A Bivalent Omicron-BA.4/BA.5-Adapted BNT162b2 Booster in ≥12-Year-Olds

Abstract Background Protection against contemporary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants requires sequence-adapted vaccines. Methods In this ongoing phase 2/3 trial, 12–17-year-olds (n = 108), 18–55-year-olds (n = 313), and >55-year-olds (n = 306) who previously received 3 original BNT162b2 30-µg doses, received a fourth dose (second booster) of 30-µg bivalent original/Omicron-BA.4/BA.5-adapted BNT162b2 (BNT162b2-Omi.BA.4/BA.5). For comparisons with original BNT162b2, participants were selected from another phase 3 trial. Immunologic superiority 1 month after vaccination, with respect to 50% neutralizing titers (lower bound [LB] of 2-sided 95% confidence interval [CI] for geometric mean ratio [GMR], >1), and noninferiority with respect to seroresponse rates (LB of 2-sided 95% CI for rate difference, greater than −5%), for Omicron BA.4/BA.5 were assessed in >55-year-olds versus original BNT162b2 as a second booster. Noninferiority with respect to neutralizing titer level (LB of 2-sided 95% CI for GMR, > 0.67) and seroresponse rate (LB of 2-sided 95% CI for rate difference, greater than −10%) of Omicron BA.4/BA.5 immune response for BNT162b2-Omi.BA.4/BA.5 in 18–55 versus >55-year-olds was assessed. Results One month after vaccination in >55-year-olds, the model-adjusted GMR of Omicron BA.4/BA.5 neutralizing titers for the BNT162b2-Omi.BA.4/BA.5 versus BNT162b2 groups (2.91 [95% CI, 2.45–3.44]) demonstrated the superiority of BNT162b2-Omi.BA.4/BA.5. Adjusted difference in the percentages of >55-year-olds with seroresponse (26.77% [95% CI, 19.59–33.95]) showed noninferiority of BNT162b2-Omi.BA.4/BA.5 to BNT162b2. Noninferiority of BNT162b2-Omi.BA.4/BA.5 in 18–55-year-olds compared with >55-year-olds was met for model-adjusted GMR and seroresponse. Geometric mean titers in 12–17-year-olds increased from baseline to 1 month after vaccination. The BNT162b2-Omi.BA.4/BA.5 safety profile was similar to the profiles for booster doses of bivalent Omicron BA.1-modified BNT162b2 and original BNT162b2 reported in previous studies. Conclusions Based on immunogenicity and safety data up to 1 month after vaccination in participants who previously received 3 original BNT162b2 doses, a BNT162b2-Omi.BA.4/BA.5 30-µg booster has a favorable benefit-risk profile. Clinical Trials Registration NCT05472038 Sequence-adapted vaccines are required to protect against contemporary SARS-CoV-2 variants. In this phase 2/3 trial in ≥12-year-olds who previousl