Phase 1/2/3 trial of BNT162b2, BNT162b1, and BNT162b2SA COVID-19 vaccines in 46,969 healthy individuals

This was a Phase 1/2/3, randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection, and efficacy study in healthy individuals, with an actual enrollment of 46,969 participants. The study consisted of two parts: Phase 1 aimed to identify preferred vaccine candidate(s) and dose level(s), and Phase 2/3 was an expanded cohort and efficacy part. The study evaluated the safety, tolerability, and immunogenicity of three different SARS-CoV-2 RNA vaccine candidates (BNT162b1, BNT162b2, BNT162b2SA) against COVID-19 and the efficacy of one candidate. The vaccine was administered as a 2-dose schedule separated by 21 days, at various dose levels in Phase 1, as a booster, and in three age groups (Phase 1: 18-55 years, 65-85 years; Phase 2/3: ≥12 years, stratified as 12-15, 16-55, or >55 years). The candidate selected for efficacy evaluation in Phase 2/3 was BNT162b2 at a dose of 30 µg. Participants who originally received placebo were offered BNT162b2 at defined points. To assess boostability and potential heterologous protection against emerging SARS-CoV-2 variants of concern (VOCs), an additional 30 µg dose of BNT162b2 was given to Phase 1 participants approximately 6 to 12 months after their second dose of BNT162b1 or BNT162b2. This provided an early assessment of the safety and immunogenicity of a third dose. The assessment of boostability was further expanded in a subset of Phase 3 participants at selected US sites who received a third dose of BNT162b2 at 30 µg or a third and potentially a fourth dose of prototype BNT162b2VOC at 30 µg (BNT162b2SA, based on the South African variant). Another subset of Phase 3 participants received a third, lower dose of BNT162b2 at 5 or 10 µg. To further describe potential homologous and heterologous protection against emerging VOCs, a new cohort of COVID-19 vaccine-naïve participants who had not experienced COVID-19 was enrolled to receive BNT162b2SA as a 2-dose series separated by 21 days. To reflect current and anticipated recommendations for COVID-19 vaccine boosters, participants in C4591001 who met specified recommendations and had not already received one were offered a third dose of BNT162b2 after their second dose. Primary outcomes for Phase 1 included the percentage of participants with local reactions within 7 days after dose 1, the percentage with local reactions within 7 days after dose 2, and the percentage with systemic events within 7 days after dose 1. The study started on April 29, 2020, with primary completion on February 10, 2023, and results were posted on March 25, 2026.

This was a massive, multi-stage effort to find a safe and effective COVID-19 vaccine. The study tested three different RNA vaccine candidates in nearly 47,000 healthy people. The goal was to pick the best formula and the right dose. The research unfolded in phases. First, scientists worked to identify the preferred vaccine candidate and dose. Then, they expanded the study to test how well that chosen vaccine actually worked at preventing COVID-19. The candidate selected for this large-scale efficacy test was called BNT162b2, given as two shots, 21 days apart. The study included people from age 12 up to 85, looking at how the vaccine performed in different age groups. A key part of the research was understanding 'boostability'—whether giving an extra dose months later could strengthen protection, especially against new variants of the virus. To test this, some participants received a third dose of the original vaccine or a version tweaked to target a specific variant. The study also enrolled a new group of people who had never had COVID-19 or a vaccine to test a two-dose series of that variant-targeted shot. Throughout, the study closely tracked local reactions (like pain at the injection site) and systemic events (like fever) after each dose to build a clear picture of safety.