A Phase 1/2/3 Study to Evaluate the Safety, Tolerability, and Immunogenicity of an RNA Vaccine Candidate Against COVID-19 in Healthy Children

This is a Phase 1/2/3 study in healthy children.

Dependent upon safety and/or immunogenicity data generated during the course of this study, and the resulting assessment of benefit-risk, the safety, tolerability, and immunogenicity of BNT162b2 in participants \<6 months of age may subsequently be evaluated.

Phase 1 Dose-Finding

Is the open-label dose-finding portion of the study that will evaluate safety, tolerability, and immunogenicity of BNT162b2 administered on a 2-dose (separated by approximately 21 days) schedule in up to 3 age groups (participants ≥5 to \<12 years, ≥2 to \<5 years, and ≥6 months to \<2 years of age).

Dose finding is being initiated in this study in participants ≥5 to \<12 years of age based on the acceptable blinded safety assessment of the 30-µg dose in 12- to 15-year-olds in the C4591001 study.

The purpose of Phase 1 is to identify preferred dose level(s) of BNT162b2 from up to 3 different dose levels in each age group.

Dependent upon safety and/or immunogenicity data generated during the course of this study, it is possible that dose levels may not be started, may be terminated early, and/or may be added with dose levels below the lowest stated dose.

Update as part of protocol amendment 6: All participants will receive a third dose of BNT162b2. For participants ≥6 months to \<5 years, the third dose will occur at least 8 weeks after the second dose. In participants ≥5 to \<12 years, the third dose will occur at least 6 months after the second dose. The interval between the second and third doses will be based on the participant's age at the time of enrollment. The dose level of the third dose of BNT162b2 will be based on age at the time of vaccination: participants \<5 years of age at the time of the third dose will receive the 3-µg dose level, participants ≥5 to \<12 years of age at the time of the third dose will receive the 10-µg dose level, and participants ≥12 years of age at the time of the third dose will receive the 30-µg dose level.

Participants will have blood drawn prior to both Dose 1 and Dose 2 and 7 days after Dose 2 to assess immunogenicity to determine the selected BNT162b2 dose level for Phase 2/3. Participants will also have blood drawn prior to Dose 3 and 1, 6, and 12 months after Dose 3.

Phase 2/3 Selected-Dose

Is the portion of the study that will evaluate the safety, tolerability, and immunogenicity in each age group at the selected dose level from the Phase 1 dose-finding portion of the study. Efficacy will be evaluated within or across age groups in which immunobridging is successful, depending on accrual of a sufficient number of cases in those age groups.

Participants will have blood drawn at baseline prior to Dose 1 and 6 months after Dose 2. Immunobridging to participants 16 to 25 years of age in the C4591001 study will be based on immunogenicity data collected at (1) baseline and 1 month after Dose 2 and (2) baseline and 1 month after Dose 3. The persistence of the immune response will be based on immunogenicity data collected in participants at (1) baseline and 1 and 6 months after Dose 2 and (2) baseline and 1, 6, 12, and 18 months after Dose 3. In addition, efficacy against confirmed COVID-19 and against asymptomatic infection will also be assessed in participants ≥5 to \<12 years of age.

At designated US sites, an additional optional whole blood sample of approximately 10 mL will be obtained prior to Dose 1 and at 7 days and 6 months after Dose 2 from up to approximately 60 participants ≥10 years of age. Additional samples will be obtained prior to Dose 3 and 1 month after Dose 3 (original BNT162b2 group only). These samples will be used on an exploratory basis to investigate the postvaccination cell-mediated immune response at these time points.

At the 6-month follow-up visit, all participants will be unblinded. Participants who originally received placebo will be offered the opportunity to receive BNT162b2 as part of the study. Participants who originally received placebo and become eligible for receipt of BNT162b2 or another COVID-19 vaccine according to local or national recommendations prior to the 6 month follow-up visit (Visit 5 or 405) (detailed separately and available in the electronic study reference portal) will have the opportunity to receive BNT162b2 (10 µg or 3 µg) based on age at the time of vaccination.

Update as part of protocol amendment 6: All participants will receive a third dose of BNT162b2. For participants ≥6 months to \<5 years, the third dose will occur at least 8 weeks after the second dose. In participants ≥5 to \<12 years, the third dose will occur at least 6 months after the second dose. The interval between the second and third doses will be based on the participant's age at the time of enrollment. The dose level of the second and third doses of BNT162b2 will be based on age at the time of vaccination: participants \<5 years of age at the time of the second/third dose will receive the 3-µg dose level, participants ≥5 to \<12 years of age at the time of the second/third dose will receive the 10-µg dose level, and participants ≥12 years of age at the time of the second/third dose will receive the 30-µg dose level.

Phase 2/3 Obtaining Serum Samples for Potential Troponin I Testing

If testing of troponin I levels in individuals who did not receive BNT162b2 indicates that troponin I level could be a reliable indicator of potential subclinical myocarditis, obtaining serum samples for potential troponin I testing during the period of increased risk of clinical myocarditis may help characterize the absence/presence and frequency of subclinical myocarditis. To assess, an additional group of participants will be included: ≥5 to \<12 years: randomized 2:1 to receive BNT162b2 10 µg or placebo, and ≥12 to \<16 years of age: open-label receipt of BNT162b2 30 µg.

Update as part of protocol amendment 7: All participants will receive a third dose of BNT162b2. For all participants (≥5 to \<12 and ≥12 to \<16 years of age), the third dose will occur at least 5 months after Dose 2.

The dose level of the second and third doses of BNT162b2 will be based on age at the time of vaccination: participants ≥5 to \<12 years of age at the time of the second/third dose will receive the 10-µg dose level, and participants ≥12 years of age at the time of the second/third dose will receive the 30-µg dose level.

Update as part of protocol amendment 8: The Lower-Dose Evaluation portion of the protocol has been removed.

Participation in the study will cease 6 months after the third dose of BNT162b2.

Eligibility Criteria:
Inclusion Criteria

1. Male or female participants ≥6 months to \<12 years of age, at the time of randomization, at Visit 1 for the dose-finding/selected-dose evaluation. For the obtaining-serum-samples-for-potential-troponin I-testing portion of the study: Male or female participants between ≥5 and \<16 years of age.
2. Participants' parent(s)/legal guardian(s) and participants, as age appropriate, who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Healthy participants who are determined by medical history, physical examination, and clinical judgment of the investigator to be eligible for inclusion in the study.

   Note: Healthy participants with preexisting stable disease, defined as disease not requiring significant change in the therapy or hospitalization for worsening disease during the 6 weeks before enrollment, can be included.
4. Participants are expected to be available for the duration of the study and whose parent(s)/legal guardian can be contacted by telephone during study participation.
5. Negative urine pregnancy test for female participants who are biologically capable of having children.
6. Female participant of childbearing potential or male participant able to father children who is willing to use a highly effective method of contraception as outlined in this protocol for at least 28 days after the last dose of study intervention if at risk of pregnancy with her/his partner; or female participant not of childbearing potential or male participant not able to father children.
7. The participant or participant's parent(s)/legal guardian is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol. Depending on the age of the participant and according to local requirements, participants will also be asked to provide assent as appropriate (verbal or written).

Exclusion Criteria

1. Phase 1 only: Past 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.
2. Phase 1 only: Known infection with HIV, HCV, or HBV.
3. Receipt of medications intended to prevent COVID-19.
4. Previous or current diagnosis of MIS-C.
5. 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. Note: This includes both conditions that may increase the risk associated with study intervention administration or a condition that may interfere with the interpretation of study results
6. History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s).
7. Immunocompromised individuals with known or suspected immunodeficiency, as determined by history and/or laboratory/physical examination.
8. Individuals with a history of autoimmune disease or an active autoimmune disease requiring therapeutic intervention, including but not limited to systemic lupus erythematosus. Note: Stable type 1 diabetes and hypothyroidism are permitted.
9. Bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.
10. Female who is pregnant or breastfeeding.
11. Previous vaccination with any coronavirus vaccine.
12. 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. If systemic corticosteroids have been administered short term (\<14 days) for treatment of an acute illness, participants should not be enrolled into the study until corticosteroid therapy has been discontinued for at least 28 days before study intervention administration. Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted.
13. 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.
14. Participation in other studies involving study intervention within 28 days prior to study entry and/or during study participation.
15. Previous participation in other studies involving study intervention containing LNPs.
16. Participants who are direct descendants (child or grandchild) of investigational site staff members or Pfizer/BioNTech employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.