. The study showed that, following the booster dose, the anti-RBD IgG significantly increased and peaked at day 14 for all vaccines (p< 0.001). Comparing pre and post-boost, the Moderna vaccine induced an anti-RBD IgG 23-fold increase (126.9 vs. 2921 BAU/ml) and showed a higher level than the other vaccine groups. 90-97% of individuals boosted with Pfizer and Moderna induced IFN-γ responses at 14 days [Suntronwong N, 2022 ].

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

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

Effectiveness results
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. 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 ].

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.  Moderna effectiveness against Delta variant for symptomatic infection was 57.4% (95% CI 52.6 to 61.8) 4 weeks after the first dose, 80.4% (95% CI 67.3 to 88.2) 25 weeks after the second dose, 94.7% (95% CI 89.3 to 97.3) 2-4 weeks after a Pfizer-BioNTech booster and 96.4% (95% CI 91.4 to 98.5) 2-4 weeks after  Moderna booster [Andrews N, 2022 ].

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

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

Buchan et al. conducted a test-negative case-control study using linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination and health administration in Ontario (Canadá) to estimate the vaccine effectiveness (VE) against symptomatic infections and severe outcomes associates with these infections. Of 134,435 total participants (> 18 years older), 16,087 were Omicron-positive cases , 4261 were Delta-positive cases, and 114 087 were test-negative controls. Symptomatic Infection against OMICRON BNT16b2: 60% (CI 95% 55-65). VE against Omicron severe outcome BNT16b2: 95% (95% CI 87-98).  VE  against Delta symptomatic infection BNT16b2: 97% (95% CI 96-98). VE against Delta severe outcome BNT16b2: 99% (95% CI 98-99). [Buchan SA, 2022 ]

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

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

Monge S et al,  was a nationwide Cohort study conducted in Spain. We linked data from three nationwide population registries in Spain (Vaccination Registry, Laboratory Results Registry, and National Health System registry) . In this study were included 7, 036, 433 participantes ≥ 40 years . The aim of this study was to estimate the effectiveness of mRNA-based vaccine boosters against infection with the omicron variant. The estimated effectiveness from day 7 to 34 after a booster was 51.3% (95%CI 50.2-52.4), with Pfizer Booster was 46,2% (95% CI 43,5–48,7).  Estimated effectiveness was 43,6% (95% CI 40,0 –47,1) when the booster was administered between 151 days and 180 days after complete vaccination and 52,2% (95% CI 51,0–53,3) if administered more than 180 days after primary scheduled completion.[Monge S, 2022 ]

Stowe et al. conducted a test-negative case-control study in UK, to estimate Vaccine Effectiveness (VE) against hospitalisation with the Omicron and Delta variants using PCR testing linked hospital records (Emergency Care Data Set; ECDS). The total number of tests in the study period was 409,985 of which 115,720 were cases and 294,265 controls.

VE against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 18 to 64 years of age:

Primary Schedule ChAd0x1-S Booster mRNA-1273
After 14-34 days: 88.3% (95% CI 84.3 to 91.3)
After 70+ days: 74.1% (95% CI 56.3 to 84.7)

Primary Schedule BNT162b2 Booster mRNA-1273
After 14-34 days: 87.3% (95% CI 81.2 to 91.3)
After 70+ days: 60.6% (95% CI 27.7 to 78.5)

VE against hospital admissions from ECDS within 14 days of the test date by the Omicron variant in symptomatic individuals 65 years of age and older:

Primary Schedule ChAd0x1-S Booster mRNA-1273
After 14-34 days: 98.1% (95% CI 92.1 to 99.5)
After 70+ days: 89.6% (95% CI 73.8 to 95.9)

Primary Schedule BNT162b2 Booster mRNA-1273
After 7-13 days: 89.0% (95% CI 17.2 to 98.5)
After 14-34 days: 91.2% (95% CI 75.5 to 96.9)

[Stowe J, 2022 ]

Grewal R et al. was a case-control study (test negative design) conducted in the United States. The aim of this study was to estimate the marginal effectiveness of a fourth versus third dose and the vaccine effectiveness of the mRNA COVID-19 vaccines BNT162b2 and mRNA-1273 against any infection, symptomatic infection, and severe outcomes (hospital admission or death) related to the Omicron variant. Vaccine effectiveness of two doses of Pfizer and Moderna booster against the Omicron variant against any infection was 36% (95% CI, 28% to 44%), against symptomatic infection was 57% (95% CI, 40% to 69%) and against severe outcomes 81% (95% CI, 67% to 89%). [Grewal R, 2022 ].

Agrawal et al was a retrospective cohort study conducted in the United Kingdom that included 16,208,600 participants, of which 7,589,080 received a Pfizer-BioNTech primary schedule and 8,619,520 received a ChAdOx1 primary schedule. The study was based on data from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) database, Vaccine Management System, Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II), and Secure Anonymised Information Linkage Databank platform, during the Omicron period, between December 2021 and February 2022. The adjusted Rate Ratio (aRR) 3-5 weeks after booster vaccination against hospitalization was 0.58 (95% CI, 0.46-0.73) for the Pfizer-BioNTech primary schedule and Moderna booster group and 0.41 (95% CI, 0.33-0.50) for the ChAdOx1 primary schedule and Moderna booster group. [Agrawal U, 2022 ]

Baum U et al was a cohort study conducted in Finland including 896,220 participants aged 70 years and older. The study was based on a nationwide register-based cohort, between December 27th 2020 and March 31st 2022. Vaccine effectiveness (VE) of the booster against hospital admission was 91% (95% CI, 87% to 94%) for the Pfizer schedule+Moderna booster, 91% (95% CI, 81% to 96%) for the Moderna schedule+Pfizer booster, and 94% (95% CI, 92% to 98%) for the AstraZeneca schedule+Moderna booster. VE against ICU admission was 92% (95% CI, 79% to 97%) for the Pfizer schedule+Moderna booster, 100% for the Moderna schedule+Pfizer booster, and 100% for the AstraZeneca schedule+Moderna booster. [Baum U, 2022 ]

Safety of the vaccine

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 pseudouridine, 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. [Karikó K, 2008 ].

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 ].

Mutations of mRNA sequence of SARS-CoV-2, such as E484K, N501Y or K417N, can potentially reduce vaccine-elicited response. The evidence on these and other variants is still evolving but mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy [Wang Z, 2021 ].

 

Reproductive toxicity
A study performed in rats assessing postnatal reproductive toxicity of Moderna COVID-19 vaccine was submitted to FDA on December 4, 2020. FDA review concluded that a dose of 100 μg given prior gestation periods did not have any adverse effects on female reproduction, fetal/embryonal development, or postnatal developmental [FDA, 2020 ].

Developmental and reproductive toxicology (DART) studies in rats concluded that the vaccine at a dose of 100 μg, given prior to mating and during gestation periods, did not have any adverse effects (including on female reproduction, fetal/embryonic development, or postnatal developmental).

Safety of the vaccine in clinical trials

Main safety outcomes of Moderna COVID-19 vaccine

Key messages

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

Moderna COVID-19 vaccine did not increase the risk of serious adverse events.









Any adverse event after the 2nd dose (within 7 days after injection)

The relative risk of any adverse event after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.94 (95% CI 1.58 to 2.38). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose by 94%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 6255 people not receiving Moderna COVID-19 vaccine out of 14578 presented this outcome (439 per 1000) versus 13556 out of 14691 in the group that did receive it (851 per 1000). In other words, 412 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 41.2%, or that the intervention increased the risk of any adverse event after the 2nd dose by 41.2 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose.

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









Local adverse events after the 2nd dose (within 7 days after injection)

The relative risk of local adverse events after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 3.67 (95% CI 2.26 to 5.95). This means Moderna COVID-19 vaccine increased the risk of local adverse events after the 2nd dose by 267%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 2757 people not receiving Moderna COVID-19 vaccine out of 14578 presented this outcome (200 per 1000) versus 13029 out of 14691 in the group that did receive it (734 per 1000). In other words, 534 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 53.4%, or that the intervention increased the risk of local adverse events after the 2nd dose by 53.4 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced local adverse events after the 2nd dose.

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









Systemic adverse events after the 2nd dose (within 7 days after injection)

The relative risk of systemic adverse events after the 2nd dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.98 (95% CI 1.56 to 5.67). This means Moderna COVID-19 vaccine increased the risk of systemic adverse events after the 2nd dose by 198%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 5343 people not receiving Moderna COVID-19 vaccine out of 14578 presented this outcome (342 per 1000) versus 11678 out of 14691 in the group that did receive it (1018 per 1000). In other words, 676 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 67.6%, or that the intervention increased the risk of systemic adverse events after the 2nd dose by 67.6 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 1. Which means that 1 people need to receive the vaccine for one of them to experienced systemic adverse events after the 2nd dose.

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 non-serious adverse reactions associated with Moderna COVID-19 vaccine were pain at the injection site (91.6%), followed by fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%); local adverse reactions occurred more frequently after second dose, and were generally less frequent in younger participants (≥65 years of age).

Serious adverse events (within 28 days after any injection)

The relative risk of serious adverse events in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 0.95 (95% CI 0.73 to 1.25). No statistically significant differences between groups were found for serious adverse events.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 104 people not receiving Moderna COVID-19 vaccine out of 104 presented this outcome (65 per 10000) versus 98 out of 15184 in the group that did receive it (62 per 10000). In other words, 3 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk of 0.03%, or that the intervention reduced the risk of serious adverse events by 0.03 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 3333. Which means that 3333 people need to receive the vaccine for one of them to experienced serious adverse events.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as moderate. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: no concerns; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Safety of the vaccine in subgroups

Any adverse event after the 2nd dose (Females subgroup) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in the females subgroup in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.96 (95% CI 1.91 to 2.01). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in the females subgroup by 96%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in the females subgroup. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 3292 people not receiving Moderna COVID-19 vaccine out of 6847 presented this outcome (428 per 1000) versus 6635 out of 7045 in the group that did receive it (838 per 1000). In other words, 410 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 41%, or that the intervention increased the risk of any adverse event after the 2nd dose in the females subgroup by 41 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in the females subgroup.

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

Any adverse event after the 2nd dose (Males subgroup) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in the males subgroup in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.36 (95% CI 2.29 to 2.43). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in the males subgroup by 136%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in the males subgroup. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 2963 people not receiving Moderna COVID-19 vaccine out of 7731 presented this outcome (428 per 1000) versus 6921 out of 7646 in the group that did receive it (1011 per 1000). In other words, 583 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 58.3%, or that the intervention increased the risk of any adverse event after the 2nd dose in the males subgroup by 58.3 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in the males subgroup.

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

Any adverse event after the 2nd dose (≥65 years) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in the ≥65 year old participants in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 2.45 (95% CI 2.34 to 2.56). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in the ≥65 year old participants by 145%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in the ≥65 year old participants . Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 1334 people not receiving Moderna COVID-19 vaccine out of 3649 presented this outcome (428 per 1000) versus 3304 out of 3691 in the group that did receive it (1048 per 1000). In other words, 620 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 62%, or that the intervention increased the risk of any adverse event after the 2nd dose in the ≥65 year old participants by 62 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 2. Which means that 2 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in the ≥65 year old participants .

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

Any adverse event after the 2nd dose (12-17 years) (within 7 days after 2nd injection)

The relative risk of any adverse event after the 2nd dose in children between 12 to 17 years of age in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.74 (95% CI 1.66 to 1.83). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 2nd dose in children between 12 to 17 years of age by 74%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 2nd dose in children between 12 to 17 years of age. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 680 people not receiving Moderna COVID-19 vaccine out of 1220 presented this outcome (428 per 1000) versus 2405 out of 2478 in the group that did receive it (745 per 1000). In other words, 317 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 31.7%, or that the intervention increased the risk of any adverse event after the 2nd dose in children between 12 to 17 years of age by 31.7 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 3. Which means that 3 people need to receive the vaccine for one of them to experienced any adverse event after the 2nd dose in children between 12 to 17 years of age.

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

Summary of findings (iSoF)

Safety of the vaccine in subgroups

Sex
Randomized trials
The proportion of females in the COVE trial was 47.3% (14366 out of 30351 participants) [Baden LR, 2021 ].
Safety profile of Moderna COVID-19 vaccine was similar across sex groups.

Other comparative studies
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 ].

Age
Randomized trials
25% (7512/30351) of the participants in the COVE trial were aged 65 years or over (mean age: 70.6 years; range: 40-95 years) [Baden LR, 2021 ]. 
           
Severe adverse reactions were generally less frequent in participants ≥65 years of age as compared to younger participants [FDA, 2020 ].
Lymphadenopathy (axillary swelling and tenderness of the vaccination arm) was observed in 12.4% of vaccine recipients ≥65 years of age, as compared with 5.8% of placebo recipients [FDA, 2020 ]. 
           
The phase 2, open-label study QHD00028 is currently evaluating the efficacy/safety of the vaccine in fully vaccinated adults with mRNA-1273 65 years of age and older [Sanofi Pasteur, a Sanofi Company, 2021 ].
           
The phase 4, randomized controlled trial mRNA-1273-D3-2021 is currently evaluating the efficacy/safety of the vaccine in vaccinated residents ≥65 years that received  [Mark Loeb, 2021 ].
           
Children and adolescents
Randomized trials
The TeenCove or study P203 (NCT04649151) was a phase 2/3 trial sponsored by Moderna evaluating vaccine efficacy in adolescents from 12 to 17 years of age. Results of the study showed that in the mRNA-1273 group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 93.1% and 92.4%, respectively), headache (in 44.6% and 70.2%, respectively), and fatigue (in 47.9% and 67.8%, respectively); in the placebo group, the most common solicited adverse reactions after the first or second injections were injection-site pain (in 34.8% or 30.3%, respectively), headache (in 38.5% and 30.2%, respectively), and fatigue (in 36.6% and 28.9%, respectively). No serious adverse events related to mRNA-1273 or placebo were noted [Ali K, 2021 ]. 
   
P204 study (mRNA-1273-P204) is an ongoing phase 2/3, randomized trial sponsored by ModernaTX, Inc. It was first registered in March 15, 2021 and plans to enroll 6750 participants with children between 6 months of age and less than 12 years of age, finalizing in June 10, 2023. Participants will be randomized to receive intramuscular injections of the vaccine at different doses (defined in the different states of the study), 28 days apart, on Day 1 and Day 29. [ModernaTX, Inc., 2021 ].
           
Other comparative studies 
Cheng DR  et al was a population based study conducted in Australia. The study included 454,974 12 to17 years old participants who had received 871,689 mRNA doses (782,964 Pfizer and 88,725 Moderna). The aim was to describe myocarditis adverse events following immunisation reported following any COVID-19 mRNA vaccines in the adolescent population.  Confirmed myocarditis reporting rates were8.3 per 100 000 doses in this age group (aggregated data for both mRNA vaccines). [Cheng DR, 2022 ]

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

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

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

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

DeSilva et al. was a retrospective matched-cohort study including 45,232 pregnant women between 16-49 years, who received the Pfizer-BioNTech, Moderna or Janssen vaccines and matched unvaccinated controls. The adjusted rate ratios (aRR) for acute maternal outcomes during days 0-21 after receiving the Moderna vaccine were 1.99 (95% CI, 1.14-3.46) for skin and soft tissue or local allergic reactions, 4.65 (95% CI, 2.13-10.15) for fever, 2.88 (95% CI, 1.93-4.3) for malaise and 1.78 (95% CI, 0.93-3.4) for lymphadenopathy. [DeSilva M, 2022 ]

Breast-feeding
Randomized trials
No clinical trial evaluating vaccines to prevent COVID-19 has included breast-feeding females.

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

Immunocompromised persons
Randomized trials
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 randomized, multi-site, adaptive, open-label clinical trial DAIT ACV01 is currently evaluating the efficacy/safety of the vaccine in participants with autoimmune disease requiring immunosuppressive medications [National Institute of Allergy and Infectious Diseases (NIAID), 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 ].

Safety of the vaccine post-authorization

Comparative studies
Albalawi O et al. was a study conducted in the United States. The study enrolled the general population that received Pfizer-BioNTech, Moderna, and Janssen vaccines. Based on data from Vaccine Adverse Event Reporting System (VAERS) between 15 December 2020 to 19 March 2021. Total non-serious reporting rate was 28.4 per 100,000 doses administered and total serious reporting rate was 5.6 per 100,000 doses administered. Results of the study showed that the Moderna group had more deaths than the Pfizer-BioNTech group (7% 95% CI-14% to 33%). [Albalawi OM, 2021 ].

Maxime Taquet et al. was a retrospective cohort conducted in the United States. The study enrolled 537 913 participants: 389,034 with COVID-19 and 389,034 with mRNA vaccine. The aim was to estimate the absolute risk of cerebral venous thrombosis (CVT) and portal vein thrombosis (PVT) in the two weeks following a diagnosis of COVID-19, and to assess the relative risks (RR) compared to influenza or the administration of an mRNA vaccine against COVID-19. RR for CVT was 6.33 (95% CI, 1.87-21.4) for Pfizer or Moderna vaccine versus COVID-19 (control) and 2.67 (95% CI, 1.04-6.81) for Pfizer or Moderna vaccine versus Influenza (control). RR of PVT was 4.46 (95% CI, 3.12-6.37) for Pfizer or Moderna vaccine versus COVID-19 (control) and 1.43 (95% CI, 1.10-1.88) for Pfizer or Moderna vaccine versus Influenza (control). [Taquet M, 2021 ]
           
Magnus MC et al. was a case-control study conducted in Norway. The study enrolled 13,956 participants, with 103 participants receiving Moderna vaccine. 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 reported a miscarriage Adjusted Odds Ratio of 0.84 (95%CI 0.56 to 1.25) 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 a Spontaneous abortions adjusted Odds Ratio of 1.03 (95%CI 0.94 to 1.11) in vaccinated individuals. [Kharbanda EO, 2021 ]

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

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

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 Moderna COVID-19 Vaccine was 2.23 (95% CI 0.06 to 12.4) for individuals who received only one dose and 5.18 (95% CI 0.63 to 18.7) 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 Moderna adverse events compared to the general population was: 1 for cerebral thrombosis, 2.2 for Guillán-Barre syndrome, 0.4 for myocarditis and 0.5 for pericarditis [Gallo K, 2022 ].

Goddard K et al. was a comparative cohort study conducted in the United States. The study included 2,891,498 individuals with administered doses of the BNT162b2 vaccine and 1,803,267 with doses of the mRNA-1273 vaccine. Participants aged 18 to 39 years were followed with weekly updated data, supplemented by a review of medical records for cases of myocarditis and pericarditis. The adjusted RR of myocarditis and pericarditis for the 0-7 day risk interval was 9.2 after an mRNA-1273 vaccine. After the second dose of mRNA-1273, RR for myocarditis and pericarditis was 18.8 (95% CI 6.7-64.9) [Goddard K, 2022 ].

Massari M et al. was a self-controlled case study conducted in Italy. The study included 2,861,809 persons aged 12 to 39 years received mRNA vaccines: 2,405,759 received Pfizer–BioNTech vaccine and 456,050 received Moderna vaccine. This study used data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of myocarditis/pericarditis between 27 December 2020 and 30 September 2021. Within the 21-day risk interval, 114 myocarditis/pericarditis events occurred, the relative incidences (RI) were 2.22 (1.00 to 4.91) and 2.63 (1.21 to 5.71) after the first and second dose of Moderna. During the (0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after the first dose of Moderna, with an RI of 6.55 (2.73 to 15.72) [Massari M, 2022 ].

Botton J et al. was a self-controlled case series conducted in France. The study included participants  (5,253 first dose of mRNA-1273; 4,099 Second dose of mRNA-1273; and 28 third mRNA-1273 dose) aged 18 to 74 years hospitalized for pulmonary embolism, acute myocardial infarction, hemorrhagic stroke, or ischemic stroke between December 27, 2020, and December 20, 2021. This study assessed the short-term risk for severe cardiovascular events after COVID-19 vaccination in France's 46.5 million adults. The primary outcome was hospitalizations for cardiovascular events (Myocardial infarction, pulmonary embolism, or stroke). The Relative Incidence during the second week after the second dose of the mRNA-1273 vaccine for Myocardial Infarction was 1.21 (95 % CI, 0.90 - 1.62),  0.88 (95 % CI, 0.56 - 1.40) for Pulmonary Embolism,  1.12 (95 % CI, 0.77 - 1.62) for  Ischemic Stroke, and  0.45 (95 % CI, 0.16 - 1.23) for  Hemorrhagic Stroke [Botton J, 2022 ].

Fell DB et al. was a retrospective cohort study conducted in Canada. The study included all liveborn and stillborn infants from pregnancies conceived at least 42 weeks before the end of the study period and with gestational age ≥20 weeks or birth weight ≥500 g [Vaccine product received for dose 1: 34,526 BNT162b2, 8,453 mRNA-1273 (Moderna), 120 Other (ChAdOx1); Vaccine product for those who received two doses of mRNA vaccine during pregnancy: 19,866 BNT162b2+BNT162b2, 5,321 mRNA-1273+mRNA-1273, 4,387 BNT162b2+mRNA-1273 or mRNA-1273+BNT162b2], between  1 May to 31 December 2021.   This study assessed the risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy. The primary outcome was preterm birth and very preterm birth events as a live birth before  37  and  32  completed weeks of gestation.  [Fell DB, 2022 ]. The adjusted hazard ratio for preterm birth <37 weeks in those who received ≥1 vaccine doses during pregnancy was 1.02 (95% CI 0.96-1.08), 0.96 (95% CI 0.90-1.03) for spontaneous preterm birth <37 weeks, 0.80 (95% CI 0.67 - 0.95) for very preterm birth <32 weeks, 0.98 (95% CI 50.93 - 1.03) for small for gestational age at birth, 0.65 (95% CI 0.51 - 0.84) for Stillbirth [Fell DB, 2022 ].

Imai et al. conducted a comparative case-control study in Japan, with the aim of evaluating the incidence and risk factors for immediate hypersensitivity reactions (IHSR) and immunuzation stress-related responses (ISRR). 614,151 healthy adult participants received the Moderna vaccine. The individuals who presented IHSR were assigned to group 1, the individuals who presented ISRR were assigned to group 2 and the individuals who did not present any reaction to the control group. 3014 occasions post-immunization adverse reactions were observed in 2913 individuals, 101 individuals showed adverse effects at both doses. 318 events were IHSR in 306 patients (11%) and 2558 were ISRR in 2478 individuals (85%). [Imai K, 2022 ]

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

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

Lloyd PC et al was a retrospective cohort study conducted in United States. The study included data from 9,604,918 doses from the Optum database, 14,146,413 doses from the HealthCore database and 14,146,413 doses from the CVS Health database. This study utilized sequential testing to detect potential safety signals following vaccination by comparing observed rates of adverse events following vaccination to historical background rates.  Rate ratios (RR) of observed adverse events rates compared to historical (or expected) rates prior to COVID-19 vaccination from the Optum, HealthCore, and CVS Health Databases were RR 1.03, 0.91 and 1.15 for acute myocardial infarction, RR 0.90, 0.90 and 1.05 for deep vein thrombosis, RR 0.93, 1.19 and 1.36 for pulmonary embolism and RR 1.13, 0.67 and 0.78 for Disseminated Intravascular Coagulation. [Lloyd PC, 2022 ]

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

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

Calvert C et al was a comparative cohort study conducted in Scotland that data from the COPS study database, including 93,900 pregnant women, 18,780 vaccinated and 75,120 controls. The study assessed the incidence of adverse pregnancy outcomes after COVID-19 vaccination. The adjusted odds ratio after Moderna vaccination for miscarriage was 1.04 (95% CI, 0.76–1.43), and 1.28 (95% CI, 0.55–2.99) for ectopic pregnancy. [Calvert C, 2022 ]

Le Vu S et al. was a case control study conducted in France that used data from National Health Data System (SNDS), focused on the period from May 12th to October 31st 2021. It included 1,612 cases of myocarditis and 16,120 matched controls; 1,613 cases of pericarditis and 16,130 matched controls. The adjusted Odds Ratio (OR) 1-7 days following the second vaccine dose for developing myocarditis was 30 (95% CI, 21–43), and for pericarditis 5.5 (95% CI, 3.3–9). [Le Vu S, 2022 ]

Patone et al. conducted a case series study of 42 842 345 people aged 13 years and older receiving at least 1 dose of COVID-19 vaccines in England between December 1st 2020 and December 15th 2021. They evaluated the association between vaccination and myocarditis. The risk of myocarditis was increased in the first 1-28 days after a second dose of Moderna with an incidence rate ratio of 11.76 (95% CI, 7.25–19.08), and persisted to 2.64 (95% CI, 1.25–5.58) after a booster dose. [Patone M, 2022 ]

Straus W et al was a retrospective cohort study conducted in the United States including 568,668,391 doses of Moderna, based on data from the Moderna global safety database. The study evaluated the risk of myocarditis after vaccination. The observed versus expected rates of myocarditis and myopericarditis within 7 days after mRNA-1273 vaccination (rate ratio) was 0.80 (95% CI, 0.7–0.93) after the first dose, 2.71 (95% CI, 2.4–3.06) after the second dose, and 0.73 (95% CI, 0.59–0.91) after the booster dose. [Straus W, 2022 ]

Corrao G et al. was a retrospective cohort study conducted in Italy that included 9,184,146 vaccine recipients. The study was based on data from the Lombardy Vaccine Integrated Platform and evaluated the risk of myocarditis and pericarditis after vaccination. The adjusted hazard ratio for developing myocarditis was 4.58 (95% CI, 3.32–6.33) after the first dose, 3.54 (95% CI, 2.06–6.08) after the second dose and 5.49 (95% CI, 3.72–8.1) after the booster dose. The adjusted hazard ratio (aHR) for developing pericarditis was 1.59 (95% CI, 1.01–2.51) after the first dose, 2.18 (95% CI, 1.54–3.08) after the second dose and 2.02 (95% CI, 0.28–14.55) after the booster dose. [Corrao G, 2022 ]

Non-comparative studies
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 [Pawlowski C, 2021 ].

Pushkar A 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 the FDA vaccine Adverse Event Reporting System (VAERS) as of February 12th, 2021 [Zhao H., 2021 ].

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

Presby D et al. is a retrospective cohort conducted in the 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 ].

Gee j et al. conducted a non-comparative study in the United States, which included 1,602,065 vaccine recipients (Moderna or Pfizer). 814,648 (50.8%) received Pfizer-BioNTech and 787,417 (49.2%) received Moderna vaccines. The requested local and systemic reactions were similar among people who received the first doses of the Pfizer-BioNTech and Moderna vaccines. Injection site pain, fatigue, headache, myalgia, and chills were reported more frequently. Members reported more reactions on the day after vaccination than on any other day. [Gee J, 2021 ].
    
Shimabukuro T et al. (CDC Report) was a retrospective cohort study conducted in the United States. The study enrolled 35,691 (Moderna or Pfizer vaccines) pregnant women who received the Moderna or Pfizer COVID-19 vaccine. Although not directly comparable, the calculated proportions of adverse pregnancies and neonatal outcomes in people vaccinated against COVID-19 who had a full pregnancy were similar to the incidences reported in studies with pregnant women that were conducted before the COVID-19 pandemic. Among the 221 pregnancy-related adverse events reported to Vaccine Adverse Event Reporting System (VAERS), the most frequently reported event was miscarriage (46 cases) [Shimabukuro TT, 2021 ].

Abbattista M 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 Pfizer-BioNTech, 5.63 (95% CI, 4, 74-6.64) for Moderna, 21.60 (95% CI, 20.16-23.11) for AstraZeneca and 11.48 (95% CI, 9.57-13, 67) for Janssen. 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 ].

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 ].

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 ]. 

Kant A 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 ].

Nguyen S et al. was a observational, cross-sectional, pharmacovigilance cohort study that examined individual case safety reports from VigiBase®, the World Health Organization’s pharmacovigilance  database. The study aimed to identify cases of tranverse myelitis (TM) following SARS-CoV-2 vaccination with Pfizer/BioNTech, Moderna, Oxford–AstraZeneca and Novavax vaccines. The study results showed that 6,921,165 adverse events were reported, with 818 reports correspoding to TM. 84 (17%) of the cases were related to the Moderna vaccine. [Nguyen S, 2022 ].

Toledo-Salinas et al. conducted a nationwide observational study among recipients of 61,414,803 doses of seven different COVID-19 vaccines, between December 2020 - October 2021 in Mexico, to identify the observed incidence of anaphylaxis in recipients of different anti-SARS-CoV-2 vaccines. Unadjusted incidence of anaphylaxis per million doses administered was 5.28 (95% CI 2.42–11.52) for mRNA-1273. [Toledo-Salinas C, 2022 ]

Mascolo A et al. conducted an observational study to investigate the adverse events following immunization (AEFI) with COVID-19 vaccines during pregnancy from the EudraVigilance database. The study included 1,315,315 Individual Case Safety Reports from the European Union for the year 2021, of which 3,252 reports were related to COVID-19 vaccines during pregnancy. 967 persons received the Moderna vaccine. The most reported AEFI (54.91%) were non-pregnancy-specific adverse events. Among pregnancy-specific adverse events, the most frequent was the termination of pregnancy and risk of abortion. [Mascolo A, 2022 ]

García-Grimshaw M was a non-comparative study conducted in Mexico that reported the incidence of Guillain-Barré syndrome (GBS) following COVID-19 vaccination. The study informed the adverse events of 81,842,426 first or second doses of seven COVID-19 vaccines (Coronavac, Moderna, Pfizer, AstraZeneca, Sputnik V, CanSino, and Janssen), with 2,318,057 doses corresponding to the Moderna vaccine. 97 cases of GBS were identified through passive epidemiological surveillance, 3 of them related to the Moderna vaccination, with an unadjusted incidence of 1.29 (95% CI 0.44-3.81) per million doses administered. [García-Grimshaw M, 2022 ]

Naveed Z was a study conducted in Canada, including 3,095,414 individuals receiving 2 doses of mRNA vaccines: 2,223,454 received Pfizer and 871,960 received Moderna. The study assessed the risk of developing myocarditis, pericarditis and myopericarditis after COVID-19 mRNA vaccination. The rate per million doses for myocarditis, pericarditis and myopericarditis 21 days after the second dose was 35.55 (95% CI, 24.15-50.46), 22.93 (95% CI, 14.01-35.42) and 56.20 (95% CI, 41.58-74.30), respectively. [Naveed Z, 2022 ]

Naveed Z was a study conducted in Canada, including 10,255,385 doses of mRNA vaccines: 6,989,921 doses of BNT162b2 and 3,265,464 doses of mRNA-1273. The study assessed the risk of developing myocarditis after COVID-19 vaccination. The overall rate of myocarditis per 100,000 was 1.44 (95% CI, 1.06–1.91) for Moderna vaccine doses using a 7-day risk window, using a 21-day risk window the rate was 1.75 (95% CI, 1.32–2.26) for Pfizer vaccines. [8ba679dcd2ecc509a1a8dad29a49fc443bd9190]

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.

References

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