COVID-19 Pandemic
Effectiveness of COVID-19 mRNA Vaccines by Genetic Match to Circulating SARS-CoV-2 Strains — IVY Network, 26 Hospitals, September 2023–April 2025 Kevin C. Ma* Kevin Ma Ma Ma Ma Ma Ma Ma Ma Ma Ma Ma Ma Ma Ma National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA
Background: SARS-CoV-2 has evolved through a combination of gradual accumulation of spike protein mutations and infrequent saltation events, such as the transition from Omicron XBB to JN.1 lineages. Saltation has been associated with decreased vaccine effectiveness (VE) of COVID-19 vaccines but less is known about the impact of gradual spike evolution on VE.
Methods: This multicenter test-negative, case-control VE analysis was conducted using data collected over two seasons (September 13, 2023–April 30, 2025) from 26 hospitals in 20 U.S. states in the IVY Network. Cases in hospitalized adults had COVID-19–like illness and a positive SARS-CoV-2 test with sequencing of clinical specimens; controls in hospitalized adults had COVID-19–like illness but tested negative. Counts of S31 deletions and nonsynonymous mutations in the S1 spike protein domain relative to each season’s vaccine strain were tabulated for each case. Multinomial logistic regression was used to estimate VE stratified by S1 mutation count category after adjusting for age, sex, race and ethnicity, admission date, and U.S. Health and Human Services region.
Results: 2,727 COVID-19 cases with sequencing results and 14,870 controls were enrolled September 2023 to April 2025 (median age = 66 years; 51% female; 58% non-Hispanic White). Circulating SARS-CoV-2 viruses diverged from the vaccine strain over time, with an average increase of one S1 mutation approximately every 81 days. VE against COVID-19–associated hospitalizations was 68% (95% CI, 22%–87%) for SARS-CoV-2 viruses with 0–2 mutations, 49% (23%–67%) for 3 mutations, 45% (23%–60%) for 4 mutations, 44% (13%–64%) for 5 mutations, and 38% (1%–62%) for 6–10 mutations.
Conclusions: During 2023–2025, COVID-19 mRNA vaccines provided protection against hospitalization as SARS-CoV-2 viruses accumulated spike mutations, suggesting some robustness of current mRNA COVID-19 vaccine protection against low to moderate antigenic drift.
