High-Level Highlights
The latest real-world data from the Investigating Respiratory Viruses in the Acutely Ill (IVY) Network provides critical insights into the performance of the updated 2024-2025 COVID-19 vaccines. Key findings include:
- Vaccine effectiveness (VE) against COVID-19-associated hospitalization was estimated at 40% (95% CI, 27%-51%).
- Protection was significantly higher against the most severe outcomes, reaching 79% (95% CI, 55%-92%) against invasive mechanical ventilation (IMV) or death.
- The vaccines demonstrated sustained durability, with protection against hospitalization remaining stable through 179 days post-vaccination.
- Effectiveness varied by lineage, with higher VE against KP.3.1.1 (49%) compared to XEC (34%) and LP.8.1 (24%), though the latter may be influenced by longer intervals since dose receipt.
Background and Clinical Importance
As SARS-CoV-2 continues its rapid evolutionary trajectory, the JN.1 lineage and its descendants—such as KP.3.1.1, XEC, and LP.8.1—have become the dominant circulating strains. These variants are characterized by specific mutations in the spike protein, including the S31 deletion and various amino acid substitutions (T22N, F59S), which are associated with increased immune evasion. For clinicians and public health officials, the central question remains: do the updated 2024-2025 vaccine formulations provide sufficient protection against severe disease caused by these highly mutated variants?
While early pandemic goals focused heavily on preventing infection, the current clinical priority has shifted toward mitigating the burden of severe disease, hospitalization, and mortality. Evaluating the effectiveness of the 2024-2025 vaccine formula is essential for refining seasonal vaccination strategies and maintaining healthcare system capacity during peak respiratory virus seasons.
Study Design and Methodology
To address these questions, the IVY Network conducted a multicenter, test-negative, case-control study across 26 hospitals in 20 US states between September 1, 2024, and April 30, 2025. The study included 8,493 adult patients (median age 66 years) hospitalized with COVID-19-like illness.
Participant Selection
Case patients (n=1,888) were defined as those with COVID-19-like symptoms who tested positive for SARS-CoV-2 via nucleic acid or antigen testing. Control patients (n=6,605) presented with similar symptoms but tested negative for the virus. Whole-genome sequencing (WGS) was successfully performed on 50.4% of case patient samples to identify specific lineages, including KP.3.1.1, XEC, and LP.8.1.
Exposure and Outcomes
The primary exposure was the receipt of a 2024-2025 COVID-19 vaccine at least seven days prior to the onset of illness. The primary outcomes were COVID-19-associated hospitalization and a composite of severe in-hospital outcomes, including supplemental oxygen therapy, acute respiratory failure, intensive care unit (ICU) admission, and invasive mechanical ventilation or death.
Key Findings: Robust Protection Against Severity
The results underscore a vital clinical message: while the vaccine provides moderate protection against hospitalization, its primary value lies in preventing the most catastrophic clinical outcomes.
Overall Vaccine Effectiveness
The adjusted VE against COVID-19-associated hospitalization was 40% (95% CI, 27%-51%). Notably, when the analysis was restricted to the most severe outcomes—invasive mechanical ventilation or death—the VE rose to 79% (95% CI, 55%-92%). This suggests that even when the vaccine does not prevent hospitalization, it significantly alters the clinical trajectory of the disease, preventing progression to critical illness.
Durability of Protection
One of the most encouraging findings was the durability of the immune response. Protection against hospitalization was sustained through the 90-to-179-day window post-vaccination. This provides reassurance that a single seasonal dose can offer protection throughout the traditional winter surge of respiratory viruses.
Lineage-Specific Performance
The study allowed for a granular look at how the vaccine performed against specific JN.1 descendants:
- KP.3.1.1: VE was 49% (95% CI, 25%-67%).
- XEC: VE was 34% (95% CI, 4%-56%).
- LP.8.1: VE was 24% (95% CI, -19% to 53%).
It is important to interpret the lower VE for LP.8.1 with caution. The median time since dose receipt for patients with LP.8.1 was 141 days, compared to 60 days for KP.3.1.1. This suggests that the observed differences in lineage-specific VE may be partially confounded by the natural waning of immunity over time rather than just the mutations themselves.
Expert Commentary and Clinical Implications
The findings from this study reinforce the current CDC and public health recommendations for annual COVID-19 vaccination, particularly for older adults and those with underlying clinical vulnerabilities. The 79% effectiveness against critical illness is a powerful metric for clinicians to share with vaccine-hesitant patients who may feel that “getting the shot doesn’t stop the virus.”
Biological Plausibility
The consistency of VE across lineages containing the S31 deletion and other substitutions (37%-41%) suggests that the 2024-2025 vaccine formula induces a sufficiently broad polyclonal antibody response and T-cell activation to recognize conserved epitopes on the spike protein, even as the virus attempts to evade neutralizing antibodies.
Study Limitations
Despite the robust multicenter design, several limitations exist. The test-negative design, while standard, can be subject to selection bias if healthcare-seeking behavior differs between vaccinated and unvaccinated individuals. Additionally, the sample size for specific lineages like LP.8.1 resulted in wider confidence intervals, limiting the precision of those specific estimates. Lastly, the study focused on hospitalized adults, so these findings may not generalize to mild or asymptomatic infections in the community.
Summary for Practice
The 2024-2025 COVID-19 vaccines are an effective tool for preventing severe disease and death in the face of an evolving viral landscape. For the clinical community, these data support the continued push for seasonal vaccination. While the virus continues to drift, the vaccine’s ability to keep patients out of the ICU and off ventilators remains its most critical attribute.
Funding and Reference
This study was supported by the Centers for Disease Control and Prevention (CDC). The IVY Network is a collaborative effort involving multiple academic medical centers and the CDC.
Reference: Ma KC, Webber A, Lauring AS, et al. Estimated Effectiveness of 2024-2025 COVID-19 Vaccination Against Severe COVID-19. JAMA Netw Open. 2026;9(2):e2557415. doi:10.1001/jamanetworkopen.2025.57415.
