Pfizer-BioNTech COVID-19 vaccine

Extended version of the vaccine

Pfizer-BioNTech COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure

Listed for emergency use on 31 December 2020 [WHO, 2020 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 16 years of age and over [WHO, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency use in individuals aged 12 years and over [World Health Organization, 2021 ].

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

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

Regulatory Authorities of Regional Reference in the Americas


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

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

Health Canada
Authorized for emergency use on 9 December 2020 [Health Canada, 2020 ].
5 May 2021: Authorized for emergency use in individuals 12 to 15 years of age [Government of Canada, 2021 ].

Public Health Institute (ISP, Chile)
Authorized for emergency use on 16 December 2020 [Instituto de Salud Publica de Chile, 2021 ].
31 May 2021: Authorized for emergency use in individuals 12 to 16 years of age [Instituto de Salud Pública de Chile, 2021 ].

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

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

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

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

Authorization in jurisdictions in Latin America and the Caribbean
Costa Rica
Curaçao
Dominican Republic
Ecuador
El Salvador
Guadeloupe
Maldives
Martinique
Panama
Paraguay
Peru
Puerto Rico
Saint Vincent and the Grenadines
San Martin
Trinidad and Tobago
Turks and Caicos Islands
Uruguay

Authorization in other jurisdictions
Albania
Algeria
Andorra
Australia
Austria
Azerbaijan
Bahrain
Bangladesh
Belgium
Bhutan
Bonaire
Bosnia and Herzegovina
Botswana
Brunei
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
European Union
Faroe Islands
Finland
France
Georgia
Germany
Greece
Greenland
Hong Kong
Hungary
Iceland
Iraq
Ireland
Israel
Italy
Japan
Jordan
Kenya
Kuwait
Latvia
Lebanon
Libya
Liechtenstein
Lithuania
Luxembourg
Malaysia
Malta
Moldova
Monaco
Mongolia
Netherlands
New Zealand
Nigeria
North Macedonia
Norway
Oman
Pakistan
Philippines
Poland
Portugal
Qatar
Romania
Rwanda
Saudi Arabia
Serbia
Singapore
Slovakia
Slovenia
South Africa
South Korea
Spain
Sri Lanka
Sweden
Switzerland
Thailand
Trinidad and Tobago
Tunisia
Turkey
Ukraine
Vatican
West Bank

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

Manufacturing

Manufacturer

Drug substance [WHO, 2021 ]
BioNTech Manufacturing GmbH, Germany. Pfizer and BioNTech are manufacturing the vaccine in their own facilities in the United States and in Europe. The license to distribute and manufacture in China was purchased by Fosun, alongside its investment in BioNTech.

BioNTech Manufacturing Marburg, Germany.
Rentschler Biopharma SE, Germany.
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC, USA.

Other manufacturers

Drug product [WHO, 2021 ]
Main manufacturer of the drug product:
Baxter Oncology GmbH. Westfalen, Germany.
BioNTech Manufacturing GmbH. Mainz, Germany.
Pfizer Manufacturing Belgium NV, Belgium.
Novartis. Stein, Switzerland.
Mibe GmbH Arzneimittel. Brehna, Germany.
Delpharm Saint-Remy. Saint-Remy sur Avre, France.
Sanofi-Aventis Deutschland GmbH, Germany.
Siegfried Hameln GmbH, Germany.

Filling and packaging
Pfizer Inc; USA: Process of molecular cloning of DNA plasmids that code for the spike protein by infusing them into Escherichia coli bacteria. For all markets, this stage is conducted in the United States, at a small Pfizer pilot plant.

Pfizer Manufacturing Belgium, Belgium: The Pfizer plant in Puurs is responsible for all vials for destinations outside the United States.

Diluent Suppliers
Pfizer Perth, Australia.
Fresenius Kabi, USA.

General characteristics

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

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

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

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

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

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

 

 

Dosage form and ingredients
The pharmaceutical form is a concentrated dispersion for intramuscular injection that is provided in a multidose vial (vial: 6 doses, after dilution, of 0.3 mL, total vial volume: 0.45 mL)

The vaccine contains the following ingredients:

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

Excipients
((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315)
2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159)
1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC)
Cholesterol
Potassium chloride
Potassium dihydrogen phosphate
Sodium chloride
Disodium phosphate dihydrate
Sucrose
Water for injections

 

 Ready to use formulation [WHO, 2021 ], [EMA, 2021 ]

Pfizer COVID-19 vaccine new formulation «Ready-To-Use» or «Tris/Sucrose» is based on the current recommended vaccine and does not require dilution prior to administration. It is formulated at 0.1 mg/mL RNA. One dose (0.3 mL) contains 30 micrograms of Pfizer COVID-19 vaccine. This line extension is for a 6-dose multi-dose vial only.

Risk considerations

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

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

Dosing and schedule

Dose-finding studies

For countries that have not yet achieved high vaccine coverage rates in the high-priority groups who are experiencing a high incidence of COVID-19 cases combined with vaccine supply constraints, WHO recommends that such countries should focus on achieving a high first dose coverage in the high priority groups by extending the inter-dose interval up to 12 weeks [World Health Organization, 2021 ].

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

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

BNT162-03 was a randomized, placebo-controlled, observer-blind phase I trial sponsored by BioNTech RNA Pharmaceuticals GmbH and conducted in China between August 2020 - August 2021. It was registered with NCT04523571. The trial included healthy adults aged ≥18 and ≤55 and adults aged ≥65 and ≤85. The sample size was 144. The mean age of the younger participants ranged from 37.9 to 42.0 years, and the mean age among the over participants ranged from 68.5 to 70.7 years in the treatment groups. The proportion of women was 50% across treatment groups. Participants were randomly assigned in a 1:1:1 ratio to receive the low-dose BNT126b1 or high-dose BNT126b1 or placebo. The intervention was administered as a prime dose and a boost dose of vaccine candidate BNT162b1 at either 10μg in 0.5ml or 30μg in 0.5ml, or 0.5ml placebo, administered into the deltoid, 21 days apart. The vaccine-induced highest neutralizing titers were observed on day 43 (21 days after the BNT162b1 boost dose) for the younger and over adults in the BNT162b1 group. Participants who received the 30 μg dose appeared to have a relatively higher virus-neutralizing antibody response than those who received the 10 μg dose. The over participants generally had a lower peak neutralizing antibody response than the younger participants. Moreover, BNT162b1 induced robust interferon-γ T cell responses to a peptide pool including the RBD in younger and over adults. Geometric mean neutralizing titers reached 2.1-fold in the young adult's group and 1.3-fold in the over adults group versus a panel of COVID-19 convalescent human sera obtained at least 14 d after positive SARS-CoV-2 polymerase chain reaction test [Li J, 2021 ].

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

There is no evidence yet about the effects of the coadministration of Pfizer-BioNTech COVID-19 vaccine with other vaccines included in routine vaccination programs

Indications and contraindications

Indications

Persons aged 12 years and over [World Health Organization, 2021 ].

WHO recommends that countries should consider using BNT162b2 in children aged 12 to 15 only when high vaccine coverage with 2 doses has been achieved in the high priority groups as identified in the WHO Prioritization Roadmap [World Health Organization, 2021 ].

Children 12-15 years of age with comorbidities that put them at significantly higher risk of serious COVID-19 disease, alongside other high-risk groups, may be offered vaccination [World Health Organization, 2021 ].

Contraindications

Pfizer-BioNTech COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the Pfizer-BioNTech COVID-19 vaccine. In particular, should not be administered to individuals with a known history of severe allergic reaction to polyethylene glycol (PEG) or related molecules [World Health Organization, 2021 ] [WHO, 2021 ]. (See the list of ingredients under 'General characteristics' in the extended version).

Food, insect venom and contact allergies and allergic rhinitis, eczema and asthma are not considered a contraindication to vaccination. The vial stoppers are not made with natural rubber latex, and there is no contraindication or precaution to vaccination for persons with a latex allergy. In addition, as BNT162b2 does not contain eggs or gelatine, there is no contraindication or precaution to vaccination for persons with allergies to any food substances [World Health Organization, 2021 ].
The second dose of the vaccine should NOT BE GIVEN to those who have experienced immediate allergic reaction to the first dose of Pfizer-BioNTech COVID-19 vaccine [World Health Organization, 2021 ].

Precautions

A history of anaphylaxis to any other vaccine or injectable therapy (i.e. intramuscular, intravenous, or subcutaneous vaccines or therapies), is not a contraindication to vaccination. For such persons, a risk assessment should be conducted by a health professional. Such persons should be observed for 30 minutes after vaccination [World Health Organization, 2021 ].

Individuals with an immediate non-anaphylactic allergic reaction to the first dose (such as urticaria, angioedema or respiratory symptoms, that occur within 4 hours of administration) should not receive additional doses, unless recommended after review by a health professional. However, subject to individual risk–benefit assessment, BNT162b2 could be provided under close medical supervision if it is the only available vaccine for persons at high risk of severe COVID-19 [World Health Organization, 2021 ].

As a small number of anaphylactic reactions have also been reported in vaccines without a history of anaphylaxis, it is recommended that Pfizer-BioNTech COVID-19 vaccine should be administered only in settings where anaphylaxis can be treated. Until more data are available with regard to anaphylaxis after BNT162b2 vaccination, all vaccinees should be observed for at least 15 minutes after vaccination [World Health Organization, 2021 ].

A possible causal association with very rare cases of myocarditis in young men (16−24 years of age) is currently being investigated [World Health Organization, 2021 ].

Adverse events reports suggest an increased risk of myocarditis and pericarditis, particularly following the second dose and onset of symptoms within a few days after vaccination. Vaccinated individuals should be instructed to seek immediate medical attention if they develop the following symptoms: chest pain, shortness of breath, or feelings of having fluttering after vaccination [FDA, 2021 ].

Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection. Including symptomatic SARS-CoV-2 infection, vaccination should be deferred until they have recovered from acute illness [World Health Organization, 2021 ].

Persons with a history of Bell’s palsy may receive vaccination if there are no contraindications. Currently there is no conclusive evidence between the cases related with vaccination [WHO, 2021 ].

Data are not available on the potential benefits or risks of the vaccine to breastfed children. However, as BNT162b2 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 breastfeeding child. On the basis of these considerations, WHO recommends the use of BNT162b2 in lactating women as in other adults. WHO does not recommend discontinuing breastfeeding because of vaccination [World Health Organization, 2021 ].

As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [WHO, 2020 ].

WHO recommends an extended primary series including an additional (third) dose (30 μg) for severely immunocompromised persons (ICPs). The most appropriate timing for the additional dose may vary depending on the epidemiological setting and the extent and timing of immune suppressive therapy, and should be discussed with the treating physician. WHO further recommends that close contacts (in particular caregivers) of such individuals should be vaccinated if eligible. Additional public health and social measures at household level to protect immunocompromised persons are also warranted depending on the local epidemic circumstances [World Health Organization, 2021 ].

WHO does not recommend pregnancy testing before vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2021 ].

The interaction of concomitant administration of Pfizer-BioNTech COVID‑19 Vaccine with other vaccines has not yet been studied. [WHO, 2020 ].

There should be a minimum interval of 14 days between administration of this vaccine and any other vaccine against other conditions, until data on co-administration with other vaccines become available [World Health Organization, 2021 ].

Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection [World Health Organization, 2021 ].
Although there are currently no medical contraindications on the vaccinating of a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].

Although there are currently no contraindications on the vaccinating of a person who has had contact with a COVID-19 case, it is recommended to defer vaccination until the quarantine has been completed (14 days after the last exposure) [PAHO, 2020 ].

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

Clinical studies - general characteristics

Randomized trials

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

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

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

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

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

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

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

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

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

 

 

Ongoing randomized trials

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

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

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

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

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

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

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

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

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

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

SWITCH is an ongoing multicenter, randomized, single-blind, controlled trial (registered with the number NCT04927936 [Erasmus Medical Center, 2021 ]) sponsored by Erasmus Medical Center that is being conducted in Netherlands. It was first registered in June 2021 and plans to enroll 432 health care workers aged 18 to 65 years that will receive a homologous or heterologous boosting of Janssen vaccine, Moderna vaccine, or Pfizer vaccine. It is expected to run until September 2022.

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

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

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

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

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

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

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

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

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

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

Other studies providing efficacy or safety data

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

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

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

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

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

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

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

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

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

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

Dagan N et al. was a cohort study conducted in Israel. The study enrolled 1,193,236 general population that received Pfizer-BioNTech COVID-19 vaccine. Based on data from Israel’s largest health care organization (Clalit Health Services) during the period from December 20, 2020, to February 1, 2021.

Barda N et al. was an observational study conducted in Israel. The study enrolled 1,736,832 general population that received Pfizer-BioNTech COVID-19 vaccine. Based on data from Israel’s largest health care organization (Clalit Health Services) during the period from December 20, 2020, to May 24, 2021.

Other ongoing registered studies 

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

900/24-12-2020 is an ongoing cohort study (registered with the number NCT04743388 [National and Kapodistrian University of Athens, 2021 ]) sponsored by the National and Kapodistrian University of Athens that is being conducted in Greece. It was first registered in February 2021 and plans to enroll 600 healthy volunteers ≥ 18 years old with the objective of determining both the degree and duration of the immunity provided after receiving BNT162b2 mRNA Vaccine. It is expected to run until April 2022.

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

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

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

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

COVIVAC-ID is an ongoing single group assignment study (registered with the number NCT04844489 [Assistance Publique - Hôpitaux de Paris, 2021 ]) sponsored by Assistance Publique - Hôpitaux de Paris that is being conducted in France. It was first registered in April 2021 and plans to enroll 485 vaccinated immunocompromised people (autoimmune or auto-inflammatory disease, HIV infection, multiple sclerosis, solid cancer, organ transplantation) to determine the humoral and cellular response to BNT162b2 vaccination and efficacy against SARS-CoV-2 variants. It is expected to run until December 2022.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

VAX4FRAIL is an ongoing non-randomized study (registered with the number NCT04848493 [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ]) sponsored by Azienda Unità Sanitaria Locale Reggio Emilia that is being conducted in Italy. It was first registered in April 2021 and plans to enroll 1300 frail subjects with impaired immuno-competence, due to their underlying diseases or ongoing therapies that received SARS-CoV-2 with Pfizer-BioNTech or Moderna vaccines. It is expected to run until April 2022.

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

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

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

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

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

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

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

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

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

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

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

Methods used to assess efficacy

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

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

Methods used to evaluate safety

C4591001 trial [Polack, Fernando P., 2020 ]

Primary safety endpoints

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

Efficacy and effectiveness of the vaccine

Efficacy of preclinical studies on the vaccine

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

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

Efficacy of the vaccine in clinical trials

Main immunogenicity outcomes

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

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

Key messages

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

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


Main efficacy outcomes of Pfizer-BioNTech COVID-19 vaccine

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

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

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

In the trials identified in this review, 162 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 18325 presented this outcome (9 per 1000) versus 8 out of 18198 in the group that did receive it (0 per 1000). In other words, 9 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 95%, or that the intervention reduced the risk of contracting COVID-19 by 95 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 111. Which means that 111 people need to receive the vaccine for one of them to not contracting COVID-19.

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

Contracting COVID-19 after the first dose (median follow-up time of 2 months)

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

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

In the trials identified in this review, 275 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21687 presented this outcome (13 per 1000) versus 50 out of 21669 in the group that did receive it (2 per 1000). In other words, 11 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 82%, or that the intervention reduced the risk of contracting COVID-19 after the first dose by 82 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the is 91. Which means that 91 people need to receive the vaccine for one of them to not contracting COVID-19 after the first dose.

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


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

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

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

In the trials identified in this review, 4 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21259 presented this outcome (0 per 1000) versus 1 out of 21314 in the group that did receive it (0 per 1000). In other words, 0 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 75%, or that the intervention reduced the risk of contracting severe COVID-19 by 75 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 10000. Which means that 10000 people need to receive the vaccine for one of them to not contracting severe COVID-19.

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

Mortality

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



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

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

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

In the trials identified in this review, 69 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 18325 presented this outcome (4 per 1000) versus 4 out of 18198 in the group that did receive it (0 per 1000). In other words, 4 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 94%, or that the intervention reduced the risk of contracting COVID-19 (16-64y) by 94 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 250. Which means that 250 people need to receive the vaccine for one of them to not contracting COVID-19 (16-64y).

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

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

The relative risk of contracting COVID-19 (>65y) in the group that received Pfizer-BioNTech COVID-19 vaccine versus the group that received placebo vaccine was 0.08 (95% CI 0.01 to 0.65). This means Pfizer-BioNTech COVID-19 vaccine reduced the risk of contracting COVID-19 (>65y) by 92%, compared with placebo vaccine.

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

In the trials identified in this review, 12 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 18325 presented this outcome (1 per 1000) versus 1 out of 18198 in the group that did receive it (0 per 1000). In other words, 1 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 92%, or that the intervention reduced the risk of contracting COVID-19 (>65y) by 92 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 1000. Which means that 1000 people need to receive the vaccine for one of them to not contracting COVID-19 (>65y).

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


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

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

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

In the trials identified in this review, 34 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 1861 presented this outcome (18 per 1000) versus 3 out of 2636 in the group that did receive it (1 per 1000). In other words, 17 less people per did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 92%, or that the intervention reduced the risk of contracting COVID-19 (5-15 y) by 92 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 59. Which means that 59 people need to receive the vaccine for one of them to not contracting COVID-19 (5-15 y).

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

Summary of findings table (iSoF)

Efficacy and effectiveness of the vaccine in subgroups

Age

Randomized trials

The proportion of patients >55 years of age in the C4591001 trial was 42.2% (15,921 out of 37,706 participants) [Polack, Fernando P., 2020 ]. vaccine efficacy in the different age groups was consistent with that observed in the overall population. Efficacy was 95.6% (89.4 to 98.6) in the group 16 to 55 years, 93.7% (80.6 to 98.8) in >55 years, 94.7% (66.7 to 99.9) in ≥65 years and 100.0% (−13.1 to 100.0) in ≥75 years [Polack, Fernando P., 2020 ].

The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2,260 out of 3,358 participants) [Frenck RW, 2021 ].

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

In the group that included 1,983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3 to 100). In the group that included all 2,229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95% 78.1 to 100) [Frenck RW, 2021 ].

The phase 3, randomized, double-blind trial B7471026 is currently evaluating the efficacy/safety of the vaccine in vaccinated adults 65 years of age and older [Pfizer, 2021 ]. The proportion of participants 65-85 years in the BNT162-03 was 50% (72 out of 144 participants) [Li J, 2021 ].

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

Other studies

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

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

 
Sex

Randomized trials

The proportion of females in the C4591001 trial was 49.4% (18,631 out of 37,706 participants) [Polack, Fernando P., 2020 ]. vaccine efficacy was consistent in the different sex groups. Efficacy was 96.4% (88.9% to 99.3%) in males and 93.7% (84.7% to 98.0%) in females.

Other studies

In Bjork et al [Jonas Bjork, 2021 ], no difference in vaccine effectiveness was observed between females and males.

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

 

Race and ethnic group

Randomized trials

The proportion of white participants in the C4591001 trial was 79% (31,266 out of 37,706 participants) [Polack, Fernando P., 2020 ].

vaccine efficacy was consistent in the different racial and ethnic groups. Efficacy was 95.2% (89.8% to 98.1%) in whites, 100.0% (31.2% to 100.0%) in Black or African Americans, and 94.4% (82.7% to 98.9%) in Hispanic or Latinos.

 

Children and adolescents

Randomized trials

The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2,260 out of 3,358 participants) [Frenck RW, 2021 ].

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

In the group that included 1983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3% to 100%). In the group that included all 2,229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95%, 78.1% to 100%) [Frenck RW, 2021 ].


Other studies

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

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

 

Pregnancy

Randomized trials

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

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

 

Breast-feeding

Randomized trials

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

Other studies

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

The cohort O'Connor DL et al is currently evaluating the effectiveness/safety of the vaccine in lactating mothers [Deborah O'Connor, 2021 ].

 

Immunocompromised people

Randomized trials

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

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

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

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


Other studies

The study COVIVAC-ID [Assistance Publique - Hôpitaux de Paris, 2021 ] plans to enroll 485 vaccinated immunocompromised people (autoimmune or auto-inflammatory disease, HIV infection, multiple sclerosis, solid cancer, organ transplantation) to determine the humoral and cellular response to vaccination and efficacy against SARS-CoV-2 variants.

The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna and Astra-Zeneca vaccines [University Hospital, Strasbourg, France, 2021 ].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

Persons living with HIV

Randomized trials

The proportion of people living with HIV in the C4591001 trial was 0.32% (121 out of 37,706 participants) [Polack, Fernando P., 2020 ].

vaccine efficacy for this subgroup in the C4591001 trial has not yet been reported [Polack, Fernando P., 2020 ].

 

Chronic lung disease

Randomized trials

Available data are currently insufficient to assess efficacy in persons with chronic lung disease.

 

Cardiac disease

Randomized trials

Available data are currently insufficient to assess efficacy in persons with cardiac disease.

 

Diabetes

Randomized trials

Available data are currently insufficient to assess efficacy in persons with diabetes.

 

Liver disease

Randomized trials

Available data are currently insufficient to assess efficacy in persons with liver disease.

Other studies

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

 

Persons with recent COVID-19

Randomized trials

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

Other data on vaccine efficacy and effectiveness

Main effectiveness outcomes of Pfizer COVID-19 vaccine (Other studies)

Contracting COVID-19

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

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

Muhsen K et al. was a comparative cohort study conducted in Israel. The study enrolled 9,162 participants: 6,960 vaccine group; 2,202 Control group. Based on data from Health care workers from a tertiary care facility adhering to routine testing since July 2020. Outcome measured at ≥ 14 days after the second dose. Results showed vaccine effectiveness of 89% (95% CI 83 to 93) [Khitam Muhsen, 2021 ]." Cabezas C et al. was a comparative cohort study conducted in Spain. The study enrolled 116,783 participants: 98,494 vaccine group; 18,289 Control group. Based on data from three cohorts from Catalonia from December 27 2020 to March 5, 2021. Outcomes were measured at ≥ 12 days after vaccination. Results showed vaccine effectiveness in nursing home residents was 92% (95% CI 91 to 93); nursing home staff was 88% (95% CI 85 to 90), and healthcare workers was 95% (95% CI 93 to 96) [Carmen Cabezas, 2021 ].

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

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

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

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

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

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

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

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

 

Contracting severe COVID-19

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

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

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

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

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

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

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

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

 

Transmission

No studies reported or assessed this outcome.

 

SARS-CoV-2 variants

Immunogenicity outcomes

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

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

Tarke A et al. was a comparative cohort study conducted in the United States. The study enrolled 80 healthy adults (14 received Pfizer, 13 received Moderna, 28 COVID-19 group, 23 unexposed group). This study evaluated the T cell responses from individuals recovered from COVID-19 and T cell responses from recent Moderna mRNA-1273 or Pfizer/BioNTech BNT162b2 vaccines for their capacity to recognize peptides derived from the ancestral reference sequence and the gamma variant. Comparison of the variant to the ancestral sequence showed no significant differences for CD4+ and CD8+ T cell reactivity in the activation-induced marker assay for P.1 (CD4+ T cells: p = 0.29) (CD8+ T cells: p = 0.09) [Tarke A, 2021 ].

 

Randomized trials

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

 

Other studies

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

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

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

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

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

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

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

Booster dose

Immunogenicity outcomes

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

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

 

Effectiveness outcomes

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

 

Arbel R et al. was a cohort study conducted in Israel. The study enrolled 843,208 participants: 758,118 third dose group; 85,090 second dose group. Based on data for all members of Clalit Health Services who were 50 years of age or older at the start of the study and had received two doses of BNT162b2 at least 5 months earlier, between August 6, 2021 and September 29, 2021. Outcome was measured 7 days after the third dose. The study results showed a
adjusted hazard ratio for Death of 0.10 (95%CI 0.07 to 0.14) [Arbel R, 2021 ].

Bar-On YM et al. was a cohort study conducted in Israel. The study enrolled 4,696,865 participants and was based on data from the Israel Ministry of Health database regarding 4,696,865 persons 16 years of age or older who had received two doses of BNT162b2 at least 5 months earlier, for the period from July 30 to October 10, 2021. Outcome was measured 7 days after the third dose. The study results showed an adjusted rate difference ranging from 57.0 to 89.5 infections per 100,000 person-days for confirmed infection and an adjusted rate difference ranging from 5.4 and 1.9 cases of severe illness per 100,000 person-days for severe illness [Bar-On YM, 2021 ].

 

Heterologous vaccine regimens

Immunogenicity outcomes

Com-COV was a multi-center single-blind phase II randomized parallel study. The trial included 830 healthy adults 50 years and older: 115 Pfizer/ AstraZeneca vaccine; 114 ​​AstraZeneca/ Pfizer vaccine group; 234 Control group (Two doses of AstraZeneca or Pfizer COVID-19 vaccine). Immunogenicity was measured anti-SARS-CoV-2-spike binding antibody (bAb) levels 28 days following the second dose. Results showed SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher versus homologous vaccine schedule [Liu X, 2021 ]. CombiVacS was a phase 2, open-label, randomized, controlled trial. The trial included 676 adults aged 18-60 years: 450 Intervention group (ChAd/BNT ); 226 Control group. Immunogenicity was measured 14 days following the second dose. BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response [Borobia AM, 2021 ].

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

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

Heterologous-booster regimens

Immunogenicity outcomes

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

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

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

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

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

 

Allergic reactions

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

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

Safety of the vaccine in clinical trials

Key messages

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

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

Main safety outcomes of Pfizer-BioNTech COVID-19 vaccine

Incidence of any adverse events (measured at 2 months )

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

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

In the available trial, 2638 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21631 presented this outcome (122 per 1000) versus 5770 out of 21621 in the group that did receive it (267 per 1000). In other words, 145 more people per 1000 did develop the outcome because of the vaccine. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 7.

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

Non-serious adverse events

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

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

Serious adverse events (measured at 2 months )

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

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

In the available trial, 111 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 21631 presented this outcome (5 per 1000), versus 126 out of 21621 in the group that did receive it (6 per 1000). In other words, 1 more person per 1000 experienced serious adverse events due to receiving the vaccine. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 1000.

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



Safety of the vaccine in subgroups

Incidence of any adverse events (5-15y) (measured at 2 months )

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

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

In the trials identified in this review, 136 people not receiving Pfizer-BioNTech COVID-19 vaccine out of 1879 presented this outcome (72 per 1000) versus 234 out of 2649 in the group that did receive it (80 per 1000). In other words, 8 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 12%, or that the intervention increased the risk of any adverse events by 12 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTH is 125. Which means that 125 people need to receive the vaccine for one of them to not any adverse events.

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


Summary of findings table (iSoF)

Safety of the vaccine in subgroups

Sex

Randomized trials

The proportion of females in the C4591001 trial was 49.4% (18,631 out of 37,706 participants) [Polack, Fernando P., 2020 ].

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

Other studies

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

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

 

Age

Randomized trials

The proportion of participants >55 years of age in the C4591001 trial was 42.2% (15,921 out of 37,706 participants) [Polack, Fernando P., 2020 ].

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

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

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

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

In the 65-85 years old group, 83% of participants in the 10 µg BNT162b1 dose group, 92% of participants in the 30 µg BNT162b1 dose group, and 8% of participants in the placebo group reported at least one solicited adverse reaction. Reactogenicity was dose-level dependent and was most evident in the group receiving 30 µg, BNT162b1. Older participants did not have increased reactogenicity after the BNT162b1 boost dose [Li J, 2021 ].

Grade 3 fever was reported in 8% of older participants who received 30 µg BNT162b1. One male participant in the older age group experienced an episodic grade 3 fever accompanied by pain and pruritus at the injection site after the prime BNT162b1 dose at 30 µg and electively withdrew before receiving the boost vaccination [Li J, 2021 ].

Other studies

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

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

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

Children and adolescents

Randomized trials

In the phase 2/3 components of the C4591001 trial, reactogenicity was measured in a subset that included 8,183 participants (≥12 years of age). Reactogenicity data were collected by participants'e-diary reporting local reactions and systemic events for 7 days after each dose.
This preliminary data provides support of safety on adolescents 12 to 15 years of age [FDA, 2020 ].

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

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

The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2,260 out of 3,358 participants) [Frenck RW, 2021 ].

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

In both age cohorts (12-5 years and 16-25 years), BNT162b2 recipients reported more local events than placebo recipients. Local events were generally mild to moderate in severity, reported at similar frequencies in both age cohorts ), and typically resolved within 1 or 2 days. Injection-site pain was the most common local reaction in all groups. Severe injection-site pain after any BNT162b2 dose was reported in 1.5% of 12-to-15-year-old participants and in 3.4% of 16-to-25-year-old participants; no severe pain was reported after placebo administration [Frenck RW, 2021 ].

In both age cohorts (12-5 years and 16-25 years), headache and fatigue were the most frequently reported systemic events. After BNT162b2 injection, severe headache and severe fatigue were reported in a lower percentage of 12-to-15-year-old participants than of 16-to-25-year-old participants. Fever with a temperature ≥38°C occurred after the second dose of BNT162b2 in 20% of 12 to 15-year-old recipients and in 17% of 16 to 25 years old recipients. Fever with a temperature higher than 40°C occurred 1 day after the first dose of BNT162b2 in 0.1% of the 12-to-15-year-old participants [Frenck RW, 2021 ].

Other studies

C4591007 is an ongoing non-randomized study evaluating the safety in healthy children ages 12 years and less [BioNTech SE, 2021 ].

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

 

Pregnancy

Randomized trials

A total of 23 participants reported pregnancy during the trial. Nine of them withdrew from the study but the follow-up on these participants continues in order to assess pregnancy outcomes [Polack, Fernando P., 2020 ].

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

Other studies

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

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

 

Breast-feeding

Randomized trials

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

Comparative studies

The cohort O'Connor DL et al is currently evaluating the effectiveness/safety of the vaccine in lactating mothers [Deborah O'Connor, 2021 ].

Golan et al. was a prospective cohort study that enrolled 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Results showed no severe maternal or infant adverse effects. Vaccine-related products, PEGylated proteins, were not found at significant levels in milk after vaccination [Golan Y et al., 2021 ].

 

Persons/ individuals with comorbidities

Randomized trials

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

Comparative studies

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

 

Immunocompromised persons

Randomized trials

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

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

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

Comparative studies

The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna and Astra-Zeneca vaccines [University Hospital, Strasbourg, France, 2021 ].

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

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

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

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

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

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

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

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

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

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

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

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

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

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

 

Persons living with HIV

Randomized trials

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

Safety of the vaccine post-authorization

Post-authorization studies

Comparative post-authorization studies

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

Maxime Taquet et al. is a comparative cohort study conducted in United States. The study enrolled 537,913 patients with a confirmed diagnosis of COVID-19. Based on data from ​a federated electronic health records network recording anonymized data from 59 healthcare organizations from January 20, 2020, and March 25, 2021. The authors compared the adverse events between Moderna or Pfizer and Influenza vaccine groups. Results of the study showed that the Moderna/Pfizer group had more cerebral sinus and venous thrombosis (567%, 95% IC 98% to 2,134%), and portal vein thrombosis 640% (95% CI 387% to 1,024%) than the Influenza group [Maxime Taquet, 2021 ]

Hippisley-Cox J et al. is a comparative study conducted in England. The study enrolled 29,121,633 patients with the first dose of Ox-AstraZeneca, Pfizer vaccines or with a positive test of SARS-CoV-2. Based on data from electronic health records, the Office for National Statistics and the United Kingdom's health service (NHS) between 1 December 2020 and 24 April 2021. The authors compared the incidence rate ratio (IRR) pre-post vaccination. The results of the study showed that the Pfizer vaccine had an increased risk of thrombocytopenia (IRR 1.08 95% CI 0.94 to 1.23), lower risk of venous thromboembolism (IRR 0.89 95% CI 0.81 to 0.99) and had no difference in arterial thromboembolism (IRR 1.02 95% CI 0.95 to 0.99) [Hippisley-Cox J, 2021 ].

 

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

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

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

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

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

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

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

Non-comparative studies

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

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

David Presby et al. is a retrospective cohort conducted in United States. The study enrolled 50,977 (AstraZeneca (AZ, n=2,093), Janssen/Johnson & Johnson (J&J&J, n=3 888), Moderna (n=23,776; M1, 14,553 first dose; M2, 9,223 second dose), or Pfizer/BioNTech (n=35,929; P&B1, 22,387 first dose; P&B2, 13,542 second dose) participants. Based on data from subscribers to the WHOOP platform using data collected through April 14, 2021 [David Presby, 2021 ].

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

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

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

Kaur RJ et al. was a non-comparative study that reported 4,863 cardiovascular adverse events. Common adverse events observed with the study vaccines were tachycardia (16.41%), flushing (12.17%), hypertension (5.82%), hypotension (3.60%), and peripheral coldness (2.41%). According to the disproportionality analysis (IC025 values), acute myocardial infarction, cardiac arrest, and circulatory collapse were associated with vaccines in the age group> 75 years. Hypertension, severe hypertension, supraventricular tachycardia, sinus tachycardia, and palpitations were associated in all age groups and in both sexes [Jeet Kaur R, 2021 ].

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

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

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

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

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

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

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

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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