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 December 31, 2020 [WHO, 2020 ]
EUL/WHO Authorization: Authorized for emergency use in individuals 16 years of age and older [WHO, 2021 ]
SAGE/WHO Recommendation: Individuals aged 12 years and above [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: In individuals 16 years of age and older [EMA, 2020 ].
28 May 2021: In 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: 22 December 2020
[ADMINISTRACIÓN NACIONAL DE MEDICAMENTOS, 2020 ]

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

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

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

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use : 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)
December 11, 2020
Emergency Use Authorization (US) in individuals 16 years of age and older [FDA, 2020 ]

May 10, 2021
Emergency Use Authorization (EUA) in individuals 12 to 15 years of age [FDA, 2021 ].

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use :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
Saint Vincent and the Grenadines
San Martin
Turks and Caicos Islands
Uruguay

Authorization in other jurisdictions
Albania
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
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
Tunisia
Turkey
Ukraine
Vatican
West Bank

Manufacturing

Manufacturer
Drug Product: Pfizer Europe MA EEIG; Belgium. It is involved in the process of combining the mRNA with lipid nanoparticles, then filling vials, boxing vials, and freezing them. Croda International subsidiary Avanti Polar Lipids is providing the requisite lipids.

Other manufacturers
Drug substance [WHO, 2021 ]
BioNTech Manufacturing GmbH. Mainz and Marburg, 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.
Rentschler Biopharma SE, Germany.
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC, USA.
Drug product [WHO, 2021 ]
Baxter Oncology GmbH. Westfalen, Germany
BioNTech Manufacturing GmbH. Mainz, Germany
Novartis. Stein, Switzerland
Mibe GmbH Arzneimittel. Brehna, 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

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

Risk considerations

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 ].

Dosification 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 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.

The vaccine-induced highest neutralizing titers were observed on day 43 (21 days after the BNT162b1 boost dose) for the younger and older 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 older 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 older adults. Geometric mean neutralizing titers reached 2.1-fold in the young adult's group and 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 ].

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 above [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 ].
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 [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 should be administered only in settings where anaphylaxis can be treated [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 ].
Food, contact or seasonal allergies, including to eggs, gelatin and latex, are not considered precautions or contraindications [WHO, 2021 ].
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded [WHO, 2020 ].
Anxiety or stress‐related reactions may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting [WHO, 2020 ].
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 ]
Persons who have received monoclonal antibodies or convalescent plasma as part of COVID-19 treatment, vaccination should be deferred for at least 90 days to avoid interference of treatment with vaccine-induced immune response [WHO, 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 ].
Available data on administration in pregnant females are still insufficient to inform vaccine-associated risks in pregnancy. WHO recommends the use of Pfizer vaccines in pregnant women when the benefits of vaccination to the pregnant woman outweigh the potential risks. To help pregnant women make this assessment, they should be provided with information about the risks of COVID-19 in pregnancy, the likely benefits of vaccination, and the current limitations of safety data. WHO does not recommend pregnancy testing before vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [World Health Organization, 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 ].
Immunocompromised persons may have lower immune response to vaccine. Information about vaccine safety and efficacy should be provided to inform individual benefit-risk assessment [WHO, 2021 ].
Controlled HIV-positive persons, on highly active antiretroviral therapy can be vaccinated. Available data for HIV-positive persons who are not well controlled is currently insufficient to allow assessment of vaccine efficacy and safety in this group [WHO, 2021 ].
Persons with autoimmune conditions without contraindications to vaccination, may be vaccinated [WHO, 2021 ].

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 ].
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
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.
Appropriate medical treatment used to manage immediate allergic reactions must be immediately available in the event an acute anaphylactic reaction occurs following administration of Pfizer-BioNTech COVID-19 Vaccine.

Storage and logistics

Storage:

Pfizer-BioNTech COVID-19 vaccine is provided as a concentrated frozen dispersion stored at -75°C/-103°F (between -90°C to -60°C [-130°F to -76°F])
Ultra-low temperatures:
• at -80°C to -60°C (-112°F to -76°F) in freezer, or
• at -90°C to -60°C (-130°F to -76°F) in thermal shipper as temporary storage for up to 30 days from delivery (should be re-iced every 5 days if opened up to 2 times a day, less than 3 minutes at a time)
Diluent storage: Room temperature (up to 30 °C [86°F])

Shelf life at different temperatures:
Undiluted vaccine at storage temperature -90°C to -60°C (-130°F to -76°F): 6 months after the time of manufacturing.

The storage period of the unopened thawed vial at 2−8 °C (36°F to 46°F) is up to 1 month (31 days) [World Health Organization, 2021 ] [FDA, 2021 ]
Diluted vaccine at 2°C to 30°C (36°F to 86°F): 6 hours after dilution


Do not refreeze thawed vials.
Do not freeze diluted vaccine.
Minimize exposure to room light.
Avoid exposure to direct sunlight and ultraviolet light.

Conditions before use: At room temperature (up to 30°C [86°F]) before dilution and use.

Logistic at the time of administration

Thaw before dilution: [WHO, 2021 ]
Before dilution, vials must reach room temperature and be diluted within 2 hours
Thaw vaccine up to 3 hours at 2°C to 8°C (36°F to 46°F) in refrigerator or for 30 minutes at 25°C (77°F) before dilution.

Dilute before use: [WHO, 2021 ]
1. Before dilution, invert vaccine vial gently 10 times, do not shake.

2. Draw into the mixing syringe 1.8 mL of diluent.

3. Add 1.8 mL of diluent into the vaccine vial; level/equalize the pressure in the vial before removing the needle by withdrawing 1.8 mL of air into the empty diluent syringe.

4. Discard diluent syringe in safety box (do not reuse) and discard diluent vial.

5. Gently invert the vial with diluted vaccine 10 times to mix; do not shake.

6. Inspect to make sure that the vaccine is an off-white uniform dispersion; do not use if discoloured or if containing particles.

7. Record date and time of dilution on the vaccine vial label.
8. Draw up the vaccine dose at the time of administration, pre-loading vaccine into syringes is not recommended. Use all vaccine within 6 hours after dilution.

Storage after first puncture

Record the date and time the vial should be discarded.
Administration:
[WHO, 2021 ]
1.Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 mL reuse prevention syringe (RUP) or a 5 mL RUP syringe, and a 23G × 1 ”(0.60 × 25 mm) intramuscular injection needle.
To extract 6 doses from the same vial, syringes and / or needles with a low dead volume (35 microliters maximum) should be used.
If conventional syringes and needles are used, there may not be enough volume to draw a sixth dose from the same vial.
3. Gently invert the vial with the diluted vaccine to mix and withdraw the 0.3 mL dose. If the amount of vaccine remaining in the vial cannot provide a full 0.3 mL dose, discard the vial and the excess volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.
Discard the unused vaccine within 6 hours of dilution.

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded [WHO, 2020 ].
Disposal
Due to the high risk that discarded vials of COVID-19 vaccines can be recovered, it is essential that they are guaranteed to be safely disposed at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

Clinical studies - general characteristics

Randomized trials
C4591001 is a phase 1/2/3 randomized trial sponsored by BioNTech and conducted in the United States between May 2020 and November 2020. It was registered with the number NCT04368728 [Biontech SE, 2020 ].
The phase 1 component of the trial included 195 healthy adults 18 years of age or older. Participants were randomly assigned to 13 groups comprising 15 participants each; in each group, 12 participants received vaccine and 3 received placebo. The vaccines were administered in different doses and schedules [Walsh EE, 2020 ]. The phase 2/3 component included 37706 adults 16 years of age or older who were healthy or had stable chronic medical conditions. The mean age of the participants was 52 years old, and the proportion of females was 49%. Participants were randomly assigned in a 1:1 ratio to receive the vaccine (30 µg, 0.3 mL volume per dose) or placebo [Polack, Fernando P., 2020 ]
C4591001 was a phase 2/3, randomized trial sponsored by BioNTech SE and conducted at 162 sites worldwide (United States, Argentina, Brazil, South African, Germany, and Turkey) April 2020-March 2021. It was registered with NCT04368728.
The trial included healthy persons 12 years of age or older.
The sample size was 6035. 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 ]

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 1530 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 4000 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 3000 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 older 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 1200 healthy adults or with mild or moderate stable comorbidities 18 years of age and older that will receive Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273. 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 older that will receive Ad26.COV2.S administered as a booster vaccination. It is expected to run until 44621.

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 3500 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 [Karamanoğlu 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 1500 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 10000 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 4504 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 haematological malignancies 18 years of age and older 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 older 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 older 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 older 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 3340 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 44621.

Methods used to assess efficacy and effectiveness

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 assess 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 the vaccine in preclinical studies

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 available trial, 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. 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. In other words, 111 individuals need to receive the vaccine for 1 individual to not contract COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high. 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 available trial, 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. 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 91.

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 available trial, 4 people not receiving Pfizer-BioNTech COVID-19 Vaccine out of 21259 presented this outcome (less than 1 per 1000) versus 1 out of 21314 in the group that received Pfizer-BioNTech COVID-19 Vaccine (less than 1 per 1000). In other words, less than 1 person per 1000 did not 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 NNTB is 10000.

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.

Summary of findings table (iSoF)



Efficacy and effectiveness of the vaccine on subgroups

Age

Randomized trials
The proportion of patients >55 years of age in the C4591001 trial was 42.2% (15921 out of 37706 participants) [Polack, Fernando P., 2020 ].
Vaccine efficacy in the different age groups was consistent with that observed in the overall population. Efficacy was 95.6% (89.4 to 98.6) in the group 16 to 55 years, 93.7% (80.6 to 98.8) in >55 years, 94.7% (66.7 to 99.9) in ≥65 years and 100.0% (−13.1 to 100.0) in ≥75 years [Polack, Fernando P., 2020 ].
The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants) [Frenck RW, 2021 ].
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants) [Frenck RW, 2021 ].
In the group that included 1983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3 to 100). In the group that included all 2229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95%, 78,1 a 100) [Frenck RW, 2021 ].
The phase 3, randomized, double-blind trial B7471026 is currently evaluating the efficacy/safety of the vaccine in vaccinated adults 65 years of age and older [Pfizer, 2021 ].
The proportion of participants 65-85 years in the BNT162-03 was 50% (72 out of 144 participants) [Li J, 2021 ].
The older participants generally had a lower peak neutralizing antibody response than the younger participants. The vaccine-induced highest neutralizing titers were observed on day 43 (21 days after the BNT162b1 boost dose) for the older adults in the BNT162b1 group. Moreover, geometric mean neutralizing titers reached 1.3-fold in the older adults group versus a panel of COVID-19 convalescent human sera obtained at least 14 d after positive SARS-CoV-2 polymerase chain reaction test [Li J, 2021 ].
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% (18631 out of 37706 participants) [Polack, Fernando P., 2020 ].
Vaccine efficacy was consistent in the different sex groups. Efficacy was 96.4% (88.9 to 99.3) in males and 93.7% (84.7 to 98.0) in females.
Other 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% (31266 out of 37706 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% (2260 out of 3358 participants) [Frenck RW, 2021 ].
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants) [Frenck RW, 2021 ].
In the group that included 1983 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (95% CI, 75.3 to 100). In the group that included all 2229 participants in the 12-to-15-year-old cohort, vaccine efficacy from 7 days after the second dose was 100% (IC del 95%, 78,1 a 100) [Frenck RW, 2021 ].
Other 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 older were excluded from the C4591001 trial, so no data are available for this subgroup [Polack, Fernando P., 2020 ].
C4591015 is an ongoing phase 2/3, randomized trial evaluating the efficacy in this subgroup [BioNTech SE, 2021 ].
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 older [Ospedale di Circolo - Fondazione Macchi, 2021 ].
The phase 2, non-randomized study C4591024 is currently evaluating the effectiveness/safety of the vaccine in immunocompromised participants ≥2 Years Of Age [BioNTech SE, 2021 ].
The non-randomized study IROC is currently evaluating the effectiveness/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].
The non-randomized study LymphVAX is currently evaluating the effectiveness/safety of the vaccine in women with a history of breast cancer [Massachusetts General Hospital, 2021 ].
The non-randomized study VIOLA is currently evaluating the effectiveness/safety of the vaccine in COVID-negative Multiple Sclerosis patients treated with ocrelizumab [NYU Langone Health, 2021 ].
The phase 4, non-randomized study Covid Vaccin Allo is currently evaluating the effectiveness/safety of the vaccine in patients allo-hematopoietic cell transplantation recipients [University of Liege, 2021 ].
The non-randomized study VAX4FRAIL is currently evaluating the effectiveness/safety of the vaccine in frail subjects with impaired immuno-competence, due to their underlying diseases or ongoing therapies that received SARS-CoV-2 with Pfizer-BioNTech or Moderna vaccines [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].
The phase 4, non-randomized study EREVA is currently evaluating the effectiveness/safety of the vaccine in adults immunocompromised or non-immunocompromised volunteers [Centre Hospitalier Régional d'Orléans, 2021 ].
The phase 1 and 2, interventional, non-randomized study PACIFIC is currently evaluating the effectiveness/safety of the vaccine in children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old) [Assistance Publique - Hôpitaux de Paris, 2021 ].
The non-randomized study CPAT is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].

Persons living with HIV

Randomized trials
The proportion of people living with HIV in the C4591001 trial was 0.32% (121 out of 37706 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-1

Other data from vaccine efficacy and effectiveness

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. Based on the data from 596,618 individuals, vaccine effectiveness at days 14 through 20 after the first dose, and at 7 or more days after the second dose was: 46% (95% CI, 40 to 51) and 92% (95% CI, 88 to 95) for documented infection; 57% (95% CI, 50 to 63) and 94% (95% CI, 87 to 98) for symptomatic COVID-19; 74% (95% CI, 56 to 86) and 87% (95% CI, 55 to 100) for hospitalization; 62% (95% CI, 39 to 80) and 92% (95% CI, 75 to 100) for severe disease. Estimated effectiveness for days 14 through 20 after the first dose in preventing death was 72% (95% CI, 19 to 100).

Duration of protection

The exact duration of protection afforded by the vaccine is unknown as it is still being determined by ongoing clinical trials.
Limitations of vaccine effectiveness

Individuals may not be fully protected until 14 days after their second dose. As with all vaccines, vaccination with Pfizer-BioNTech COVID‑19 Vaccine may not protect all vaccine recipients.
SARS-CoV-2 variants

Randomized trials
Preliminary data show after two BNT162b2 doses, effectiveness against symptomatic SARS-CoV-2 infection with the Beta (B.1.351) variant was 75,0% (IC 95% 70,5-78,9%); with the Delta (B1.617.2) variant was 88% (95% IC 78,2-93,2%) ; and with the Alpha (B.1.1.7) variant was 93% (95% CI 90,4-95,5%) [World Health Organization, 2021 ].
Other studies
Haas et al conducted an observational study utilizing national surveillance data from January 2021 to March 2021 in Israel, sponsored by Israel MoH and Pfizer [Eric J. Haas, 2021 ]. B.1.1.7 variant prevalence during that period was 93.9%. Estimates of vaccine efficacy at ≥ 7 days after the second dose were 94.1% (95% CI 93.4 to 94.7) and even higher at ≥14 days after the second dose the vaccine.
Multiple studies have assessed the humoral response, cellular response and population effectiveness of the vaccine against B.1.1.7, B.1.351, P.1 and other variants [Diamond M, 2021 ],[Adrienn Angyal, 2021 ],[Helen Marie Parry, 2021 ],[Eric J. Haas, 2021 ],[Lilleri D, 2021 ],[Adrienn Angyal, 2021 ],[Xuping Xie, 2021 ],[Timothy A. Bates, 2021 ],[Xie X, 2021 ],[Monin-Aldama L, 2021 ],[Alexander Muik, 2021 ],[Matthias Becker, 2021 ],[Xie X, 2021 ],[Jamie Lopez Bernal, 2021 ],[B Shayak, 2021 ],[Assistance Publique - Hôpitaux de Paris, 2021 ],[Sonia Jangra, 2021 ],[Planas D, 2021 ],[Collier DA et al., 2021 ],[Alona Kuzmina, 2021 ],[Kristin Andrejko, 2021 ],[Yang Liu, 2021 ],[Skelly D, 2021 ],[Alison Tarke, 2021 ],[Takuya Tada, 2021 ],[Sheila F Lumley, 2021 ],[Shi P, 2021 ],[Talia Kustin, 2021 ],[Collier DA, 2021 ],[Ugur Sahin, 2020 ],[Zijun Wang, 2021 ],[Stamatatos L et al., 2021 ],[Woldemeskel BA, 2021 ],[Hoffmann M, 2021 ],[Garcia-Beltran WF et al.,2021 ],[Christophe Rodriguez, 2021 ],[Victoria Jane Hall, 2021 ],[Gongyi Zhang, 2021 ],[Muik A, 2021 ],[Ariel Munitz, 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

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. No reasons for concern were detected in relation to risk of bias, inconsistency, indirect evidence, imprecision or publication bias.

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% vs 23% among younger vaccine recipients and 51% vs 17% in older recipients%); headache (52% vs 24% among younger vaccine recipients and 39% vs 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.


Summary of findings table (iSoF)


Safety of the vaccine in subgroups

Sex

Randomized trials
The proportion of females in the C4591001 trial was 49.4% (18631 out of 37706 participants) [Polack, Fernando P., 2020 ].
The proportion of females that experienced adverse effects with Pfizer-BioNTech COVID‑19 Vaccine versus the group that received placebo vaccine was not reported in detail. However, no specific safety concerns were identified in this subgroup.
Other 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 ].

Age

Randomized trials
The proportion of participants >55 years of age in the C4591001 trial was 42.2% (15921 out of 37706 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 ].

Children and adolescents

Randomized trials
In the phase 2/3 components of the C4591001 trial, reactogenicity was measured in a subset that included 8183 participants (≥12 years of age). Reactogenicity data were collected by participants‘ e-diary reporting local reactions and systemic events for 7 days after each dose.
This preliminary data provides support of safety on adolescents 12 to 15 years of age [FDA, 2020 ].
Younger adolescents 12 to 15 years of age (49/100 in the vaccine group and 51/100 in the placebo group) contributed to a preliminary reactogenicity data analysis. In this age group, pain at the injection site was the most frequent local reaction, reported in 71.4% of participants in the vaccine group, compared to 17.6% in the placebo group after Dose 1 [FDA, 2020 ].
Most systemic events in younger adolescents were mild to moderate in severity. Severe events were relatively infrequent in both groups, occurring in no more than 1 or 2 participants after either dose [FDA, 2020 ]
The proportion of participants 12-15 years in the C4591001 trial was 67.3% (2260 out of 3358 participants) [Frenck RW, 2021 ].
The proportion of participants 16-25 years in the C4591001 trial was 32.7% (1098 out of 3358 participants) [Frenck RW, 2021 ].
In both age cohorts (12-5 years and 16-25 years), BNT162b2 recipients reported more local events than placebo recipients. Local events were generally mild to moderate in severity, reported at similar frequencies in both age cohorts ), and typically resolved within 1 or 2 days. Injection-site pain was the most common local reaction in all groups. Severe injection-site pain after any BNT162b2 dose was reported in 1.5% of 12-to-15-year-old participants and in 3.4% of 16-to-25-year-old participants; no severe pain was reported after placebo administration [Frenck RW, 2021 ].
In both age cohorts (12-5 years and 16-25 years), headache and fatigue were the most frequently reported systemic events. After BNT162b2 injection, severe headache and severe fatigue were reported in a lower percentage of 12-to-15-year-old participants than of 16-to-25-year-old participants. Fever with a temperature ≥38°C occurred after the second dose of BNT162b2 in 20% of 12 to 15-year-old recipients and in 17% of 16 to 25 years old recipients. Fever with a temperature higher than 40°C occurred 1 day after the first dose of BNT162b2 in 0.1% of the 12-to-15-year-old participants [Frenck RW, 2021 ].
Other 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 wer: 95.6% injection-site pain, 80.6% fatigue, 65.0% headache, 46.0% fever or felt feverish. Adverse neonatal outcomes included preterm birth (in 9.4%) and small size for gestational age (in 3.2%); no neonatal deaths were reported (Data based on 827 participants in the v-safe pregnancy registry who received an mRNA Covid-19 vaccine, BNT162b2 or mRNA-1273). Among 221 pregnancy-related adverse events reported to the VAERS, the most frequently reported event was spontaneous abortion (46 cases) [Shimabukuro TT, 2021 ].
An analysis of the CDC v-safe COVID-19 Pregnancy Registry in 19,252 pregnant people who received the vaccine did not show obvious safety signals [Shimabukuro TT, 2021 ].
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 older [Ospedale di Circolo - Fondazione Macchi, 2021 ].
The phase 2, non-randomized study C4591024 is currently evaluating the effectiveness/safety of the vaccine in immunocompromised participants ≥2 Years Of Age [BioNTech SE, 2021 ].
The non-randomized study IROC is currently evaluating the effectiveness/safety of the vaccine in cancer patients 18 years of age and older [Indiana University, 2021 ].
The non-randomized study LymphVAX is currently evaluating the effectiveness/safety of the vaccine in women with a history of breast cancer [Massachusetts General Hospital, 2021 ].
The non-randomized study VIOLA is currently evaluating the effectiveness/safety of the vaccine in COVID-negative Multiple Sclerosis patients treated with ocrelizumab [NYU Langone Health, 2021 ].
The phase 4, non-randomized study Covid Vaccin Allo is currently evaluating the effectiveness/safety of the vaccine in patients allo-hematopoietic cell transplantation recipients [University of Liege, 2021 ].
The non-randomized study VAX4FRAIL is currently evaluating the effectiveness/safety of the vaccine in frail subjects with impaired immuno-competence, due to their underlying diseases or ongoing therapies that received SARS-CoV-2 with Pfizer-BioNTech or Moderna vaccines [Azienda Unità Sanitaria Locale Reggio Emilia, 2021 ].
The phase 4, non-randomized study EREVA is currently evaluating the effectiveness/safety of the vaccine in adults immunocompromised or non-immunocompromised volunteers [Centre Hospitalier Régional d'Orléans, 2021 ].
The phase 1 and 2, interventional, non-randomized study PACIFIC is currently evaluating the effectiveness/safety of the vaccine in children with acute leukemia (1 to 15 years old) and their siblings (≥12-15 years old) [Assistance Publique - Hôpitaux de Paris, 2021 ].
The non-randomized study CPAT is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients [National Institute of Allergy and Infectious Diseases (NIAID), 2021 ].
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
Furer et al found a prevalence of reactivation of herpes zoster of 1.2% (n=6/491) in patients with autoimmune inflammatory rheumatic diseases that received the vaccine, compared to none (0/99) in controls [Furer V, 2021 ].
Barda N, 2021 reported an observational study conducted in Israel. 1,736,832 individuals aged 16 years or older were included in this study to evaluate the safety of the BNT162b2 mRNA vaccine. Results showed that vaccination was most strongly associated with an elevated risk of myocarditis RR 3.24 (CI 95% 1.55 to 12.44), lymphadenopathy RR 2.43 (CI 95% 2.05 to 2.78), appendicitis RR 1.40 (CI 95% 1.02 to 2.01), and herpes zoster infection RR 1.43 (CI 95% 1.20 to 1.73). On the other hand, SARS-CoV-2 infection was associated with a substantially increased risk of myocarditis RR 18.28 (CI 95% 3.95 to 25.12) and of additional serious adverse events, including pericarditis, arrhythmia, deep-vein thrombosis, pulmonary embolism, myocardial infarction, intracranial hemorrhage, and thrombocytopenia [Barda N, 2021 ].

Non-comparative studies
Menni et al conducted a phase 4 study from a real world setting investigating self-reported systemic and local effects within eight days of vaccination in 387,471 individuals from the COVID Symptom Study app in the United Kingdom who received one (n=209,251) or two (n=13,478) doses of the the vaccine between December 2020 and February 2021. Systemic side effects were reported in 11.8% after the first and 20.3% after the second dose and were more prevalent among individuals with pre-existing COVID-19 infection and among those aged <55 years [Cristina Menni, 2021 ].

Kadali et al was a cross-sectional study conducted in the United States [Kadali RAK, 2021 ]. The study included 803 healthcare workers that had received the vaccine and showed 12.83% of the recipients were temporarily unable to perform continues activities of daily living, 12.33% temporarily took time off from work, 2.49% required help from an outpatient provider, 0.62% required help from emergency department and 0.25% required hospitalization. Never the less, the intention to receive the second dose was 97.61%. The most commonly reported symptoms were soreness, fatigue, myalgia, headache, chills, fever, joint pain, nausea, muscle spasm, sweating, dizziness, flushing, feelings of relief, brain fogging, anorexia, localized swelling, decreased sleep quality, itching, tingling, diarrhea, nasal stuffiness and palpitations.

Postintroduction vaccine pharmacovigilance data thus far have not identified any acute safety problems, with a reactogenicity and adverse events profile similar to that reported in the absence of pregnancy [World Health Organization, 2021 ].

Based on previous experience with other vaccine use during pregnancy, the effectiveness of BNT162b2 in pregnant women is expected to be comparable to that observed for nonpregnant women in similar age groups. Data from small studies have demonstrated that COVID-19 mRNA vaccines are immunogenic in pregnant women and that vaccine-elicited antibodies are transported to infant cord blood and breast milk, suggesting possible neonatal as well as maternal protection [Collier AY, 2021 ], [Kathryn J Gray, 2021 ].
Post-introduction vaccine pharmacovigilance data thus far have not identified any acute safety problems, with a reactogenicity and adverse events profile similar to that reported in the absence of pregnancy. Based on previous experience with other vaccine use during pregnancy, the effectiveness of the mRNA-1273 in pregnant women is expected to be comparable to that observed for non-pregnant women in similar age groups. Data from small studies have demonstrated that COVID-19 mRNA vaccines are immunogenic in pregnant women and that vaccine-elicited antibodies are transported to infant cord blood and breast milk, suggesting possible neonatal as well as maternal protection [Kathryn J Gray, 2021 ], [Collier AY, 2021 ]. As data from additional studies become available, recommendations will be updated accordingly [WHO, 2021 ].

Pawlowski C et al. was a retrospective cohort study that enrolled 266,094 participants (94,818 Pfizer doses). The study compare incidence rates of Cerebral venous sinus thrombosis in a 30-day time windows before and after vaccination. In total, 3 cases of Cerebral venous sinus thrombosis were observed within the 30 days following Pfizer-BioNTech vaccination, including one individual with a prior history of thrombosis and another individual with recent trauma in the past 30 days [Colin Pawlowski, 2021 ].
Hippisley-Cox J et al. was a self-controlled case series study that enrolled 29,121,633 participants (19,608,008 with Oxford-AstraZeneca and 9,513,625 with Pfizer-BioNTech) aged ≥16 years who had first doses of the ChAdOx1 or BNT162b2 mRNA vaccines. The study found an increased risk of arterial thromboembolism after BNT162b2 mRNA vaccination (incidence rate ratio 1.06, 95% CI:1.01 to 1.10 at 15-21 days). Secondary analyses found increased risk of Cerebral venous sinus thrombosis after BNT162b2 mRNA vaccination (3.58, 95% CI: 1.39 to 9.27 at 15-21 days), and an increased risk of ischaemic stroke after BNT162b2 mRNA vaccination (1.12, 95% CI: 1.04 to 1.20 at 15-21 days) [Hippisley-Cox J, 2021 ]
Menni C et al was a cross-sectional study that enrolled 387,471 people who received one (n=209,251) or two (n=13,478) doses of the BNT162b2 vaccine, or one dose of ChAdOx1 nCoV-19 vaccine (n=178,220).Systemic side effects were reported in 11.8% of participants after the first BNT162b2 dose and 20.3% after the second dose. Systemic effects were more prevalent among individuals with preexisting COVID-19 infection (34%) in the BNT162b2 vaccine group; than among individuals without known prior infection. In addition, side effects were more frequent among those aged <55 years (BNT162b2:19.9%) compared to those aged >55 years (BNT162b2:9.2%) [Cristina Menni, 2021 ].


Spontaneous report data
Disclaimer: Reporting suspected adverse reactions after authorization of the medicinal product is important because it allows continuous monitoring of the benefit/risk balance of the vaccines. However, they do not indicate a causal association between the vaccine and the observed effects. Furthermore, this information should not be used to estimate the frequency of adverse events in people receiving the vaccine or to make comparisons between different vaccines. The information emerging about possible adverse effects needs to be carefully evaluated in order to first establish if the adverse effect might have been caused by the vaccine.

Dutta et al [Siddhartha Dutta, 2021 ] assessed a total of 103954 adverse events reported from 32044 subjects in the WHO database (VigiBase). The majority of severe adverse events (74%) were reported for Pfizer vaccine.
An analysis of the CDC v-safe COVID-19 Pregnancy Registry including data from December 2020 to February 2021 from the “v-safe after vaccination health checker” surveillance system, the v-safe pregnancy registry, and the Vaccine Adverse Event Reporting System (VAERS) was published in April 2021 [Shimabukuro TT, 2021 ]. In a sample of 19252 pregnant people of 16 to 54 years of age who received the vaccine, no obvious safety signals were observed.

Monitoring

The following post-authorization monitoring activities have been recommended by WHO:
· Safety surveillance and monitoring. Monitoring the following serious adverse events: myocarditis, thromboembolic events, thrombosis with thrombocytopenia syndrome (TTS), anaphylaxis and other serious allergic reactions, Bell`s palsy, and transverse myelitis; cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death.
· Vaccine effectiveness over time.
· Ongoing collection of safety data in vaccine recipients.
· Surveillance for COVID-19 among vaccinated individuals, looking for vaccine-induced enhanced disease (possibly as vaccine-induced antibody levels decline)
· Safety data from inadvertently vaccinated pregnant females during trials and post-authorization.
· Safety data from pregnant females who receive vaccine because they are members of prioritized groups, e.g. health workers.
· Prospective studies on the safety of the vaccine in pregnant females.
· Impact on infants of vaccination of breastfeeding mothers.
· Safety data on vaccination in immunocompromised people, including individuals living with HIV and people with autoimmune disease.
· Impact of delayed second dose as currently implemented by certain countries.

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