Receipt of a 2025-2026 COVID-19 vaccine was associated with additional short-term protection against medically attended COVID-19 among immunocompetent adults during the first months of the 2025-2026 respiratory virus season, according to interim data from the CDC-funded VISION Network.

In a test-negative case-control study, researchers estimated vaccine effectiveness at 50% against COVID-19–associated emergency department and urgent care encounters and 55% against COVID-19–associated hospitalization among adults aged 18 years or older.

The study used data from the Virtual SARS-CoV-2, Influenza, and Other Respiratory Viruses Network (VISION), which included 253 emergency department and urgent care (ED/UC) sites and 179 hospitals across 7 US states. Researchers evaluated patients aged 18 years or older who sought care for COVID-19-like illness and underwent SARS-CoV-2 testing from September 3 to December 31, 2025.

Cases were defined as patients with a positive molecular or antigen SARS-CoV-2 test result. Controls were defined as patients with a negative molecular SARS-CoV-2 test result. Vaccine effectiveness was estimated by comparing the odds of 2025-2026 COVID-19 vaccination among cases vs controls, with adjustment for age, sex, race and ethnicity, calendar time, and geographic region.

Vaccination was defined as receipt of a 2025-2026 COVID-19 vaccine at least 7 days prior to the encounter. Researchers excluded patients who received a COVID-19 vaccine less than 7 days prior to their eligible ED/UC encounter or hospitalization, received a 2025-2026 dose less than 2 months following a prior COVID-19 vaccine dose, received more than one 2025-2026 dose, or were immunocompromised.

The 2025-2026 vaccine formulation targeted JN.1 and JN.1-derived sublineages. The US Food and Drug Administration had recommended preferential use of the LP.8.1 strain; Moderna and Pfizer-BioNTech vaccines were based on Omicron LP.8.1, while the Novavax vaccine was based on the JN.1 lineage.

Among 85,725 ED/UC encounters, 3,941 patients tested positive for SARS-CoV-2. A 2025-2026 COVID-19 vaccine had been received by 206 of 3,941 cases and 9,453 of 81,784 controls. Estimated vaccine effectiveness against COVID-19-associated ED/UC encounters was 50%.

Among 26,073 hospitalizations for COVID-19-like illness, 1,022 patients tested positive for SARS-CoV-2. A 2025-2026 COVID-19 vaccine had been received by 60 of 1,022 cases and 3,080 of 25,051 controls. Estimated vaccine effectiveness against COVID-19-associated hospitalization was 55%.

Findings were similar among patients aged 65 years or older. In this group, estimated vaccine effectiveness was 48% against COVID-19-associated ED/UC encounters and 53% against COVID-19-associated hospitalization.

Because median time since dose receipt was 47 days for ED/UC encounters and 46 days for hospitalizations, the findings primarily reflected short-term early-season protection rather than durability across the full respiratory virus season.

The estimates compared patients who received a 2025-2026 COVID-19 vaccine dose with those who did not receive a 2025-2026 dose, regardless of prior COVID-19 vaccination history. The researchers noted that the analysis did not account for previous SARS-CoV-2 infection or earlier COVID-19 vaccine doses, including original monovalent, bivalent, 2023-2024, or 2024-2025 doses. As a result, the estimates should be interpreted as the added benefit of a 2025-2026 dose in a population with high levels of infection-induced immunity, vaccine-induced immunity, or both, rather than as a comparison between vaccinated and immunologically naive patients.

The researchers situated their findings within broader hospitalization burden estimates: COVID-19 was associated with an estimated 390,000 to 550,000 hospitalizations in the US from October 2024 to September 2025, with the highest hospitalization rate among adults aged 65 years or older. Hospitalization rates were lower during the early part of the 2025-2026 respiratory virus season, but the CDC estimated that 99,000 to 180,000 COVID-19-associated hospitalizations had occurred in the US from October 1, 2025, to February 28, 2026.

During the analysis period, the primary circulating SARS-CoV-2 lineages were descendants of Omicron JN.1, including XFG and NB.1.8.1. The researchers noted that increased SARS-CoV-2 circulation shortly prior to the availability of the 2025-2026 vaccines may have increased population-level immunity against JN.1-lineage strains, potentially lowering vaccine effectiveness estimates compared with those expected in a population with less recent infection.

The study had several limitations. Some patients may have sought care at an ED/UC site or hospital for reasons unrelated to COVID-19 despite testing positive for SARS-CoV-2. Vaccination status may have been misclassified, and residual confounding from unmeasured factors, including behavioral modifications to prevent SARS-CoV-2 exposure and outpatient antiviral treatment, may have influenced the findings.

Low COVID-19-associated hospitalization rates and low vaccination rates also limited statistical power, preventing estimation of vaccine effectiveness against critical illness, including intensive care unit admission, invasive mechanical ventilation, and death. These factors also prevented estimates among adults aged 18 to 64 years, pediatric patients, and adults with immunocompromise.

The findings may not be generalizable to all US patients. Data came from 5 VISION sites: HealthPartners, Kaiser Permanente Northern California, Kaiser Permanente Northwest, Regenstrief Institute, and the University of Colorado.

In an accompanying commentary, Natalie Dean, PhD, of Emory Rollins School of Public Health, wrote that the test-negative design remains a practical approach for routine vaccine effectiveness monitoring in the US, where vaccination, outcome, and population data are often dispersed across databases. She noted that the design can help address differences in health care–seeking behavior by using controls who also sought care, but emphasized that observational studies remain vulnerable to confounding and other biases.

Dean also addressed the publication history of the study, noting that it drew attention in April 2026 following a Washington Post report that it had been delayed and then rejected from the CDC Morbidity and Mortality Weekly Report. She wrote that MMWR has historically been used for rapid dissemination of public health findings, including routine vaccine effectiveness estimates from CDC-funded surveillance networks.

"Now is the time to strengthen, not weaken, this infrastructure to support timely public health decision-making," Dean wrote.

Disclosures: The study was supported by CDC contracts to Westat Inc and Kaiser Foundation Hospitals. The CDC, with the VISION Steering Committee and study staff, was involved in the design and conduct of the study; collection, management, analysis, and interpretation of data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication. Several researchers reported stock ownership, grants, contract funding, or other financial relationships involving vaccine manufacturers and research organizations outside the submitted work. Dean reported grants from the National Institutes of Health National Institute of Allergy and Infectious Diseases, the CDC, and Bavarian Nordic; personal fees from Westat, Janssen, International Vaccines Institute, and Emergent Biosolutions; and ongoing CDC collaborations outside the submitted work.

Source: JAMA Network Open