Safety and Immunogenicity of a Fourth Dose of Omicron BA.1-Adapted BNT162b2 COVID-19 Vaccines in Adults 18-55 Years Old

Clinical Snapshot

Key Findings

• P Value: Not reported in abstract

• Effect Size: Geometric mean fold rises for BA.1 neutralization: 15.4-24.6 across vaccine groups

• Primary Outcome: Safety profile similar to original BNT162b2 with slightly higher local reactions and systemic events for 60 μg monovalent BA.1

• Nnt Or Sensitivity: Substantial neutralizing responses achieved in all vaccine groups with variant-specific enhancement

• Confidence Interval: 95% CI ranges from 12.4-31.4 for BA.1 responses

Clinical Application

Highly feasible given existing mRNA vaccine infrastructure and cold chain capabilities Relevant for TGA consideration of variant-adapted boosters. Aligns with ATAGI recommendations for updated vaccines targeting circulating variants. Cost-effectiveness would need PBS evaluation. Australian adults aged 18-55 years who have received primary COVID-19 vaccination series

Abstract

BACKGROUND: Emergence of severe acute respiratory syndrome coronavirus 2 sublineages warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019. METHODS: In this phase 3 trial, adults 18‒55 years old who had previously received three 30 μg doses of BNT162b2 vaccine were randomized to receive a 60 or 30 μg dose of bivalent Omicron BA.1‒adapted BNT162b2 comprising equal amounts of ancestral and monovalent messenger RNA BA.1 (bivalent BA.1) or a 60 μg dose of monovalent Omicron BA.1‒adapted BNT162b2 (monovalent BA.1). Safety (local reactions, systemic events, adverse events [AEs], and serious AEs) was the primary objective. Exploratory analyses assessed immune responses against Omicron BA.1, BA.4, and BA.5 subvariants and ancestral strain. RESULTS: Among the 1054 randomized participants who received monovalent BA.1 or bivalent BA.1, frequencies of local reactions, systemic events, and AEs were slightly higher with 60 µg monovalent BA.1 than either bivalent BA.1 dose level. One month after vaccination, bivalent BA.1 (30 and 60 μg) and monovalent BA.1 (60 μg) induced substantial neutralizing responses against Omicron BA.1 (50% neutralizing titer geometric mean fold rises [GMFRs], 15.4 [95% CI 12.4-19.2], 17.1 [13.7-21.4], and 24.6 [19.3-31.4], respectively) and ancestral strain (GMFRs, 6.2 [5.1-7.6], 7.3 [6.0-8.9], and 7.0 [5.7-8.7], respectively). In a smaller (n = 30/treatment arm) sentinel cohort, all study vaccines modestly neutralized Omicron BA.4 and BA.5. CONCLUSIONS: Bivalent and monovalent BA.1‒adapted vaccines had a safety profile similar to the original BNT162b2 30 μg and induced substantial neutralizing responses against Omicron BA.1 and ancestral strains. CLINICAL TRIALS REGISTRATION: NCT04955626.

References

1. 1.Winokur, P., Diya, O., Fitz-Patrick, D., Dever, M., Gayed, J., Lockhart, S., Xu, X., Zhang, Y., Bangad, V., Wadsworth, L. T., Cannon, K., Cardona, J. F., Usdan, L., Ginis, J., Mensa, F. J., Zou, J., Xie, X., Lu, C., Buitrago, S., Scully, I. L., Cooper, D., Koury, K., Jansen, K. U., Türeci, Ö., Şahin, U., Swanson, K. A., Gruber, W. C., & Kitchin, N. (2026). Safety and immunogenicity of a fourth dose of Omicron BA.1-adapted BNT162b2 COVID-19 vaccines in adults 18-55 years old. Clinical Infectious Diseases. https://doi.org/10.1093/cid/ciag026