2024-2025 COVID-19 Vaccine Effectiveness Against Hospitalization and Severe Outcomes

A multicenter test-negative, case-control analysis conducted by the IVY Network evaluated the effectiveness of the 2024–2025 COVID-19 vaccines among 8,493 adults hospitalized across 26 U.S. hospitals in 20 states between September 1, 2024 and April 30, 2025.

The study provides contemporary estimates of vaccine impact on COVID-19–associated hospitalization and severe in-hospital outcomes during a season dominated by evolving JN.1 descendant lineages.

Overall vaccine effectiveness (VE) against COVID-19–associated hospitalization was 40% (95% CI, 27%–51%), with protection sustained through 90–179 days after vaccination. Protection was substantially higher against the most severe in-hospital outcome: VE against the composite of invasive mechanical ventilation (IMV) or death was 79% (95% CI, 55%–92%), significantly exceeding protection against hospitalization alone. VE estimates increased stepwise with clinical severity, including protection against supplemental oxygen use, acute respiratory failure, and ICU admission.

Subgroup analyses demonstrated lower VE point estimates in older adults and in immunocompromised patients, indicating meaningful residual risk of hospitalization and early clinical deterioration despite vaccination. Among immunocompromised adults aged 65 years or older, VE against hospitalization was 36% (95% CI, 6%–57%), with wide confidence intervals reflecting limited precision. These findings suggest that hospital bed utilization and early escalation of care may remain concentrated in older and immunocompromised populations, even as vaccination substantially reduces progression to IMV or death among those admitted.

Lineage-specific analyses based on whole-genome sequencing showed comparable VE against hospitalization due to KP.3.1.1 and XEC lineages in the early postvaccination period, while estimates against LP.8.1 were lower and imprecise, coinciding with longer time since vaccination. Overall, the findings indicate that the 2024–2025 COVID-19 vaccines provided consistent protection against severe disease across multiple JN.1 descendant lineages, reinforcing their role in mitigating the most catastrophic hospital outcomes during the 2024–2025 season.