COVID-19 Vaccine Receipt Was Associated with Better Clinical Outcomes in U.S. Veterans
December 30, 2025
By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Synopsis: An observational study from the Department of Veterans Affairs found that individuals who received the 2024-2025 COVID-19 vaccine and the influenza vaccine on the same day had fewer emergency department visits, COVID-19-associated hospitalizations, and deaths related to COVID-19 compared to a group that only received the influenza vaccine.
Source: Cai M, Xie Y, Al-Aly Z. Association of 2024-2025 Covid-19 vaccine with Covid-19 outcomes in U.S. veterans. N Engl J Med. 2025;393:1612-1623.
The development of the messenger ribonucleic acid (mRNA) vaccine against SARS-CoV-2 was a major milestone in humanity’s long struggle against infectious disease. The vaccine has proven to be highly effective against symptomatic COVID-19 disease and for protecting against severe infection. Unfortunately, the public has become complacent about the COVID-19 vaccine since the height of the pandemic. By late December 2024, only 21% of adults in the United States had received the 2024-2025 COVID-19 vaccine. Cai and colleagues sought to obtain up-to-date evidence for the continued effectiveness of the COVID-19 vaccine to inform vaccine policy determinations.
The study was an observational cohort analysis that compared the effectiveness of receiving the 2024-2025 COVID-19 vaccine concurrently with the seasonal influenza vaccine on the same day to only receiving the influenza vaccine. Patients were eligible to be included who were at least 18 years of age, had at least one primary care physician (PCP) visit within the Veterans Affairs (VA) system in the 18 months prior to vaccination, received their COVID-19 vaccine in the VA system between Sept. 3, 2024, and Dec. 31, 2024, and also had received at least one dose of the 2023-2024 COVID-19 vaccine in the VA system. Patients were excluded who did not receive the influenza vaccine, who received a COVID-19 vaccine within 90 days of study enrollment, or who tested positive for SARS-CoV-2 or influenza within 90 days of enrollment.
There were three primary outcomes for the study. These included having a COVID-19 emergency department (ED) visit, a hospitalization resulting from COVID-19, or a death attributed to COVID-19. A COVID-19-related death was defined as death that occurred within 30 days after a positive COVID-19 test result. The follow-up period was six months.
There were 164,132 patients in the dual vaccine group and 131,839 in the influenza vaccine-only group. The patient demographics were similar for both groups. At six months of follow up, compared to receipt of influenza vaccine alone, those who received COVID-19 vaccine had a lower risk of COVID-19-associated ED visits (vaccine effectiveness, 29.3%; 95% confidence interval [CI], 19.1 to 39.2). Furthermore, they had a lower risk of COVID-19-associated hospitalization (vaccine effectiveness, 39.2%; 95% CI, 21.6 to 54.4) and COVID-19-associated death (vaccine effectiveness, 64.0%; 95% CI, 23.0 to 85.8). Vaccine effectiveness against a composite of all three outcomes was 28.3% (95% CI, 18.2 to 38.2). Subgroup analysis based on age (< 65 years, 65 to 75 years, and > 75 years) and the presence or absence of major comorbid conditions, including immune compromise, found that COVID-19 vaccination was effective for all three primary endpoints. Overall vaccine effectiveness waned over six months, from 37.1% at day 1 to 21.4% by day 180.
Commentary
The development and implementation of mRNA COVID-19 vaccines was a triumph for biomedical science, reducing the rate of severe disease by approximately 90%. Unfortunately, misinformation and deliberate government decisions are undermining public trust in these valuable tools. The study by Cai and colleagues found that the COVID-19 vaccine was associated with a decreased risk of adverse clinical outcomes in U.S. veterans. It is a valuable addition to the growing body of evidence that COVID-19 vaccines remain effective and crucial for improving public health.
Vaccine effectiveness waned over the six-month follow-up of the study. The mechanisms of COVID-19 vaccine waning are not fully understood. Indeed, it has been hypothesized that waning efficacy contributes to disease surges in the summer. Further studies are needed on methods to enhance the durability of the vaccine’s protection.
The authors attempted to assess for unmeasured confounding variables by using E values, which quantify the minimum strength of association an unmeasured confounding variable would require with both the exposure and outcome to nullify a study’s result. In observational studies, a higher E value indicates that the result is more resistant to confounding because a very powerful unmeasured confounder would be needed to explain away the findings. The E values for the study were > 1.7, indicating a low likelihood that an independent residual confounder was present.
The study had a few limitations. First, since it was conducted using electronic medical records from the VA, the demographic composition of the cohort (primarily older, white, and male) may limit the generalizability of the results. Second, there was no way for the investigators to adjust for differences in behaviors that affect the risk of acquiring COVID-19. For example, patents who received the COVID-19 vaccine may have tried harder to avoid exposure to COVID-19. Third, it was an observational study, which can suggest correlation but cannot prove causality. Finally, the investigators did not provide any data on adverse events from either the COVID-19 or influenza vaccines.
The COVID-19 vaccine has saved millions of lives and reduced an immense amount of human suffering. Thus, the study by Cai and colleagues is a reminder that the COVID-19 vaccine remains an important intervention for U.S. veterans, many of whom are older with chronic medical conditions, as well as the U.S. public at large.
Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC, is Professor of Medicine, Division of Infectious Diseases, Northeast Ohio Medical University, Rootstown, OH.