Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults

This is a Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals.

The study consists of 2 parts: Phase 1: to identify preferred vaccine candidate(s) and dose level(s); Phase 2/3: an expanded cohort and efficacy part.

The study will evaluate the safety, tolerability, and immunogenicity of 3 different SARS-CoV-2 RNA vaccine candidates against COVID-19 and the efficacy of 1 candidate:

• As a 2-dose (separated by 21 days) schedule;
• At various different dose levels in Phase 1;
• As a booster;
• In 3 age groups (Phase 1: 18 to 55 years of age, 65 to 85 years of age; Phase 2/3: ?12 years of age [stratified as 12-15, 16-55 or >55 years of age]).

The candidate selected for efficacy evaluation in Phase 2/3 is BNT162b2 (mid-dose).

Participants ?16 years of age who originally received placebo will be offered the opportunity to receive BNT162b2 at defined points as part of the study.

In order to describe the boostability of BNT162, and potential heterologous protection against emerging SARS-CoV-2 VOCs, an additional dose of BNT162b2 will be given to Phase 1 participants approximately 6 to 12 months after their second dose of BNT162b1 or BNT162b2. This will provide an early assessment of the safety of a third dose of BNT162, as well as its immunogenicity.

The assessment of boostability will be further expanded in a subset of Phase 3 participants who will receive a third dose of BNT162b2 or a third and potentially a fourth dose of prototype BNT162b2VOC (BNT162b2s01, based upon the South African variant and hereafter referred to as BNT162b2SA).

To further describe potential homologous and heterologous protection against emerging SARS-CoV-2 VOCs, a new cohort of participants will be enrolled who are COVID-19 vaccine-naïve (ie, BNT162b2-naïve) and have not experienced COVID-19. They will receive BNT162b2SA given as a 2-dose series, separated by 21 days.

• SARS-CoV-2 Infection
• COVID-19

• Biological: BNT162b1
  Intramuscular injection
• Biological: BNT162b2
  Intramuscular injection
• Other: Placebo
  Intramuscular injection
• Biological: BNT162b2SA
  Intramuscular injection

• Experimental: Low dose, 18-55 years of age (2 doses)
  Interventions:

  • Biological: BNT162b1
  • Biological: BNT162b2
• Experimental: Low-mid dose, 18-55 years of age (2 doses)
  Interventions:

  • Biological: BNT162b1
  • Biological: BNT162b2
• Experimental: Mid dose, 18-55 years of age (2 doses)
  Interventions:

  • Biological: BNT162b1
  • Biological: BNT162b2
• Experimental: Low dose, 65-85 years of age (2 doses)
  Interventions:

  • Biological: BNT162b1
  • Biological: BNT162b2
• Experimental: Low-mid dose, 65-85 years of age (2 doses)
  Interventions:

  • Biological: BNT162b1
  • Biological: BNT162b2
• Experimental: Mid dose, 65-85 years of age (2 doses)
  Interventions:

  • Biological: BNT162b1
  • Biological: BNT162b2
• Experimental: Mid dose, ?12 years of age (2 doses)
  Intervention: Biological: BNT162b2
• Placebo Comparator: Placebo, 18-55 years of age
  Intervention: Other: Placebo
• Placebo Comparator: Placebo, 65-85 years of age
  Intervention: Other: Placebo
• Placebo Comparator: Placebo, ?12 years of age
  Intervention: Other: Placebo
• Experimental: High dose, 18-55 years of age (2 doses)
  Intervention: Biological: BNT162b1
• Vaccination of Placebo recipients with BNT162b2 - Stage 1
  Participants ?16 years of age who originally received placebo and are eligible for COVID-19 vaccination following any local or national recommendations will be offered the opportunity to receive BNT162b2 as part of the study.
  Intervention: Biological: BNT162b2
• Vaccination of placebo recipients with BNT162b2 - Stage 2
  Participants ?16 years of age who originally received placebo will be offered the opportunity to receive BNT162b2 at defined points as part of the study.
  Intervention: Biological: BNT162b2
• Experimental: Booster vaccination of Phase 1 participants with BNT162b2
  Intervention: Biological: BNT162b2
• Experimental: Booster vaccination of Phase 3 participants with BNT162b2
  Intervention: Biological: BNT162b2
• Experimental: Booster vaccination of Phase 3 participants with BNT162b2SA
  Intervention: Biological: BNT162b2SA
• Experimental: Vaccination of BNT162b2-naive participants with BNT162b2SA
  Intervention: Biological: BNT162b2SA
• Experimental: Booster and further vaccination of Phase 3 participants with BNT162b2SA
  Intervention: Biological: BNT162b2SA

• Vogel AB, Kanevsky I, Che Y, Swanson KA, Muik A, Vormehr M, Kranz LM, Walzer KC, Hein S, Güler A, Loschko J, Maddur MS, Ota-Setlik A, Tompkins K, Cole J, Lui BG, Ziegenhals T, Plaschke A, Eisel D, Dany SC, Fesser S, Erbar S, Bates F, Schneider D, Jesionek B, Sänger B, Wallisch AK, Feuchter Y, Junginger H, Krumm SA, Heinen AP, Adams-Quack P, Schlereth J, Schille S, Kröner C, de la Caridad Güimil Garcia R, Hiller T, Fischer L, Sellers RS, Choudhary S, Gonzalez O, Vascotto F, Gutman MR, Fontenot JA, Hall-Ursone S, Brasky K, Griffor MC, Han S, Su AAH, Lees JA, Nedoma NL, Mashalidis EH, Sahasrabudhe PV, Tan CY, Pavliakova D, Singh G, Fontes-Garfias C, Pride M, Scully IL, Ciolino T, Obregon J, Gazi M, Carrion R Jr, Alfson KJ, Kalina WV, Kaushal D, Shi PY, Klamp T, Rosenbaum C, Kuhn AN, Türeci Ö, Dormitzer PR, Jansen KU, Sahin U. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature. 2021 Feb 1. doi: 10.1038/s41586-021-03275-y. [Epub ahead of print]
• Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, ?ahin U, Jansen KU, Gruber WC; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. doi: 10.1056/NEJMoa2034577. Epub 2020 Dec 10.
• Walsh EE, Frenck RW Jr, Falsey AR, Kitchin N, Absalon J, Gurtman A, Lockhart S, Neuzil K, Mulligan MJ, Bailey R, Swanson KA, Li P, Koury K, Kalina W, Cooper D, Fontes-Garfias C, Shi PY, Türeci Ö, Tompkins KR, Lyke KE, Raabe V, Dormitzer PR, Jansen KU, ?ahin U, Gruber WC. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med. 2020 Dec 17;383(25):2439-2450. doi: 10.1056/NEJMoa2027906. Epub 2020 Oct 14.
• Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart S, Neuzil K, Raabe V, Bailey R, Swanson KA, Li P, Koury K, Kalina W, Cooper D, Fontes-Garfias C, Shi PY, Türeci Ö, Tompkins KR, Walsh EE, Frenck R, Falsey AR, Dormitzer PR, Gruber WC, ?ahin U, Jansen KU. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020 Oct;586(7830):589-593. doi: 10.1038/s41586-020-2639-4. Epub 2020 Aug 12. Erratum in: Nature. 2021 Feb;590(7844):E26.

Inclusion Criteria:

• Male or female participants between the ages of 18 and 55 years, inclusive, 65 and 85 years, inclusive, or ?12 years, inclusive, at randomization (dependent upon study phase). For the boostability and protection-against-VOCs subset (both existing and newly enrolled), male or female participants between the ages of 18 and 55 years, inclusive, at rerandomization/enrollment. Note that participants <18 years of age cannot be enrolled in the EU.
• Participants who are willing and able to comply with all scheduled visits, vaccination plan, laboratory tests, lifestyle considerations, and other study procedures.
• Healthy participants who are determined by medical history, physical examination, and clinical judgment of the investigator to be eligible for inclusion in the study.
• Participants who, in the judgment of the investigator, are at risk for acquiring COVID-19.
• Boostability and protection-against-VOCs existing participant subset only: Participants who provided a serum sample at Visit 3, with Visit 3 occurring within the protocol-specified window.
• Capable of giving personal signed informed consent

Exclusion Criteria:

• Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.
• Phases 1 and 2 only: Known infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV).
• History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s).
• Receipt of medications intended to prevent COVID 19.
• Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT result was not available) or microbiological (based on COVID-19 symptoms/signs and a positive SARS-CoV-2 NAAT result) diagnosis of COVID 19

• Phase 1 only: Individuals at high risk for severe COVID-19, including those with any of the following risk factors:

  • Hypertension
  • Diabetes mellitus
  • Chronic pulmonary disease
  • Asthma
  • Current vaping or smoking
  • History of chronic smoking within the prior year
  • BMI >30 kg/m2
  • Anticipating the need for immunosuppressive treatment within the next 6 months
• Phase 1 only: Individuals currently working in occupations with high risk of exposure to SARS-CoV-2 (eg, healthcare worker, emergency response personnel).
• Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination.
• Phase 1 only: Individuals with a history of autoimmune disease or an active autoimmune disease requiring therapeutic intervention.
• Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.
• Women who are pregnant or breastfeeding.
• Previous vaccination with any coronavirus vaccine.
• Individuals who receive treatment with immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study.
• Phase 1 only: Regular receipt of inhaled/nebulized corticosteroids.
• Receipt of blood/plasma products or immunoglobulin, from 60 days before study intervention administration or planned receipt throughout the study.
• Participation in other studies involving study intervention within 28 days prior to study entry through and including 6 months after the last dose of study intervention, with the exception of interventional studies for prevention of COVID 19, which are prohibited throughout study participation.
• Previous participation in other studies involving study intervention containing lipid nanoparticles.
• Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies at the screening visit.
• Phase 1 only: Any screening hematology and/or blood chemistry laboratory value that meets the definition of a ? Grade 1 abnormality.
• Phase 1 only: Positive test for HIV, hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (HBc Abs), or hepatitis C virus antibodies (HCV Abs) at the screening visit.
• Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt of study intervention.
• Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.