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Publication Briefs

Age and Certain Comorbidities are Risk Factors for Breakthrough COVID-19 Infection with Severe Outcomes among Veterans

"Breakthrough" infections in individuals who have been vaccinated for COVID-19 have been observed since mid-2021 and only increased following the predominance of the omicron variant. Vaccination and boosting offer substantial protection against severe outcomes for most people; however, some who receive vaccinations remain at risk of severe infections that can result in hospitalization and death. Identifying patients who remain at risk after vaccination can help inform efforts to promote booster vaccination – and to guide distribution of antiviral drugs for early treatment or pre-exposure prophylaxis. Therefore, this nationwide, retrospective study sought to identify risk factors associated with severe COVID-19 disease despite vaccination among US Veterans. Secondary aims were to identify and quantify risk factors in subgroups that may have different risk profiles. Using data from December 15, 2020 through February 28, 2022, investigators identified 110,760 vaccinated Veterans who contracted COVID-19. The primary outcome was severe breakthrough infection, defined as death within 28 days or hospitalization with evidence of respiratory failure or hypoxia. Investigators also examined patient comorbidities (i.e., kidney disease, diabetes) and immunosuppressive drug use (i.e., chemotherapy).


  • Among 110,760 Veterans (88% male, mean age 62) with COVID-19 following vaccination, 10,612 (10%) had severe infection and 1,555 died (1%). Increasing age was most strongly associated with severe disease, with risk increasing steadily as Veterans aged (50 years and older). Deaths were rare under age 50 and nearly 60% of deaths occurred in Veterans 75 and older.
  • Immunocompromising medications and conditions and comorbidities indicating chronic heart, lung, kidney, or neurologic damage also increased the risk of having severe disease.
  • Boosting was associated with a decreased risk of severe breakthrough infection (adjusted OR = 0.5) as was COVID infection prior to initial vaccination.


  • Identification of the risk factors for severe breakthrough COVID-19 could be used to guide policies and decision-making about preventive measures for those who remain at risk of disease progression despite vaccination.


  • Missing data could have affected results, such as admission to a non-VA hospital.
  • The analysis necessitated grouping diverse immunosuppressive drugs with very different mechanisms of action.

The study was supported by VA’s Cooperative Studies Program. Dr. Wu is part of VA Palo Alto Healthcare; Drs. Strymish, Ronan, Brophy, Do, Branch-Elliman, Fillmore, and Monach are part of VA Boston Healthcare; and Dr. Branch-Elliman is part of HSR&D’s Center for Healthcare Organization and Implementation Research (CHOIR).

Vo A, La J, Wu J, Strymish J, Ronan M, Brophy M, Do N, Branch-Elliman W, Fillmore N, and Monach P. Factors Associated with Severe COVID-19 among Vaccinated Adults Treated in US Veterans Affairs Hospitals. JAMA Network Open. October 20, 2022;5(10):e2240037.

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What are HSR Publication Briefs?

HSR requires notification by HSR-funded investigators about all articles accepted for publication. These journal articles are reviewed by HSR and publication briefs or summaries are written for a select number of articles that are then forwarded to VHA Central Office leadership to keep them informed about important findings or information. Articles to be summarized are selected by HSR based on timeliness of the findings, interest of leadership, or potential impact on the organization. Publication briefs are written for only a small number of HSR published articles. Visit the HSR citations database for a complete listing of HSR articles and presentations.

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