Estimation of mRNA-1283 vs BNT162b2 COVID-19 Vaccine Effectiveness in Older US Veterans

Importance The mRNA-1283 vaccine, a novel mRNA vaccine targeting immunodominant spike regions, was first used during the 2025-2026 respiratory virus season. Older adults remain at elevated risk for severe COVID-19 outcomes, and clinical evidence of estimated vaccine effectiveness can inform seasonal vaccination policy. Objective To compare the estimated effectiveness of mRNA-1283 vs BNT162b2 vaccines against medically attended COVID-19 illness and COVID-19–associated hospitalization among US veterans aged 65 years or older. Design, Setting, and Participants This was a retrospective matched cohort study emulating a target trial. US veterans aged 65 years or older who were enrolled in a national, integrated Veterans Health Administration (VHA) health care system and received an LP.8.1-formulated mRNA-1283 or BNT162b2 vaccine between August 27, 2025, and January 31, 2026, were followed up for up to 150 days or through May 1, 2026. Exposure Receipt of LP.8.1 mRNA-1283 or BNT162b2 vaccine. Main Outcome and Measures The primary outcome was medically attended COVID-19 illness, defined by a positive SARS-CoV-2 test result linked to medical care or antiviral treatment or a primary COVID-19 diagnosis. Matching was performed on home county and calendar week of vaccination, followed by inverse probability of treatment weighting. Secondary outcomes included the individual component event of hospitalization. Measures were absolute and relative differences in 150-day cumulative incidence among patients receiving mRNA-1283 vs BNT162b2 vaccine, computed as the estimated relative vaccine effectiveness (rVE) percentage and absolute risk difference (ARD) per 10 000 persons, adjusted for demographic and clinical factors. Results The cohort included 60 340 mRNA-1283 and 321 845 BNT162b2 vaccine recipients (mean [SD] age, 76.8 [6.7] years; 94.2% male). Among the 294 499 participants in the final matched sample, medically attended COVID-19 occurred in 86 of 55 349 mRNA-1283 vaccine recipients (0.16%) and 672 of 239 150 BNT162b2 vaccine recipients (0.28%), corresponding to estimated rVE of 35.9% (95% credible interval [CrI], 20.4%-49.7%) and an adjusted ARD of −10.0 (95% CrI, −14.3 to −5.6) events per 10 000 persons. COVID-19–associated hospitalization occurred in 11 mRNA-1283 vaccine recipients (0.02%) vs 114 BNT162b2 vaccine recipients (0.05%) (estimated rVE, 47.0% [95% CrI, 5.4%-74.8%]; adjusted ARD, −2.2 [95% CrI, −3.8 to −0.2] events per 10 000 persons). Conclusions and Relevance In this cohort study of older US veterans during the 2025-2026 respiratory virus season, mRNA-1283 vaccination was associated with lower risks of medically attended COVID-19 outcomes and COVID-19 hospitalizations compared with BNT162b2 vaccination. The findings suggest that the mRNA-1283 vaccine may offer more clinically meaningful protection for older adults at high risk of severe COVID-19 outcomes and could inform seasonal vaccine selection.