The 2024-25 COVID-19 vaccine was an estimated 40% effective against hospital admission and 79% effective against invasive mechanical ventilation (IMV) or death, with similar efficacy against the KP.3.1.1 and XEC variants, although with considerable uncertainty, researchers from the US Centers for Disease Control and Prevention (CDC) reported yesterday in JAMA Network Open.
The investigators conducted a test-negative case-control study involving 1,888 adults who tested positive for COVID-19 and 6,605 uninfected peers (controls) to determine the vaccine’s efficacy against hospitalization and IMV or death by time since the last dose, variant, and spike protein mutations that allow the virus to skirt the immune system.
Participants in the multicenter Investigating Respiratory Viruses in the Acutely Ill Network included adults hospitalized for COVID-like illness from September 2024 to April 2025 at 26 hospitals in 20 states.
The main outcomes of interest were COVID-related hospital admission and severe in-hospital outcomes, including the need for supplemental oxygen, acute respiratory failure, intensive care unit (ICU) admission, and the need for IMV or death.
Protection stayed steady for 6 months
The median patient age was 66 years, and 51.1% were women. Of the 1,888 case-patients, 11.4% had received a COVID vaccine, as had 18.5% of the 6,605 controls. Of the 50.4% of COVID-19 patients who underwent whole-genome sequencing, 36.6% were infected with KP.3.1.1, 22.9% with XEC, and 14.1% with LP.8.1.
Vaccine effectiveness (VE) against COVID-related hospitalization was 40% (95% confidence interval [CI], 27% to 51%) through 90 to 179 days (about 6 months) post-vaccination. VE was higher against IMV or death, at 79% (95% CI, 55% to 92%).
The vaccine was 49% (95% CI, 25% to 67%) against hospitalization with KP.3.1.1, 34% (95% CI, 4% to 56%) against XEC, and among vaccinated case-patients due to sequential circulation patterns (60, 89, and 141 days, respectively). The VE against lineages with spike protein mutations that enable them to evade immunity was 41% (95% CI, 22% to 56%) for the S31 deletion and 37% (95% CI, 9% to 57%) for T22N and F59S substitutions.
Of 6,131 adults with healthy immune systems (immunocompetence), VE against hospitalization was 40% (95% CI, 27% to 51%), with a median time since vaccination of 80 days among case patients and 108 days in controls. The VE was 34% (95% CI, 14% to 49%) 7 to 89 days after vaccination and 52% (95% CI, 34% to 65%) at 90 to 179 days.
Among 3,450 immunocompetent adults 65 years or older, VE was 45% (95% CI, 31% to 56%) overall, 44% (95% CI, 25% to 59%) 7 to 89 days after vaccination, and 51% (95% CI, 31% to 66%) 90 to 179 days post-vaccination.
VE against severe outcomes among immunocompromised adults aged 65 years or older was 36% (95% CI, 6% to 57%), with a median time since vaccine receipt of 79 days in case-patients and 106 days for controls.
VE against death higher than that against hospital stay
Of the 1,888 case patients, 57.0% required supplemental oxygen, 19.1% experienced acute respiratory failure, 17.6% were admitted to an ICU, and 8.6% needed IMV or died. The VE for immunocompetent adults was 46% (95% CI, 31% to 59%) against the need for supplemental oxygen, 49% (95% CI, 22% to 68%) against acute respiratory failure, 60% (95% CI, 36% to 77%) against ICU admission, and 79% (95% CI, 55% to 92%) against IMV or death.
During a season without major antigenic changes to circulating SARS-CoV-2 viruses, we found sustained protection from COVID-19 vaccines through at least 90 to 179 days after vaccination.
Point estimates rose with more severe outcomes, and VE against IMV or death was significantly higher than that against hospital admission (difference in VE estimates, 39%). Estimates were comparable for immunocompetent adults 65 years or older, though VE wasn’t significantly different between in-hospital outcomes and hospitalization.
“During a season without major antigenic changes to circulating SARS-CoV-2 viruses, we found sustained protection from COVID-19 vaccines through at least 90 to 179 days after vaccination,” the authors wrote. “In June 2025, the Food and Drug Administration recommended monovalent JN.1 lineage–based COVID-19 vaccines, preferentially using the LP.8.1 strain, for 2025-2026 COVID-19 vaccine formulations.”
Despite its efficacy and the recommendation for all adults aged six months or older, uptake of the 2024-25 COVID vaccine was suboptimal, at 23% overall and 44% among adults aged 65 years or older, the authors noted.
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