Moderna COVID-19 vaccine

Extended version of the vaccine

Moderna COVID-19 vaccine

Authorization

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: Authorized for emergency use in individuals 18 years 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 from 6 years of age and older.
08 July 2022: For individual from 2 years of age and older.

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
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

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.

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

Dose-finding studies

mRNA-1273-P201 was a dose-finding, randomized, phase 2 trial sponsored by ModernaTX, Inc. and conducted in The United States between 22 May 2020 and 08 July 2020. It was registered with the trial registry number NCT04405076. The trial included healthy participants ≥18 years with a body mass index of 18 kg/m2–30 kg/m2. The sample size was 600 (2 cohorts of 300). The mean age of the participants was 37.4 years in cohort 1 (≥18 - <55 years) and 64.3 years in cohort 2 (≥55 years) and the proportion of females was 61%. Participants were randomly assigned in a 1:1:1 ratio to receive Moderna COVID-19 vaccine 50 µg, 100 µg or placebo. The vaccine induced binding antibodies and neutralizing antibodies by 28 days post-vaccination one that were higher at the 100 µg dose relative to the 50 µg dose but the difference was less apparent post-vaccination two. Binding antibodies and neutralizing antibodies increased substantially by 14 days following the second vaccination (day 43) to levels exceeding those of convalescent sera and remained elevated through day 57 [Chu L, 2021 ].

Emerging evidence regarding the interchangeability of Moderna's COVID-19 vaccine with other COVID-19 vaccines to complete the vaccination series supports the use of one dose of mRNA-1273 vaccine and one dose of another EUL-authorized COVID-19 vaccine to be a complete primary series (i.e. a heterologous schedule) [WHO, 2022 ].

Indications and contraindications

Indications

Moderna COVID-19 vaccine is indicated for individuals 12 years of age and over [WHO, 2022 ].

Children aged 12–17 years with comorbidities that put them at significantly higher risk of serious COVID-19 disease, alongside other high-risk groups, should be offered vaccination [WHO, 2022 ].

For healthy children and adolescents (aged 12 to 17), WHO recommends using Moderna COVID-19 vaccine only when high vaccine coverage (primary series and booster doses) has been achieved in the high priority groups as identified in the WHO Prioritization Roadmap [WHO, 2022 ].

WHO recommends the use of Moderna COVID-19 vaccine in pregnant individuals [WHO, 2022 ].
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 ].


Precautions
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 ].

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.

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

Persons with previous SARS-CoV-2 infection [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.

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

Co-administration with other vaccines
Inactivated influenza vaccine [WHO, 2022 ].
The Moderna COVID-19 vaccine can be co-administered with inactivated influenza vaccines.
Evidence suggests that neither adverse events and reactogenicity, nor immunogenicity are increased as a result of co-administration.
Different arms for injection should be used when both vaccines are delivered during the same visit.

Other vaccines [WHO, 2022 ].
There is no evidence yet about the effects of the coadministration of Moderna COVID-19 vaccine with other vaccines included in routine vaccination programs.
There should be a minimum interval of 14 days between administration of this vaccine and all other vaccines except influenza vaccine.

This recommendation will be updated as data on co-administration with other vaccines become available.

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

Storage and logistics

Storage

Moderna COVID-19 vaccine is provided as a frozen dispersion stored at at -25 ºC to -15 ºC (-13º to 5ºF) for up to 9 months [WHO, 2021 ].

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.
Do not store on dry ice or below -40°C (-40°F).
Keep vaccine vials in their box and place them in the storage unit.
Store in the original carton to protect from light.

Administration logistics

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 [WHO, 2021 ]

Use a sterile needle and syringe to extract a single dose of 0.5 mL from the multidose vial.

Record the date and time of first use on the vial label.

Visually inspect each dose of the vaccine in the dosing syringe prior to administration. The white to off-white dispersion may contain white or translucent product-related particulates.

Do not administer if the vaccine is discolored or contains other particulate matter.

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 ].

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 0.5 mL dose. If the amount of vaccine remaining in the vial cannot provide a full 0.5 mL 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.

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

Randomized trials

COVE (an acronym for: Coronavirus Efficacy and Safety Study) or study P301 was a phase 3 randomized clinical trial sponsored by ModernaTX, Inc. and conducted The United States between July 27, 2020, and October 23, 2020. It was registered with trial registry number NCT04470427. The trial included participants 18 years of age or older with no known history of SARS-CoV-2 infection and with circumstances that put them at an appreciable risk of SARS-CoV-2 infection, a high risk of severe COVID-19, or both. The sample size was 30420. The mean age of the participants was 51.4 years and the proportion of females was 47.3%. Participants were randomly assigned in a 1:1 ratio to receive Moderna COVID-19 vaccine or placebo vaccine. The intervention was administered as a sterile liquid at a concentration of 0.2 mg per milliliter and administered by injection into the deltoid muscle according to a two-dose regimen. Injections were given 28 days apart, in the same arm, in a volume of 0.5 ml containing 100 µg of mRNA-1273 or saline placebo. Vaccine mRNA-1273 was stored at 2° to 8°C (35.6° to 46.4°F) at clinical sites before preparation and vaccination. No dilution was required. Doses could be held in syringes for up to 8 hours at room temperature before administration [Baden LR, 2021 ].

TeenCove was a phase 2-3, randomized, placebo-controlled trial sponsored by ModernaTX, Inc and conducted United States between December 2020 to June 2022. It was registered with trial registry number NCT04649151. The trial included healthy male and female adolescents between the ages of 12 and 17 years. The sample size was 3732. The mean age of the participants was 14.3 years and the proportion of women was 49%. Participants were randomly assigned in a 2:1 ratio to receive mRNA-1273 (2489 participants) or placebo (1243 participants). The intervention was administered as two injections of either mRNA-1273 vaccine (each injection containing 100 µg, for a total dose of 200 µg) or placebo (saline solution), 28 days apart [Ali K, 2021 ].

KidCOVE is an ongoing phase 2-3 randomized trial sponsored by ModernaTX, Inc. It was first registered on 15 March 2021 (NCT04796896) and plans to enroll 6750 participants with children between 6 months of age and less than 12 years of age, finalizing on 10 June 2023. Participants will be randomized to receive intramuscular vaccine injections at different doses (at different states of the study), 28 days apart [ModernaTX, Inc., 2021 ].

Hall VG et al was an ongoing 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 ].

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

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

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

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

BOOST-TX is a phase 2 randomized trial (registered with the number 2021-002927-39 [Medical University of Vienna, 2021 ]) sponsored by the Medical University of Vienna that is being conducted in Austria. It was first registered in May 2021 and enrolled 200 kidney transplant recipients that received Pfizer or Moderna vaccines. The trial evaluated vaccines efficacy [Reindl-Schwaighofer R, 2021 ].


Other studies providing efficacy or safety data

20-0003 (expansion in older adults) was a phase 1, a non-randomized study sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and conducted in the United States of America at Kaiser Permanente Washington Health Research Institute in Seattle, the Emory University School of Medicine in Atlanta, and the National Institute of Allergy and Infectious Diseases Vaccine Research Center in Bethesda, Maryland between April 16 and May 12, 2020. It was registered with ClinicalTrials.gov number NCT04283461 [National Institute of Allergy and Infectious Diseases (NIAID), 2020 ]. 
This trial was expanded to include participants older than 56 years [Anderson EJ, 2020 ]. 
The sample size was 40. The mean age of the participants was 68.7 years and the proportion of females was 53%. 
All the participants were assigned sequentially to receive two doses of either 25 µg or 100 µg of vaccine administered 28 days apart.

The ICARUS-IBD study, was a cohort study, that enroll individuals with inflammatory bowel disease receiving the vaccine (for more information see -Efficacy of the vaccine in subgroups-) [Serre-Yu Wong, 2021 ].

Gee et al. (CDC report) was a safety monitoring non-comparative study conducted in United States. The study enrolled 13,794,904 vaccine doses (Pfizer or Moderna) participants that received Moderna COVID-19 vaccine. Based on data from Vaccine Adverse Event Reporting System and the v-safe system between 14 December 2020 and 13 January 2021.

HEROES-RECOVER was a prospective cohort study conducted in the United States. The study enrolled 5,716 (3,964 unvaccinated, 1,754 vaccinated) participants that received the Moderna COVID-19 vaccine. Based on data from HEROES-RECOVER cohorts between December 14, 2020 to April 10 2021.

Flacco et al. was a retrospective cohort study conducted in Italy. The study enrolled 2,020 participants that received Moderna COVID-19 vaccine. 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.

Khan et al. was a retrospective cohort study conducted in the United States. The study enrolled 3,380 older adults with inflammatory bowel disease participants that received Moderna COVID-19 vaccine. Based on data from the Veterans Health Administration (VHA) between December 18 2020 to April 20 2021.

Pawlowski C et al. was a retrospective cohort study conducted in the United States. The study enrolled 16,471 participants that received Moderna COVID-19 vaccine. Based on data from the Mayo Clinic health system between December 1 2020 and April 20 2021.

Desai AP et al. (CDC report) was a safety monitoring non-comparative study conducted in United States. The study enrolled 3,203 participants that received Moderna COVID-19 vaccine. Based on data from Vaccine Adverse Event Reporting System and the v-safe system between December 14 2020 through February 5 2021.

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

Andrejko et al. was a case-control study conducted in United States . The study enrolled 1,023 participants that received Moderna COVID-19 vaccine. Based on data from California Department of Public Health via a web-based reporting system from 24 February to 29 April 2021.

Malinis et al. was a cross-sectional study conducted in the United States. The study enrolled 557 (solid organ transplant recipients) participants that received Moderna COVID-19 vaccine. Based on data from Yale-New Haven Hospital on May 18, 2021.

Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324 ,033 participants that received Moderna or Pfizer COVID-19 vaccine. Based on data from a test-negative design study among patients who had symptoms consistent with covid-19 between 14 December 2020 and 19 April 2021.

Pawlowski C et al. was a retrospective study conducted in the United States. The study enrolled 266,094 participants (36,352 Moderna doses). Based on data from the Mayo Clinic health system between January 1 2017 and March 15, 2021.

Tarke A et al. was an immunogenicity study conducted in the United States. The study enrolled 30 general population that received Moderna (mRNA-1273) or Pfizer/BioNTech (BNT162b2) vaccines.

Alisa Fox et al. was a cohort conducted in United States. The study enrolled 50 Lactating females (Twenty-three participants had received Pfizer vaccine, 14 had received Moderna vaccine, and 13 had received J&J vaccine). Fifty pairs of milk samples were obtained from vaccine recipients within 1 week before vaccination and 14 days (Pfizer/Moderna) or 28 days (J&J) after completion of the vaccine regimen.

Omar M Albalawi et al. was a retrospective database analysis study conducted in United States. The study enrolled the General population that received Pfizer-BioNTech, Moderna, and Janssen Ad26.COV2.S vaccines. This retrospective analysis was conducted using the publically available database of the U.S. Vaccine Adverse Event Reporting System (VAERS). VAERS is a critical component of the national passive surveillance (spontaneous reporting) system of the approved vaccines in the U.S

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

Methods used to assess efficacy

In the COVE trial [Baden LR, 2021 ], the primary endpoint was specified as efficacy against symptomatic Covid-19 at least 14 days after the second dose among participants who were seronegative at trial entry. End points were judged by an independent adjudication committee that was unaware of group assignment.

COVID-19 cases were defined as occurring in participants who had at least two of the following symptoms: fever (temperature ≥38°C), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom (including cough, shortness of breath, or clinical or radiographic evidence of pneumonia) and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for SARS-CoV-2 by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) test. Participants were assessed for the presence of SARS-CoV-2-binding antibodies specific to the SARS-CoV-2 nucleocapsid protein (Roche Elecsys, Roche Diagnostics International) and had a nasopharyngeal swab for SARS-CoV-2 RT-PCR testing (Viracor, Eurofins Clinical Diagnostics) before each injection. SARS-CoV-2-infected volunteers were followed daily, to assess symptom severity, for 14 days or until symptoms resolved, whichever was longer. A nasopharyngeal swab for RT-PCR testing and a blood sample for identifying serologic evidence of SARS-CoV-2 infection were collected from participants with symptoms of COVID-19.

Safety evaluation methods

Safety assessments included: Solicited local adverse events; solicited systemic adverse events; unsolicited adverse reactions; adverse events leading to discontinuation from a dose; adverse events leading to discontinuation from participation in the trial; medically attended adverse events; serious adverse events.

End points were judged by an independent adjudication committee that was unaware of group assignment.

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.

Contracting COVID-19 after the first dose (measured at least 14 days after the first injection)

The relative risk of contracting COVID-19 after the first dose (>14 days) 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 after the first dose (>14 days) by 93%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 after the first dose (>14 days). Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 782 people not receiving Moderna COVID-19 vaccine out of 14164 presented this outcome (52 per 1000) versus 58 out of 14287 in the group that did receive it (4 per 1000). In other words, 48 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 4.8%, or that the intervention reduced the risk of contracting COVID-19 after the first dose (>14 days) by 4.8 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 21. Which means that 21 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.

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% (14,372 out of 30,346 participants) [El Sahly HM, 2021 ].

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

The relative risk of contracting COVID-19 in women in the group that received the Moderna COVID-19 vaccine versus the group that received the placebo vaccine was 0.07 (95% CI 0.04 to 0.1). This means the Moderna COVID-19 vaccine reduced the risk of contracting COVID-19 in women by 93%, compared with the 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% (7,512 out of 30,351 participants) [El Sahly HM, 2021 ].

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

The relative risk of Contracting COVID-19 (>75y) in the group that received the Moderna COVID-19 vaccine versus the group that received the placebo vaccine was 0.03 (95% CI 0 to 0.46). This means the Moderna COVID-19 vaccine reduced the risk of Contracting COVID-19 (>75y) by 97%, compared with the 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. No evidence 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 ].

 

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.

 

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 mRNA-1273 or BNT162b2. 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 mRNA-1273 was 92.1%  (95% CI 88.4 to 95.8)  and 94.3% (95% CI 91.2 to 97.4) for BNT162b2 fulfilling the non-inferiority of mRNA-1273. 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 ].

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 responded 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 who 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 the United States [Li LL, 2022 ], evaluating the impact of prior SARS-CoV-2 infection on the 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 the 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 a detectable humoral immune response, similar to individuals without HIV infection [Lombardi A, 2021 ]. ICARUS-IBD was a cohort study conducted in the United States (sample size = 48, including 25 receiving Moderna COVID-19 Vaccine). The study evaluated individuals with inflammatory bowel disease receiving biologics who completed two-dose vaccine schedules and found high levels of seroconversion [Serre-Yu Wong, 2021 ].

 

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 for individuals with recent infections.

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 with 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)

Vaccine effectiveness (other comparative studies)

Contracting COVID-19
Chung et al. was a nested case-control study conducted in Canada. The study enrolled 324,033 participants that received Moderna or Pfizer COVID-19 vaccine. Based on data from a test-negative design study among patients with symptoms consistent with COVID-19 between 14 December 2020 and 19 April 2021. Results showed vaccine effectiveness of 95% (95% CI 88% to 98%). [Chung H, 2021 ].

Flacco et al. was 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 97.3%) 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 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 ].

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 and 1,066,645 were fully vaccinated with Moderna. A Pfizer booster was administered to 609,153 individuals and a Moderna booster was administered to 395,634 individuals The study is based on statewide COVID-19 vaccination data from the Minnesota Immunization Information Connection (MIIC) linked via a privacy-preserving record linkage process with distributed electronic health record (EHR) data from the 11 largest health systems in Minnesota. The main results showed 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 7187 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, 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 ].

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 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 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 and 1,066,645 were fully vaccinated with Moderna. 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 Minnesota's 11 largest health systems. The main results showed that vaccine effectiveness against hospitalization after 26 weeks from the second dose was 73% (95% CI 71 to 75) 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 7187 fully vaccinated that 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, by sociodemographic and clinical characteristics that are associated with COVID-19 outcomes. Results reported vaccine effectiveness against severe infection 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 ].

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

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.

 

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 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 28,413 U/mL and 31,793 U/mL for the reduced and standard Pfizer-BioNTech vaccines, respectively and 41,171 U/mL and 51,979 U/mL for the reduced and standard Moderna vaccines. Boosting elicited an increase in median IFN-γ CD4+ T cell and CD4+ CD8+ T cell counts; there were no differences in T cell counts between the standard and reduced dose groups. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants unaffected 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 and GMTs against the Omicron variant reached 343.3 and 541.2 for the same vaccine groups  [Sitthichai Kanokudom, 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 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 28,413 U/mL and 31,793 U/mL for the reduced and standard Pfizer-BioNTech vaccines, respectively and 41,171 U/mL and 51,979 U/mL for the reduced and standard Moderna vaccines. Boosting elicited an increase in median IFN-γ CD4+ T cell and CD4+ CD8+ T cell counts; there were no differences in T cell counts between the standard and reduced dose groups. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants unaffected 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, and GMTs against the Omicron variant reached 343.3 and 541.2 for the same vaccine groups  [Sitthichai Kanokudom, 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 ].

 

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) from 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 SA 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 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)[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 1293 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 ].

 

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 SA 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 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 ].

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 ].

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 Omicron variant for symptomatic infection was 31.9% (95% CI 27.3 to 36.1) 4 weeks after the first dose, 14.9% (95% CI 3.9 to 24.7) 25 weeks after the second dose, 64.4% (95% CI 62.3 to 67.3) 2-4 weeks after a Pfizer-BioNTech booster and 66.3% (95% CI 63.7 to 68.8) 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 2 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 2 mRNA vaccine doses and increased 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 ].

Vaccine efficacy and effectiveness for booster dose

Booster dose

Immunogenicity results
Benotmane I et al. was a non-comparative study conducted in France. The study included 159 participants (kidney transplants). ​Based on data from the French National Authority for Health that assesses administering 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 in Canada from 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 the 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.


          
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 the protection afforded by booster doses of the Moderna vaccine 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 SA et al. included 20,348 tests (Omicron-positive cases=16,087; Delta-positive cases= 4,261 test-negative controls= 114,087). Data were collected from December 6 to 26, 2021. The study showed that 2 doses of COVID-19 vaccines 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. included 6,812,040 COVID-19 cases in unvaccinated persons and 2,866,517 cases in fully vaccinated persons. Data were collected between April 4, 2021, to December 25, 2021. The study showed that rates of COVID-19 cases were lowest among fully vaccinated persons with a booster dose of Moderna COVID-19 vaccine, compared with fully vaccinated persons without a booster dose, and much lower than rates among unvaccinated persons. During October - November (Delta predominance period), average weekly incidence rate ratios were 4.6 (95% CI 4.2 to 5.1)among fully vaccine persons without booster dose and 17.4 (95% CI 14.5 to 21.1) among fully vaccinated persons with a booster dose. During December (Omicron Emergence period), average weekly incidence rate ratios were 3.3 (95% CI 1.7 to 6.1) among fully vaccine persons without booster dose and 5.6 (95% CI 3.1to 10.1) among fully vaccinated persons with a booster dose [Johnson AG, 2022 ].

The VISION Network study included 222,772 encounters from 383 emergency departments (ED) and urgent care (UC) and 87,904 hospitalizations from 259 hospitals. Data were collected during periods of Delta and Omicron variant predominance between august 2021to 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 ].

Drawz PE et al. was a case-control study conducted in the United States. The study enrolled 4,547,945 participantes:1,732,112 were fully vaccinated with Pfizer, and 1,066,645 were fully vaccinated with Moderna. 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 Minnesota's 11 largest health systems. The main results showed that the booster dose effectiveness was 65% (95% CI 65 to 66) and 86% (95% CI 82 to 89) for preventing Hospitalization 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.  The effectiveness of the homologous Moderna booster against Delta and Omicron variants for symptomatic infection was 96.4% (95% CI 91.4 to 98.5) and 66.3% (95% CI 63.7 to 68.8) 2-4 weeks after boosting [Andrews N, 2022 ].

Vaccine efficacy and effectiveness for heterologous schedule

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 ].

Vaccine efficacy and effectiveness for heterologous booster schedule

Heterologous booster schedule

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

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

SWITCH  was a randomized trial sponsored by Erasmus Medical Center and conducted in the Netherlands between June 2021 to September 2022. Immunogenicity was assessed 28 days after homologous or heterologous booster vaccination. Results showed that the Janssen COVID-19 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 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 28,413 U/mL and 31,793 U/mL for the reduced and standard Pfizer-BioNTech vaccines, respectively and 41,171 U/mL and 51,979 U/mL for the reduced and standard Moderna vaccines. Boosting elicited an increase in median IFN-γ CD4+ T cell and CD4+ CD8+ T cell counts; there were no differences in T cell counts between the standard and reduced dose groups. The booster dose induced a neutralizing response against the Delta and Omicron variants in previously seronegative participants that were not affected by dosage [Sitthichai Kanokudom, 2022 ].

Poh et al. is an ongoing phase 4 randomized clinical trial conducted in Singapore, assessing the humoral response elicited by homologous and heterologous booster vaccination regimens based on a primary regimen with Pfizer-BioNTech. Interim results of two groups have been published. The study recruited 100 participants who either received a Pfizer-BioNTech (n=51) booster or a Moderna booster (n=49). Results show a booster dose increases antibody titers in all participants by 35- to 49- fold 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 ].

Munro APS 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 BNT162b2 and mRNA-1273 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 BNT162b2 group and 6,22 [3,90–9,92] in the mRNA-1273 group) [Munro APS, 2022 ].

Poh XY was a phase 4 randomized controlled study conducted in Singapore.100 BNT162b2 vaccinated individuals were enrolled and randomized 1:1 to either homologous (BNT162b2+BNT162b2+BNT162b2; ‘BBB’) or heterologous mRNA booster vaccine (BNT162b2+BNT162b2+mRNA-1273; ‘BBM’). This study assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. The primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 on Day 28. After the booster dose, anti-S titer across both intervention groups increased by 35- to 49-fold on Day 7 to a mean of 23,158 IU/mL (95% CI 19,539 to 27,454 IU/mL), with only a modest further increase by Day 28 (25,651 IU/mL (95% CI 22,444 to 29,322 IU/mL). At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22,382 IU/mL 95% CI, 18,210 to 27,517) vs BBM (29,751 IU/mL 95% CI, 25,281 to 35,011, p=0.034) as was the median level of neutralizing antibodies: BBB 99.0% (IQR 97.9 to 99.3%) vs BBM 99.3% (IQR 98.8 to 99.5%, p=0.021) [Xuan Ying Poh, 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 ].

 

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.  The effectiveness of heterologous Moderna booster after Pfizer primary scheme against Delta and Omicron variants for symptomatic infection was 94.9% (95% CI 93.0 to 96.2) and 64.4% (95% CI 62.6 to 66.1). The effectiveness of Moderna booster after the AstraZeneca scheme against Delta and Omicron variants for symptomatic infection was  94.9% (95% CI 93.8 to 95.9) and 60.9% (95% CI 59.7 to 62.1)  [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 ].

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 1st dose (within 7 days after injection)

The relative risk of any adverse event after the 1st dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 1.64 (95% CI 1.33 to 2.03). This means Moderna COVID-19 vaccine increased the risk of any adverse event after the 1st dose by 64%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event after the 1st dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 7285 people not receiving Moderna COVID-19 vaccine out of 7285 presented this outcome (494 per 1000) versus 13317 out of 15166 in the group that did receive it (811 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 1st dose 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 1st dose.

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 (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 1st dose (within 7 days after 1st injection)

The relative risk of local adverse events after the 1st dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 3.3 (95% CI 2.02 to 5.4). This means Moderna COVID-19 vaccine increased the risk of local adverse events after the 1st dose by 230%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: local adverse events after the 1st dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 3009 people not receiving Moderna COVID-19 vaccine out of 3009 presented this outcome (211 per 1000) versus 12765 out of 15166 in the group that did receive it (696 per 1000). In other words, 485 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 48.5%, or that the intervention increased the risk of local adverse events after the 1st dose by 48.5 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 NNTH is 2. Which means that 2 people need to receive the vaccine for one of them to experienced local adverse events after the 1st 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 1st dose (within 7 days after injection)

The relative risk of systemic adverse events after the 1st dose in the group that received Moderna COVID-19 vaccine versus the group that received placebo vaccine was 3.52 (95% CI 2.39 to 5.19). This means Moderna COVID-19 vaccine increased the risk of systemic adverse events after the 1st dose by 252%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: systemic adverse events after the 1st dose. Comparison: Moderna COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 3009 people not receiving Moderna COVID-19 vaccine out of 15151 presented this outcome (190 per 1000) versus 12765 out of 15166 in the group that did receive it (669 per 1000). In other words, 479 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 47.9%, or that the intervention increased the risk of systemic adverse events after the 1st dose by 47.9 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 systemic adverse events after the 1st 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 ].
The safety profile of the 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 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 on 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 vaccine injections at different doses (defined in the different states of the study), 28 days apart, on Day 1 and Day 29. [ModernaTX, Inc., 2021 ].

 

Pregnancy
Randomized trials
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 defined in the original safety data. Results showed a frequency of complaints 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 %, and 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 and results of preimplantation genetic testing for aneuploidy among cycles in which testing was performed. The study showed that the administration of the Pfizer or Moderna COVID-19 vaccine was not associated with an adverse effect on stimulation or early pregnancy outcomes after in vitro fertilization. The fertilization rate for the controlled ovarian hyperstimulation cohort was  80.7% (95% CI 78.4 to 83.0) in the vaccinated group and 78.7% in the unvaccinated groups (95% CI 77.5 to 80.0). No differences were observed between vaccinated and unvaccinated patients on univariate analysis in the secondary outcomes of eggs retrieved, mature oocytes retrieved, mature oocytes ratio, or blastulation rate. In cycles in which preimplantation genetic testing for aneuploidy was performed, vaccinated patients had a proportion of euploid embryos of 48.8% (95% CI 44.1 to 53.6) compared with 42.5% (95% CI 40.2 to 44.9) in unvaccinated patients [Aharon D, 2022 ].

 

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

 

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

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

Maxime Taquet et al. is a retrospective cohort conducted in the United States. The study enrolled 537,913 patients with a confirmed diagnosis of COVID-19. Based on data from ​a federated electronic health records network recording anonymized data from 59 healthcare organizations from January 20, 2020, and March 25, 2021. The authors compared the adverse events between Moderna or Pfizer and Influenza vaccine groups. Results of the study showed that the Moderna/Pfizer group had more cerebral sinus and venous thrombosis (567%, 95% IC 98% to 2134%) and portal vein thrombosis 640% (95% CI 387% to 1024%) than the Influenza group. [Maxime Taquet, 2021 ].

Magnus MC et al. was a case-control study conducted in Norway. The study enrolled 13,956 participants, with 103 participants receiving the 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 ].

PRESTO study showed no association between vaccines and fecundability in 2,126 participants vaccinated with Pfizer, Moderna, or Janssen COVID-19 vaccine. The fecundability rate in vaccinated versus non-vaccinated individuals was 1.08 in females (95% CI 0.95 to 1.23) and 0.95 in males (95% CI 0.83 to 1.10)[Wesselink AK, 2022 ].

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

TU TM 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 BNT162b2 vaccine and 456,050 received mRNA-1273 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 mRNA-1273. During the [0 to 7) days risk period, an increased risk of myocarditis/pericarditis was observed after the first dose of mRNA-12733, with an RI of 6.55 (2.73 to 15.72) [Massari M, 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 [Colin Pawlowski, 2021 ].

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

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

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

David Presby et al. is a retrospective cohort conducted in 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 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 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 ].

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

Yap J. et al, was a Non-comparative study conducted in Singapore. The study enrolled 7,183,889 records of both Pfizer-BioNTech and Moderna vaccination ( 1,298,117 one dose only and 2,942,886 two doses). The study aimed to report the incidence of adjudicated cases of pericarditis and myocarditis following COVID-19 mRNA vaccination [Yap J, 2022 ]. 

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

Monitoring

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

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

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

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

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

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