2024-2025 COVID-19 Vaccine Effectiveness Against Severe Disease

Key Takeaways

• Updated vaccination was associated with lower odds of COVID-19-associated hospitalization in immunocompetent adults and with higher effectiveness estimates for the most severe in-hospital outcome, especially invasive mechanical ventilation or death.
• Protection remained evident through 90 to 179 days after vaccination, and estimates were also reported for older immunocompetent and immunocompromised adults.
• Lineage-specific estimates were reported for KP.3.1.1, XEC, and LP.8.1, and similar estimates were observed for the selected spike-mutation patterns assessed, with continued monitoring emphasized.

The analysis covered adults admitted across a multistate US hospital network during the 2024-2025 season. Overall, estimated vaccine effectiveness suggested protection against COVID-19-associated hospitalization and severe in-hospital outcomes in this cohort.

This multicenter IVY Network test-negative case-control study enrolled adults aged 18 years or older hospitalized from September 1, 2024, through April 30, 2025, at 26 hospitals in 20 US states. The IVY Network analysis in JAMA Network Open included 8493 adults, with 1888 case patients and 6605 control patients. Updated vaccination was defined as receipt of BNT162b2, mRNA-1273, or NVX-CoV2705 at least 7 days before illness onset, verified by hospital records, immunization systems, or patient or proxy interviews. Case patients tested positive for SARS-CoV-2, while control patients had COVID-19-like illness but negative SARS-CoV-2 results. Outcomes were COVID-19-associated hospitalization and severe in-hospital events, including supplemental oxygen therapy, acute respiratory failure, ICU admission, and invasive mechanical ventilation or death.

Among immunocompetent adults, estimated effectiveness against hospitalization was 34% (95% CI, 14%-49%) at 7 to 89 days after vaccination and 52% (95% CI, 34%-65%) at 90 to 179 days. The overall hospitalization analysis included 6131 immunocompetent adults, with subgroup analyses of 3450 immunocompetent and 1199 immunocompromised adults aged 65 years or older. Effectiveness was 45% (95% CI, 31%-56%) among immunocompetent adults aged 65 years or older and 36% (95% CI, 6%-57%) among immunocompromised adults aged 65 years or older. Protection remained evident through 90 to 179 days, with measurable estimates in older immunocompetent and immunocompromised adults.

Among immunocompetent adults, effectiveness against supplemental oxygen therapy was 46% (95% CI, 31%-59%), and effectiveness against acute respiratory failure was 49% (95% CI, 22%-68%). Effectiveness reached 60% (95% CI, 36%-77%) for ICU admission and 79% (95% CI, 55%-92%) for invasive mechanical ventilation or death. Among case patients, 1077 received supplemental oxygen, 361 had acute respiratory failure, 333 entered the ICU, and 162 received invasive ventilation or died. Investigators assessed these in-hospital outcomes from admission through discharge, death, or hospital day 28. Point estimates increased with greater in-hospital severity.

Whole-genome sequencing was successful for 951 case specimens collected from hospitalized adults with COVID-19. Estimated effectiveness against lineage-specific hospitalization was 49% (95% CI, 25%-67%) for KP.3.1.1, 34% (95% CI, 4%-56%) for XEC, and 24% (95% CI, -19% to 53%) for LP.8.1. Estimates were 41% (95% CI, 22%-56%) for strains with the S31 deletion and 37% (95% CI, 9%-57%) for strains with T22N and F59S substitutions.

Researchers noted that LP.8.1 estimates could reflect waning or immune evasion, precision fell beyond 180 days, the number or timing of prior SARS-CoV-2 infections or vaccinations was not adjusted for, lineage identification was incomplete, generalizability was limited, and residual confounding remained. The authors concluded that continued monitoring of effectiveness by lineage and spike mutation remains important for vaccine composition and recommendations.