COVID-19 Vaccine Shows Significant Protection Against MACE in Veterans 75 or Older

Secondary Analysis Finds the Effect on All-Cause CV Events Especially Beneficial

ST. LOUIS — Past research has demonstrated that receipt of vaccines was associated with reduced COVID-19–associated cardiovascular risk. A new study took that a step further, finding evidence of vaccine effectiveness against the broader outcome—all-cause major adverse cardiovascular events (MACEs), suggesting that “likely reflects the hidden burden of undetected SARS-CoV-2 and associated complications that are amenable to reduction by COVID-19 vaccination.”

The cohort study led by the VA St Louis Health Care System and Washington University School of Medicine, both in St Louis, included slightly more than 1 million veteran participants. It found that the 2024-2025 COVID-19 vaccine was associated with a lower risk of COVID-19–associated MACE, with greater risk reductions among those 75 years or older and those with comorbidities. In addition, the researchers report that secondary analyses of all-cause MACE showed substantially larger absolute risk reductions.

Results were published in JAMA Internal Medicine.¹

One issue was whether reductions in COVID-19–associated MACEs were affected by evolving COVID-19 variants and widespread population immunity.

The cohort study was a target-trial emulation using VA electronic health records; included were veterans with vaccination encounters between Sept. 3, 2024, and Dec. 31, 2024. Participants had either same-day coadministration of the 2024-2025 COVID-19 and influenza vaccines vs. influenza vaccine alone.

The main outcome was defined as the composite end point of COVID-19–associated MACE, which included COVID-19–associated cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Secondary outcomes included all-cause MACE, hospitalization and death.

The study team estimated vaccine effectiveness (VE), calculated as 1 minus the risk ratio, and risk difference at 8 months, using inverse probability weighting.

The veterans had a median age of 70.1, and 91.8% were men. Of those, 349,085 received COVID-19 vaccination and 690 574 did not. At 8 months, results indicated that the COVID-19 vaccine was associated with lower risk of COVID-19–associated MACE (VE, 37.7% [95% CI, 18.2%-54.9%]; risk difference per 10 000 persons, 2.0 [95% CI, 0.9-3.7]).

The authors pointed out that VE for COVID-19−associated MACE was statistically significant only in those older than 75 years (VE, 50.7% [95% CI, 31.8%-65.6%]), a group that also experienced the largest absolute risk reduction (5.5 fewer events per 10 000 individuals). No statistically significant vaccine effectiveness was observed among those younger than 65 years or aged 65 to 75 years.

“While VE for COVID-19−associated MACE on the relative scale was statistically significant across subgroups of participants with and without comorbid health conditions, the absolute benefit was consistently and substantially greater for individuals with the comorbid health condition,” the researchers explained. Secondary analyses of all-cause MACE, all-cause hospitalization, and all-cause death suggested substantially larger absolute risk reductions (risk difference for all-cause MACE, 23.7 [95% CI, 14.1 to 34.7]).

“While the reduction in COVID-19–associated MACE was modest, the substantially larger reduction in all-cause MACE suggests that the vaccine’s protective association extends to the hidden burden of undetected SARS-CoV-2 and its sequelae,” the researchers explain.

In an accompanying editorial, Robert M. Califf, a cardiologist now at Duke University School of Medicine in Durham, NC, who served as the 25th Food and Drug Administration head from 2016 to 2017 and again from 2022 to 2025, questioned if the VA database could be used to answer questions that continue to feed vaccine hesitancy in the United States.²

“Despite questions regarding the applicability of findings based on VA system data to the general population, the VA database could be used to provide more detailed quantitative information about the balance of benefit and risk for the vaccines, including specific cardiovascular complications,” he suggested.

That is important, according to Califf, because “the politicization of COVID-19 vaccination and messenger RNA vaccines in general has taken a toll on the longevity and functional status of those in the U.S. Many have eschewed vaccination and experienced death or disability because of a commonly held view that COVID-19 vaccines’ risks outweigh their benefits, coupled with lingering rhetoric that continues to erode confidence in the benefits of vaccination more generally.”

Background information in the study advised that SARS-CoV-2 infection is linked to an increased risk of major adverse cardiovascular events (MACEs) that can extend far beyond the acute phase. “Multiple studies documented substantial increases in incident cardiovascular disease including myocardial infarction, ischemic stroke, heart failure and cardiovascular death, with the highest relative risks occurring in the first week after diagnosis before attenuating over subsequent months,” the authors wrote.

Despite several studies demonstrating that the COVID-19 vaccination reduces cardiovascular risk, they added, “the epidemiologic and immunologic landscape of 2024-2025 is profoundly different. SARS-CoV-2 virus has evolved over the years, with contemporary variants potentially exhibiting reduced pathogenicity and cardiovascular risk. Simultaneously, population immunity has changed due to repeated infections and prior vaccinations, altering the background risk of severe clinical outcomes after SARS-CoV-2 infection. These factors create substantial uncertainty regarding whether protective cardiovascular benefits of vaccination in prior years persist in the current epidemiologic landscape.”

While widespread hybrid immunity from vaccination and infection has led to an overall reduction in COVID-19 morbidity and mortality, “our study findings show that vaccination continues to provide protection against associated cardiovascular outcomes,” the study team explains. “The magnitude of this vaccine effectiveness, however, is lower than estimates from the early phase of the vaccine rollout. The reduced effectiveness (compared to earlier studies) is likely driven by various factors including changes in SARS-CoV-2, residual immunity from prior infections and immunizations, and decline in testing practices that limit detection of SARS-CoV-2–associated events, allowing underestimation of vaccine effectiveness.”

The authors posit that potential mechanisms that could explain COVID-19 vaccine effectiveness against cardiovascular outcomes include (1) the reduction in severity of SARS-CoV-2 infection with downstream mitigation of infection-triggered endothelial injury, inflammation, and (2) thromboinflammation, pathways associated with COVID-19–related cardiovascular events.¹

While the effects of the primary analysis showed modest benefits in those younger than 75, the secondary analyses of all-cause MACE, hospitalization and death—conducted to capture the total vaccine-mediated benefit, including possible protection against events associated with undiagnosed or untested infections—had some important ramifications.

“While the relative association with all-cause outcomes is naturally attenuated by the inclusion of the uninfected population, the absolute risk reduction was substantially larger than in the primary analysis,” according to the researchers.

“Whereas the reduction in confirmed COVID-19–associated MACE was modest (estimated at 2.0 events per 10,000 persons), the reduction in all-cause MACE was approximately 24 events per 10,000 (risk difference, 23.7 [95% CI, 14.1 to 34.7]), alongside reductions of 30 hospitalizations and 16 deaths per 10,000 vaccinated individuals.”

They noted that extrapolating those estimates to a population of 1 million people, “vaccination could plausibly be associated with averting approximately 2.370 MACE events and 1,580 deaths over an 8-month period. While these extrapolations should be interpreted with caution given the observational nature of the data, they underscore the broader population-level impact of the COVID-19 vaccine on cardiovascular health.”

The study concluded that findings of the secondary analysis “suggest that the vaccine’s benefit extends well beyond clinically confirmed COVID-19–associated sequelae by mitigating the substantial burden of events precipitated by undiagnosed SARS-CoV-2 infection that are missed by disease-specific surveillance.”

 

1. Cai M, Xie Y, Al-Aly Z. 2024-2025 COVID-19 Vaccine and Major Adverse Cardiovascular Events Among US Veterans. JAMA Intern Med. Published online June 15, 2026. doi:10.1001/jamainternmed.2026.1929
2. Califf RM. Updated COVID-19 Vaccine Boosters—The Message From Data Is Consistent but Not Getting Through. JAMA Intern Med. Published online June 15, 2026. doi:10.1001/jamainternmed.2026.1945