To Evaluate the Safety, Tolerability, Efficacy and Immunogenicity of BNT162b2 Boosting Strategies Against COVID-19 in Participants ≥12 Years of Age.

Study Overview
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Brief Summary
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Substudy A: The study will evaluate the safety, tolerability, and efficacy of a booster dose of BNT162b2 when administered to participants having previously received 2 doses of BNT162b2 at least 6 months prior to randomization. The study is designed to describe vaccine efficacy of a booster dose of BNT162b2 over time against COVID-19 At a dose of 30µg (as studied in the Phase 2/3 study C4591001) In healthy adults 16 years of age and older The duration of the study for each participant will be up to approximately 12 months. The study will be conducted in the United States, Brazil and South Africa Substudy B: The study will assess the safety and tolerability of a single dose of BNT162b2 as compared to placebo control, through the potential analysis of serum troponin levels, in participants ≥12 and ≤30 years of age who have received 2 or 3 prior doses of BNT162b2 (30-µg doses) with their last dose at least 4 months (120 days) prior to randomization. Blood samples will be collected for troponin testing The duration of the study for each participant will be up to approximately 2 months. The study will be conducted in the United States, Germany, Poland and South Africa Substudy C: The study will assess the safety, tolerability, and immunogenicity of a booster (third) dose of BNT162b2 at doses of 10 µg or 30 µg in participants who have completed a 2-dose primary series of BNT162b2 (30 µg doses) at least 5 months (150 days) prior to randomization. In healthy adults 12 years of age and older The duration of the study for each participant will be up to approximately 12 months. The study will be conducted in the United States, Germany and South Africa Substudy D: The study will assess the safety, tolerability, and immunogenicity of a 2-dose primary series of BNT162b2 OMI, and as a booster (third, fourth or fifth) dose Participants in Cohort 1 will have completed a 2-dose primary series of BNT162b2 (30-µg doses), with their last dose 90 to 240 days prior to enrolment Participants in Cohort 2 will be enrolled from Study C4591001 and C4591031 Substudy A and will have completed a 2-dose primary series and received a single booster (third) dose of BNT162b2, with their last dose 90 to 180 days prior to randomization Participants in Cohort 3 who are COVID-19 vaccine-naïve and have not experienced COVID-19 will be enrolled to receive 2 doses (primary series) of BNT162b2 OMI, 3 weeks apart, with a dose of BNT162b2 approximately 5 months (150 days) later. If participants do not consent to receive BNT162b2 as a third dose, they will not receive a third dose. No participants should receive BNT162b2 OMI as a third dose. In healthy adults 18 to 55 years of age The duration of the study for each participant will be up to approximately 12 months. The study will be conducted in the United States and South Africa Substudy E: This study will assess the safety, tolerability, and immunogenicity of high-dose BNT162b2 (60 µg), high-dose BNT162b2 OMI (60 µg), and a high-dose combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), given as a single dose In healthy adults 18 years of age and older who have received 3 prior doses of BNT162b2 (30 µg) with the most recent dose being 5 to 12 months (150 to 360 days) prior to randomization The duration of the study for each participant will be approximately 6 months. The study will be conducted in the United States Substudy F: This study will assess the safety, tolerability, and immunogenicity of high-dose BNT162b2 (60 µg), high-dose BNT162b2 OMI (60 µg), and a high-dose combination of BNT162b2 and BNT162b2 OMI at 60 µg (30 µg each), given as a single dose. In healthy adults 60 years of age and older who have received 3 prior doses of BNT162b2 (30 µg) with the most recent dose being ≥4 months prior to randomization The duration of the study for each participant will be approximately 6 months. The study will be conducted in Israel

Official Title
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A PHASE 3 MASTER PROTOCOL TO EVALUATE ADDITIONAL DOSE(S) OF BNT162B2 IN HEALTHY INDIVIDUALS PREVIOUSLY VACCINATED WITH BNT162B2

Conditions
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SARS-CoV-2 Infection, COVID-19

Intervention / Treatment
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* Biological: BNT162b2
* Other: Placebo
* Biological: BNT162b2 OMI
* Biological: Combination BNT162b2 and BNT162b2 OMI
* Biological: Combination (Bivalent) BNT162b2 and BNT162b2 OMI


Participation Criteria
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Eligibility Criteria
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Substudy A Inclusion Criteria: Male or female participants ≥16 years of age at Visit 1 (Day 1) who participated in C4591001. 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 (if required), and clinical judgment of the investigator to be eligible for inclusion in the study. Capable of giving signed informed consent. Participants who have received 2 prior doses of 30 µg BNT162b2 19-42 days apart, with the second dose being at least 175 days before Visit 1 (Day 1). 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. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. 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. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or receipt of any passive antibody therapy specific to COVID-19, from 90 days before study intervention administration, or planned receipt throughout the study. Prior receipt of any COVID-19 vaccine other than BNT162b2. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Receipt of medications intended to prevent COVID-19. Prior receipt of more than 2 doses of BNT162b2 30 µg. Participation in other studies involving study intervention within 28 days prior to study entry, other than C4591001, and/or within 28 days of confirmed receipt of BNT162b2 within the study. Substudy B Inclusion Criteria: Male or female participants 12 to 30 years of age, inclusive, who have received 2 prior doses of 30 µg BNT162b2 19 to 60 days apart, with the second dose being at least at least 4 months (120 days) before Visit 1 (Day 1) 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 (if required), and clinical judgment of the investigator to be eligible for inclusion in the study. Capable of giving signed informed consent. Exclusion Criteria: Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. 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. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or receipt of any passive antibody therapy specific to COVID-19, from 90 days before study intervention administration, or planned receipt throughout the study. Prior receipt of any COVID-19 vaccine other than BNT162b2. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Receipt of medications intended to prevent COVID-19. Prior receipt of more than 3 doses of BNT162b2 30 µg. Participation in other studies involving study intervention within 28 days prior to study entry through and including 28 days after the last dose of study intervention, with the exception of non-Pfizer interventional studies for prevention of COVID-19, which are prohibited throughout study participation. Substudy C Inclusion Criteria: Male or female participants ≥12 years of age, inclusive, who have received 2 prior doses of 30 µg BNT162b2 19 to 60 days apart, with the second dose being at least 150 days before Visit 301 (Day 1) 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 (if required), and clinical judgment of the investigator to be eligible for inclusion in the study. Capable of giving signed informed consent. Exclusion Criteria: Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behaviour or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. 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. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or receipt of any passive antibody therapy specific to COVID-19, from 90 days before study intervention administration, or planned receipt throughout the study. Prior receipt of any COVID-19 vaccine other than BNT162b2. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Receipt of medications intended to prevent COVID-19. Prior receipt of more than 2 doses of BNT162b2 30 µg. Participation in other studies involving study intervention within 28 days prior to study entry through and including 28 days after the last dose of study intervention, with the exception of non-Pfizer interventional studies for prevention of COVID-19, which are prohibited throughout study participation. Substudy D Inclusion Criteria: Male or female participants 18 to 55 years of age inclusive 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 (if required), and clinical judgment of the investigator to be eligible for inclusion in the study. Cohort 2: Participants who provided a serum sample at Visit 3 in Study C4591001, with Visit 3 occurring within the protocol-specified window. Capable of giving signed informed consent Cohort 1: Participants who have received 2 prior doses of 30 µg BNT162b2, with the second dose being 90 to 240 days before Visit 401 (Day 1) or Cohort 2: Participants who have received 3 prior doses of 30 µg BNT162b2, with the third dose being 90 to 180 days before Visit 401 (Day 1). 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. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. 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. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or receipt of any passive antibody therapy specific to COVID-19, from 90 days before study intervention administration, or planned receipt throughout the study. Cohorts 1 and 2: prior receipt of any COVID-19 vaccine other than BNT162b2. Cohort 3 only: prior receipt of any COVID-19 vaccine. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Receipt of medications intended to prevent COVID 19. Participation in other studies involving study intervention within 28 days prior to study entry through and including 28 days after the last dose of study intervention, with the exception of non-Pfizer interventional studies for prevention of COVID-19, which are prohibited throughout study participation. Substudy E Inclusion Criteria: Groups 1-6: Male or female participants >55 years of age Groups 7-9: Male or female participants 18 to 55 years of age 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 (if required), and clinical judgment of the investigator to be eligible for inclusion in the study. Capable of giving signed informed consent. Participants who have received 3 prior doses of 30 µg BNT162b2, with the third dose being 5 to 12 months (150 to 360 days) before Visit 601 (Day 1). Groups 7 to 9 (sentinel participants): Screening troponin levels must be within normal range prior to randomization. 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. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. 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. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or receipt of any passive antibody therapy specific to COVID-19, from 90 days before study intervention administration, or planned receipt throughout the study. Prior receipt of any COVID-19 vaccine other than BNT162b2. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Receipt of medications intended to prevent COVID-19. Participation in other studies involving study intervention within 28 days prior to study entry through and including 28 days after the last dose of study intervention, with the exception of non-Pfizer interventional studies for prevention of COVID-19, which are prohibited throughout study participation. Substudy F Inclusion Criteria: Male or female participants ≥60 years of age 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 (if required), and clinical judgment of the investigator to be eligible for inclusion in the study. Capable of giving signed informed consent. Participants who have received 3 prior doses of 30 µg BNT162b2, with the third dose being ≥4 months before Visit 701 (Day 1). 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. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention. 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. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination. 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. Individuals who receive treatment with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids, eg, for cancer or an autoimmune disease, or planned receipt throughout the study. Receipt of blood/plasma products, immunoglobulin, or monoclonal antibodies, from 60 days before study intervention administration, or receipt of any passive antibody therapy specific to COVID-19, from 90 days before study intervention administration, or planned receipt throughout the study. Prior receipt of any COVID-19 vaccine other than BNT162b2. Investigator site staff or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members. Receipt of medications intended to prevent COVID-19. Participation in other studies involving study intervention within 28 days prior to study entry through and including 28 days after the last dose of study intervention, with the exception of non-Pfizer interventional studies for prevention of COVID-19, which are prohibited throughout study participation.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 µg dose<br>1 dose | Biological: BNT162b2<br>* Intramuscular Injection<br>|
| Placebo Comparator: Placebo<br>1 dose | Other: Placebo<br>* Intramuscular Injection<br>|
| Experimental: 30 µg dose<br>1 dose | Biological: BNT162b2<br>* Intramuscular Injection<br>Biological: BNT162b2 OMI<br>* Intramuscular Injection<br>Biological: Combination BNT162b2 and BNT162b2 OMI<br>* 30-µg (15-µg each) or 60-µg (30-µg each) Site prepared dosing suspension from 1 vial each of diluted BNT162b2 and BNT162b2 OMI Intramuscular Injection<br>Biological: Combination (Bivalent) BNT162b2 and BNT162b2 OMI<br>* 30-µg (15-µg each) or 60-µg (30-µg each) Preformulated bivalent mixture (no dilution required) presented in a single vial Intramuscular Injection<br>|
| Experimental: 60 µg dose<br>1 dose | Biological: BNT162b2<br>* Intramuscular Injection<br>Biological: BNT162b2 OMI<br>* Intramuscular Injection<br>Biological: Combination BNT162b2 and BNT162b2 OMI<br>* 30-µg (15-µg each) or 60-µg (30-µg each) Site prepared dosing suspension from 1 vial each of diluted BNT162b2 and BNT162b2 OMI Intramuscular Injection<br>Biological: Combination (Bivalent) BNT162b2 and BNT162b2 OMI<br>* 30-µg (15-µg each) or 60-µg (30-µg each) Preformulated bivalent mixture (no dilution required) presented in a single vial Intramuscular Injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SSA - Confirmed COVID-19 incidence in participants without evidence of past SARS-CoV-2 infection | per 1000 person-years of blinded follow-up | from 7 days after the booster dose through the blinded follow-up period, which may be from 2 to 12 months | 
| SSA - Confirmed COVID-19 incidence in participants with and without evidence of past SARS-CoV-2 infection | per 1000 person-years of blinded follow-up | from 7 days after the booster dose through the blinded follow-up period, which may be from 2 to 12 months | 
| SSA - Percentage of participants reporting adverse events | As elicited by investigational site staff | from the booster dose to 1 month after the booster dose | 
| SSA - Percentage of participants reporting serious adverse events | As elicited by investigational site staff | from the booster dose to 6 months after the booster dose | 
| SSB - Percentage of participants with elevated troponin I levels | Troponin I level | through 1 month after the second vaccination | 
| SSB - Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling as self-reported on electronic diaries. | For 7 days following each vaccination | 
| SSB - Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain as self-reported on electronic diaries. | For 7 days following each vaccination | 
| SSB - Percentage of participants reporting adverse events | As elicited by investigational site staff | within 1 month after each vaccination | 
| SSB - Percentage of participants reporting serious adverse events | As elicited by investigational site staff | within 1 month after each vaccination | 
| SSC - Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling as self-reported on electronic diaries. | For 7 days following the booster dose | 
| SSC - Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain as self-reported on electronic diaries. | For 7 days following the booster dose | 
| SSC - Percentage of participants reporting adverse events | As elicited by investigational site staff | from the booster dose to 1 month after the booster dose | 
| SSC - Percentage of participants reporting serious adverse events | As elicited by investigational site staff | from the booster dose to 6 months after the booster dose | 
| SSC - the immune response to BNT162b2 10 µg and 30 µg given as the third dose in participants 12 through 17 years of age and a third dose of BNT162b2 30 µg in a randomly selected subset of participants 18 through 55 years of age from study C4591001 | GMTs at each time point GMFRs from baseline (before the third dose) to each subsequent time point after the third dose Percentage of participants with seroresponse at each time point after the third dose | At baseline (before the third dose), 1 month and 6 months after the third dose | 
| SSD - Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling as self-reported on electronic diaries. | For 7 days following each vaccination | 
| SSD - Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain as self-reported on electronic diaries. | For 7 days following each vaccination | 
| SSD - Percentage of participants reporting adverse events | As elicited by investigational site staff | from the first study vaccination (received in this study) through 1 month after the last study vaccination | 
| SSD - Percentage of participants reporting serious adverse events | As elicited by investigational site staff | from the first study vaccination (received in this study) through 6 months after the last study vaccination | 
| SSD-Superiority with respect to neutralizing titers and noninferiority with respect to seroresponse rate of the anti-Omi immune response after 1 dose of BNT162b2 OMI compared to after 1 dose of BNT162b2 given as D3 in BNT162b2-experienced participants | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI to those at 1 month after 1 dose of BNT162b2 given as the third dose in BNT162b2-experienced participants The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after 1 dose of BNT162b2 OMI and at 1 month after 1 dose of BNT162b2 given as the third dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention | 
| SSD-Superiority with respect to neutralizing titers and noninferiority with respect to seroresponse of anti-Omi immune response after 2 doses BNT162b2 OMI given as D3+D4 compared to after 1 dose BNT162b2 given as D3 in BNT162b2-experienced participants | GMR of the Omicron-neutralizing titers at 1 month after 2 doses of BNT162b2 OMI to those at 1 month after 1 dose of BNT162b2 given as the third (and fourth) dose in BNT162b2-experienced participants The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after 2 doses of BNT162b2 OMI and at 1 month after 1 dose of BNT162b2 given as the third (and fourth) dose in BNT162b2-experienced participants | 1 month after receipt of 1 or 2 doses of intervention as appropriate | 
| SSD-Superiority with respect to neutralizing titer and noninferiority with respect to seroresponse rate of the anti-Omi immune response after 1 dose BNT162b2 OMI compared to after 1 dose BNT162b2 given as the D4 in BNT162b2-experienced participants | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI to those at 1 month after 1 dose of BNT162b2 given as the fourth dose in BNT162b2-experienced participants The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after 1 dose of BNT162b2 OMI and at 1 month after 1 dose of BNT162b2 given as the fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention | 
| SSD-Superiority with respect to neutralizing titer and noninferiority with respect to seroresponse rate of the anti-Omi immune response after 2 doses BNT162b2 OMI compared to after 2 doses BNT162b2 in participants from the C4591001 study | GMR of the Omicron-neutralizing titers 1 month after the second dose of BNT162b2 OMI to 1 month after the second dose of BNT162b2 in participants selected from the C4591001 study The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after the second dose of BNT162b2 OMI and at 1 month after the second dose of BNT162b2 in participants selected from the C4591001 study | 1 month after receipt of the second dose of BNT162b2 OMI or BNT162b2 as appropriate | 
| SSE - Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling as self-reported on electronic diaries. | For 7 days following the study vaccination | 
| SSE - Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain as self-reported on electronic diaries. | For 7 days following the study vaccination | 
| SSE - Percentage of participants reporting adverse events | As elicited by investigational site staff | from the study vaccination through 1 month after the study vaccination | 
| SSE - Percentage of participants reporting serious adverse events | As elicited by investigational site staff | from the study vaccination through 6 months after the study vaccination | 
| SSE - Percentage of participants with elevated troponin I levels (18-55 years of age, sentinel cohort only) | Troponin I level | Before and 3 days after study vaccination | 
| SSE - Superiority of neutralizing titer after 1 dose of BNT162b2 OMI at 30 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI at 30 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Noninferiority of anti-Omicron immune response after 1 dose of BNT162b2 OMI at 30 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after 1 dose of BNT162b2 OMI 30 µg and at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Superiority of neutralizing titer after 1 dose of BNT162b2 OMI at 60 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI at 60 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Noninferiority of anti-Omicron immune response after 1 dose of BNT162b2 OMI at 60 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after 1 dose of BNT162b2 OMI 60 µg and at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Superiority of neutralizing titer after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Noninferiority of anti-Omicron immune response after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg and at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Superiority of neutralizing titer after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2 | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Noninferiority of anti-Omicron immune response after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg and at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSF - Percentage of participants reporting local reactions | Pain at the injection site, redness, and swelling as self-reported on electronic diaries. | For 7 days following the study vaccination | 
| SSF - Percentage of participants reporting systemic events | Fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain as self-reported on electronic diaries. | For 7 days following the study vaccination | 
| SSF - Percentage of participants reporting adverse events | As elicited by investigational site staff | from the study vaccination through 1 month after the study vaccination | 
| SSF - Percentage of participants reporting serious adverse events | As elicited by investigational site staff | from the study vaccination through 6 months after the study vaccination | 
| SSF - To describe the immune response to BNT162b2 (30 µg or 60 µg), BNT162b2 OMI (30 µg or 60 µg), and a combination of BNT162b2 and BNT162b2 OMI (30 µg or 60 µg) given as a fourth dose in BNT162b2-experienced participants | GMT of Omicron and reference-strain neutralizing titers GMFRs of Omicron and reference-strain neutralizing titers from before the study vaccination to subsequent time points Percentages of participants with seroresponse for Omicron and reference-strain neutralizing titers at each time point GMRs of Omicron and reference-strain neutralizing titers at each time point after the study vaccination between different vaccine groups | At each time point | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SSA - Confirmed severe COVID-19 (based on FDA definition) period in participants without evidence of past SARS-CoV-2 infection | per 1000 person-years of blinded follow-up | from 7 days after the booster dose through the blinded follow-up period, which may be from 2 to 12 months | 
| SSA - Confirmed severe COVID-19 (based on FDA definition) in participants with and without evidence of past SARS-CoV-2 infection | per 1000 person-years of blinded follow-up | from 7 days after the booster dose through the blinded follow-up period, which may be from 2 to 12 months | 
| SSA - Confirmed severe COVID-19 (based on CDC definition) in participants without evidence of past SARS-CoV-2 infection | per 1000 person-years of blinded follow-up | from 7 days after the booster dose through the blinded follow-up period, which may be from 2 to 12 months | 
| SSA - Confirmed severe COVID-19 (based on CDC definition) in participants with and without evidence of past SARS-CoV-2 infection | per 1000 person-years of blinded follow-up | from 7 days after the booster dose through the blinded follow-up period, which may be from 2 to 12 months | 
| SSC - Immune responses to BNT162b2 10 µg and 30 µg given as the third dose in participants 12 through 17 years of age | GMTs at each time point GMFRs from baseline (before the third dose) to 7 days after the third dose Percentage of participants with seroresponse at 7 days after the third dose | At baseline (before the third dose) and 7 days after the third dose | 
| SSD - The super superiority of the anti-Omicron immune response after 1 dose of BNT162b2 OMI compared to after 1 dose of BNT162b2 given as the third dose in BNT162b2-experienced participants | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI to those at 1 month after 1 dose of BNT162b2 given as the third dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention | 
| SSD - The super superiority of the anti-Omicron immune response after 2 doses of BNT162b2 OMI given as the third and fourth doses compared to after 1 dose of BNT162b2 given as the third dose in BNT162b2-experienced participants | GMR of the Omicron-neutralizing titers at 1 month after 2 doses of BNT162b2 OMI to those at 1 month after 1 dose of BNT162b2 given as the third (and fourth) dose in BNT162b2-experienced participants | 1 month after receipt of 1 or 2 doses of intervention as appropriate | 
| SSD - The super superiority of the anti-Omicron immune response after 1 dose of BNT162b2 OMI compared to after 1 dose of BNT162b2 given as the fourth dose in BNT162b2-experienced participants | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI to those at 1 month after 1 dose of BNT162b2 given as the fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention | 
| SSD - The noninferiority of the anti-Omicron immune response after 2 doses of BNT162b2 OMI compared to the anti-reference-strain immune response after 2 doses of BNT162b2 in participants selected from the C4591001 study | GMR of the Omicron-neutralizing titers 1 month after the second dose of BNT162b2 OMI to the reference-strain-neutralizing titers 1 month after the second dose of BNT162b2 in participants selected from the C4591001 study The difference in percentages of participants with seroresponse to the Omicron strain at 1 month after the second dose of BNT162b2 OMI and seroresponsea to the reference strain at 1 month after the second dose of BNT162b2 in participants selected from the C4591001 study | 1 month after receipt of the second dose of BNT162b2 OMI or BNT162b2 as appropriate | 
| SSD - The super superiority of the anti-Omicron immune response after 2 doses of BNT162b2 OMI compared to after 2 doses of BNT162b2 in participants selected from the C4591001 study | GMR of the Omicron-neutralizing titers 1 month after the second dose of BNT162b2 OMI to 1 month after the second dose of BNT162b2 participants selected from the C4591001 study | 1 month after receipt of the second dose of BNT162b2 OMI or BNT162b2 as appropriate | 
| SSE - Noninferiority of anti-reference-strain immune response after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the reference strain-neutralizing titers at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - Noninferiority of anti-reference strain immune response after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the reference strain-neutralizing titers at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - The super superiority of anti-Omicron immune responses after 1 dose of BNT162b2 OMI at 30 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI at 30 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - The super superiority of anti-Omicron immune responses after 1 dose of BNT162b2 OMI at 60 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of BNT162b2 OMI at 60 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - The super superiority of anti-Omicron immune responses after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 30 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 
| SSE - The super superiority of anti-Omicron immune responses after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg compared to after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants >55 years of age | GMR of the Omicron-neutralizing titers at 1 month after 1 dose of bivalent BNT162b2 and BNT162b2 OMI at 60 µg to those at 1 month after 1 dose of BNT162b2 at 30 µg given as a fourth dose in BNT162b2-experienced participants | 1 month after receipt of 1 dose of study intervention given as a fourth dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Coronavirus, Vaccine, SARS-CoV-2, RNA Vaccine