Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals
ID: NCT04368728
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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 at a dose of 30 µg. Participants 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 at 30 µg 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 at selected sites in the US who will receive a third dose of BNT162b2 at 30 µg or a third and potentially a fourth dose of prototype BNT162b2VOC at 30 µg (BNT162b2s01, based upon the South African variant and hereafter referred to as BNT162b2SA). A further subset of Phase 3 participants will receive a third, lower, dose of BNT162b2 at 5 or 10 µg. 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. To reflect current and anticipated recommendations for COVID 19 vaccine boosters, participants in C4591001 who meet specified recommendations and have not already received one, will be offered a third dose of BNT162b2 after their second dose of BNT162.
Intramuscular injection
Intramuscular injection
Intramuscular injection
Intramuscular injection
Treatment Arms Description
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.
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.
- 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: Existing participants enrolled to receive a third dose of BNT162b2 at 30 µg or BNT162b2SA; male or female participants between the ages of 18 and 55 years, inclusive, at rerandomization.
- Newly enrolled participants enrolled to receive 2 doses of BNT162b2SA; male or female participants between the ages of 18 and 55 years, inclusive, at enrollment.
- Existing participants enrolled to receive a third dose of BNT162b2 at 5 or 10 µg; male or female participants ≥18 years at rerandomization.
- 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.
- 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
- 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 non-Pfizer 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.
Primary Outcome Measures
- Percentage of Participants With Local Reactions Within 7 Days After Dose 1: Phase 1 — Time Frame: Within 7 days after Dose 1
Local reactions included redness, swelling and, pain at the injection site, recorded by participants in an electronic diary (e-diary). Redness and swelling were measured and recorded in measuring device units. 1 measuring device unit =0.5 centimeter (cm). Redness and swelling were graded as mild (greater than \[\>\] 2.0 to 5.0 cm), moderate (\> 5.0 to 10.0 cm), severe (\>10.0 cm) and Grade 4 (necrosis or exfoliative dermatitis for redness and necrosis for swelling). Pain at injection site was graded as mild (does not interfere with activity), moderate (interferes with activity), severe (prevents daily activity) and Grade 4 (emergency room visit or hospitalization for severe pain).
- Percentage of Participants With Local Reactions Within 7 Days After Dose 2: Phase 1 — Time Frame: Within 7 days after Dose 2
Local reactions included redness, swelling and, pain at the injection site, recorded by participants in an e-diary. Redness and swelling were measured and recorded in measuring device units. 1 measuring device unit =0.5 cm. Redness and swelling were graded as mild (\> 2.0 to 5.0 cm), moderate (\> 5.0 to 10.0 cm), severe (\>10.0 cm) and Grade 4 (necrosis or exfoliative dermatitis for redness and necrosis for swelling). Pain at injection site was graded as mild (does not interfere with activity), moderate (interferes with activity), severe (prevents daily activity) and Grade 4 (emergency room visit or hospitalization for severe pain).
- Percentage of Participants With Systemic Events Within 7 Days After Dose 1: Phase 1 — Time Frame: Within 7 days after Dose 1
Systemic events included fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, new or worsened joint pain recorded by participants or parents/legal guardians of participants using e-diary. Fever=temperature \>=38.0 deg C categorized as \>=38.0 to 38.4, \>38.4 to 38.9, \>38.9 to 40.0 and \>40.0 deg C. Fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain graded as mild (does not interfere with activity), moderate (some interference with activity), severe (prevents daily routine activity), Grade 4 (Emergency room visit/hospitalization). Vomiting: mild (1-2 times in 24 hours\[h\]), moderate (\>2 times in 24 h), severe (requires IV hydration), Grade 4 (emergency room visit/hospitalization for hypotensive shock). Diarrhea: mild (2-3 loose stools in 24h), moderate (4-5 loose stools in 24 h), severe (\>=6 loose stools in 24 h) and Grade 4 (emergency room visit/hospitalization).
- Percentage of Participants With Systemic Events Within 7 Days After Dose 2: Phase 1 — Time Frame: Within 7 days after Dose 2
Systemic events included fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, new or worsened joint pain recorded by participants or parents/legal guardians of participants using e-diary. Fever=temperature \>=38.0 deg C categorized as \>=38.0 to 38.4, \>38.4 to 38.9, \>38.9 to 40.0 and \>40.0 deg C. Fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain graded as mild (does not interfere with activity), moderate (some interference with activity), severe (prevents daily routine activity), Grade 4 (Emergency room visit/hospitalization). Vomiting: mild (1-2 times in 24 h), moderate (\>2 times in 24 h), severe (requires IV hydration), Grade 4 (emergency room visit/hospitalization for hypotensive shock). Diarrhea: mild (2-3 loose stools in 24h), moderate (4-5 loose stools in 24 h), severe (\>=6 loose stools in 24 h) and Grade 4 (emergency room visit/hospitalization).
- Percentage of Participants Reporting Adverse Events From Dose 1 to 1 Month After Dose 2: Phase 1 — Time Frame: From Dose 1 to 1 Month After Dose 2
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. For BNT162b1 100 mcg, participants received one dose of 100 mcg, followed by one dose of 10 mcg.
- Percentage of Participants Reporting Serious Adverse Events From Dose 1 to 6 Months After Dose 2: Phase 1 — Time Frame: From Dose 1 to 6 Months After Dose 2
An SAE was any untoward medical occurrence that occurred, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; was a congenital anomaly/birth defect and other important medical events. For BNT162b1 100 mcg, participants received one dose of 100 mcg, followed by one dose of 10 mcg.
View Secondary Outcome Measures (31)
- Geometric Mean Titers (GMTs) of Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Titers: Phase 1 — Time Frame: 7, 21 days after Dose 1; 7, 14 days and 1, 6 months after Dose 2
GMTs of severe acute respiratory syndrome coronavirus 2 neutralizing titers were reported in this outcome measure. SARS-CoV-2 neutralization assay - NT50 and SARS-CoV-2 neutralization assay - NT90 were evaluated and reported in this outcome measure.
- Geometric Mean Concentrations (GMCs) of Severe Acute Respiratory Syndrome Coronavirus 2: S1-binding and RBD-binding IgG Level Assay: Phase 1 — Time Frame: 7, 21 days after Dose 1; 7, 14 days and 1, 6 months after Dose 2
GMCs of severe acute respiratory syndrome coronavirus S1-binding and RBD-binding IgG level were reported in this outcome measure.
- Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 Neutralizing Titers: Phase 1 — Time Frame: 7, 21 days after Dose 1; 7, 14 days and 1, 6 months after Dose 2
GMFR of SARS-CoV-2 neutralizing titers were reported in this outcome measure. HIV positive participants excluded.
- Geometric Mean Fold Rise (GMFR) of SARS-CoV-2 S1-binding and RBD-binding IgG Level Assay: Phase 1 — Time Frame: 7, 21 days after Dose 1; 7, 14 days and 1, 6 months after Dose 2
GMFR of SARS-CoV-2 S1-binding and RBD-binding IgG level assay in Phase 1 were reported in this outcome measure. HIV positive participants were excluded from this analysis.
- Percentage of Participants Achieving a >= 4-Fold Rise From Before Vaccination to After Vaccination: Neutralizing Titers: Phase 1 — Time Frame: 7, 21 days after Dose 1; 7, 14 days and 1, 6 months after Dose 2
Percentage of participants achieving a \>= 4-fold rise from before vaccination to after vaccination: neutralizing titers in Phase 1 were reported in this outcome measure. HIV positive participants were excluded from this analysis.
- Percentage of Participants Achieving a >= 4-Fold Rise From Before Vaccination to After Vaccination: S1-binding and RBD-binding IgG Level Assay: Phase 1 — Time Frame: From before vaccination to after vaccination
Percentage of participants achieving a \>= 4-fold rise from before vaccination to after vaccination: S1-binding and RBD-binding IgG level assay in Phase 1 were reported in this outcome measure. HIV positive participants were excluded from this analysis.
- GMR Based on Reference Strain NT - Comparison of Participants 12 to 15 Years of Age to Participants 16 to 25 Years of Age- Participants Without Evidence of Infection up to 1 Month After Dose 2 - Dose 2 Evaluable Immunogenicity Population: Phase2/3 — Time Frame: 1 Month After Dose 2
GMR based on reference strain NT, comparison of participants 12 to 15 years of age to participants 16 to 25 years of age of participants without evidence of infection up to 1 month after dose 2 in Phase2/3 were reported in this outcome measure. HIV positive participants were excluded from this analysis.
- Incidence of Asymptomatic SARS-CoV-2 Infection Per 1000 Person Years Follow-up Without Serological or Virological Evidence (Up to Start of Asymptomatic Surveillance Period) of Past Infection: Phase 3 — Time Frame: From start of asymptomatic surveillance (Surveillance time [1000 person-years]: BNT162b2 - 0.383; Placebo - 0.200
Incidence of asymptomatic SARS-CoV-2 infection per 1000 person years follow-up without serological or virological evidence (up to start of asymptomatic surveillance period) of past infection were reported in this outcome measure.
- Incidence of Asymptomatic SARS-CoV-2 Infection Per 1000 Person Years Follow-up Without Serological or Virological Evidence of Past Infection Based on N-binding Antibody Seroconversion: Phase 3 — Time Frame: From Dose 2 to the end of the surveillance period ([1000 person-years]: BNT162b2 - 13.840, Placebo - 6.481)
Incidence of asymptomatic SARS-CoV-2 infection per 1000 person years follow-up without serological or virological evidence of past infection based on N-binding antibody seroconversion were reported in this outcome measure.
- COVID-19 Incidence Per 1000 Person-Years of Follow-up With or Without Evidence of Infection 7 Days After Second Dose of BNT162b2 Based on CDC-Defined Symptoms (Analysis for EUA): Phase 3 — Time Frame: From 7 Days After Dose 2 (Surveillance time [1000 person-years]: BNT162b2 - 2.330, Placebo - 2.343)
COVID-19 incidence per 1000 person years follow-up with or without the evidence of infection were reported in this outcome measure.
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View Official Medical/Scientific Title
A PHASE 1/2/3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLIND, DOSE-FINDING STUDY TO EVALUATE THE SAFETY, TOLERABILITY, IMMUNOGENICITY, AND EFFICACY OF SARS-COV-2 RNA VACCINE CANDIDATES AGAINST COVID-19 IN HEALTHY INDIVIDUALS