COVID-19 Vaccines Are Still Effective at Reducing Emergency Department Visits, Hospitalizations, and Especially Mortality

In the era of the Omicron variant, previous vaccinations, and previous infections, do COVID-19 vaccines still provide a clinically important benefit?

COVID-19 vaccines remain effective at reducing emergency department visits, hospitalizations, and deaths in this high-quality observational study. Vaccine effectiveness is similar to that of earlier randomized trials. Although the absolute benefit is smaller than at the beginning of the pandemic, the numbers needed to immunize to prevent an event are similar to those seen for respiratory syncytial virus and influenza vaccines. (Level of Evidence = 2b)

The Veterans Affairs researchers identified 164,132 veterans who received the COVID-19 and influenza vaccines on the same day between September 3, 2024, and December 31, 2024, and a second group of 131,839 veterans who only received the influenza vaccine during the same interval. Groups were similar at baseline (possibly because they were willing to get at least one vaccine) with regard to age (mean 72 years), sex (92% were men), tobacco use, frailty, and race. The study authors did additional adjustments using inverse probability weighting for demographics, comorbidities, health care use, and other factors known to be associated with vaccine uptake. This approach is known as a target trial emulation because it uses observational data and statistical adjustment to simulate a clinical trial.

Almost all the COVID-19 vaccines were mRNA vaccines. Patients were followed up for up to 6 months after the date of vaccination to assess for the occurrence of COVID-19–associated emergency department visits, hospitalization, or death. The primary outcome was vaccine effectiveness, which was calculated as 1 minus relative risk. Therefore, a relative risk of 0.35 for mortality equals 65% vaccine effectiveness. Vaccine effectiveness was 29% for emergency department visits (95% CI, 19%–39%), 39% for hospitalization (95% CI, 22%–54%), and 64% for mortality (95% CI, 23%–86%). Because these outcomes are now relatively rare for people infected with COVID-19, the absolute differences and number needed to immunize are less impressive. For hospitalization, the absolute risk reduction was 18.3 fewer per 10,000 people for emergency department visits (number needed to immunize = 546), 7.5 fewer per 10,000 persons for hospitalization (number needed to immunize = 1,333), and 2.2 fewer per 10,000 for mortality (number needed to immunize = 4,545). Vaccine effectiveness was consistent across subgroups by age, chronic diseases, and immunocompromise, although people in these higher-risk groups had greater absolute reductions in these outcomes and, therefore, a smaller number needed to immunize.

Study design: Cohort (prospective)

Funding source: Government

Setting: Outpatient (any)

Reference: 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(16):1612-1623.

Editor’s Note: Dr. Ebell is deputy editor for evidence-based medicine for AFP