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Research on COVID-19 mRNA Vaccine Safety in Veterans

August 10, 2022

Takeaway: COVID-19 research conducted by HSR&D investigators examines the safety of mRNA vaccines. They also developed VA hospital metrics to measure the severity of hospitalizations related to COVID-19. In addition, investigators evaluated risk factors for severe breakthrough infections following vaccination for all Veterans who had received an initial COVID-19 vaccination.

Study Supports Safety of mRNA Vaccines

This multicenter retrospective study, conducted by VA and HSR&D investigators, examined the risk of adverse events after COVID-19 vaccination (mRNA) in Veterans with and without a prior history of infection. Investigators identified Veterans who received mRNA vaccines within the VA healthcare system between December 2020 and August 2021: 3,118,802 patients received a first dose and 2,979,326 patients received a second dose, including 102,829 with a history of COVID-19 infection. The primary outcome measure was the daily incidence rate of acute care hospitalization at a VA or non-VA hospital per 100,000 vaccinated patients. Study results show that prior to vaccination, patients with a history of SARS-CoV-2 had higher proportions of mild, moderate, and severe frailty (19%, 10% and 9% respectively) compared to patients with no documented history of prior infection (14%, 6% and 3% respectively). These findings strongly support the safety of mRNA vaccines. The increase in hospitalizations among patients with a history of SARS-CoV-2 was dwarfed by the protection provided against severe COVID-19. As governments and public health organizations develop the optimal schedule for timing and number of doses of SARS-CoV-2 vaccines, it is increasingly important to identify risk factors and comorbidities that maximize immunization safety and protection from severe disease.1

COVID Hospitalization Severity Metrics

Investigators developed metrics for measuring the severity of COVID-19 hospitalizations using national VA data.1 This study found that hospitalization severity dropped dramatically following the availability of COVID-19 vaccinations, and that vaccinated patients hospitalized with a positive SARS-CoV-2 test had lower rates of severe disease than unvaccinated patients. These data were used to inform policy in the state of Massachusetts,2 which incorporated elements of the COVID-19 hospitalization severity metric into state-wide dashboards.

A follow up study evaluated the impact of boosting on hospitalization severity, and found that boosted patients had even lower rates of hospitalization with severe disease than patients with an initial vaccination series.3 This study also found that using a simple metric of “positive SARS-CoV-2 test and hospitalization” underestimates vaccine effectiveness against severe disease.

Risk Factors for Severe COVID-19 Disease

After developing a metric for measuring severe disease, investigators with VA Boston Health Care,  HSR&D’s Center for Healthcare Organization and Implementation Research (CHOIR), and VA’s Cooperative Studies Program (CSP) conducted a nationwide retrospective study and evaluated risk factors for severe breakthrough infections following vaccination for all Veterans who had received an initial COVID-19 vaccination series (within VA) before December 1, 2021 – and who subsequently tested positive for SARS-CoV-2 infection. Severe disease was defined as either death within 28 days or hospitalization with evidence of respiratory failure or hypoxemia. Study findings show that among 110,760 Veterans with breakthrough infections during the study period (December 2020 through February 2022), 10,612 (10%) had severe COVID-19 or died within 28 days of the COVID-19 diagnosis. Risk was reduced among Veterans who had received a booster vaccine or had a history of infection before vaccination, and was lower during the Omicron variant period. Increasing age had the most substantial effect on risk, which rose steadily with increasing age above age 50; risk was especially high in patients above age 80.  Immunocompromising conditions, including receipt of chemotherapy or immunosuppressive drugs, substantially increased risk as did significant comorbidities such as heart failure and chronic obstructive pulmonary disease. These findings could be used to inform outreach efforts for booster vaccinations and to inform clinical decision making about identifying patients who might benefit from pre-exposure prophylaxis and antiviral therapy.4

Westyn Branch-Elliman, MD, MMSc—an HSR&D investigator who participated in the rapid COVID-19 response investigations studies described above—also worked on a study to assess the state-wide Massachusetts Test-to-Stay program. She and her colleagues found that daily, rapid onsite testing is a safe and feasible alternative to mandatory quarantine and can be used. Findings were used to shape national infection control policy recommendations for schools and were implemented in many states nationwide. Follow-up work includes evaluations of the impacts of school closures on BMI increases in children and the impact of asymptomatic surveillance testing in schools on COVID-19 transmission.5,6 Additionally, recently published a commentary discusses the need for additional research into effective communications and messaging strategies to promote vaccine uptake and prevent deaths.7

Follow-up work

Predictive Model to Estimate Risk of Severe COVID-19 Using Near-Real Time Data

Follow-up work is ongoing to develop a predictive model that will use clinical data to estimate the risk of severe disease given specific risk factors. The prediction model will be updated in near real-time with VA clinical data in order to accurately reflect changes in the pandemic context. After development and validation, the tool will be posted on a publicly available website so that patients and providers can assess risk of severe disease given an infection – and then make informed decisions about treatment, repeated vaccine doses, and prophylaxis. This predictive model leverages the national VA electronic health record as a national resource and is a realization of a true “learning healthcare system.”

Factors Associated with The Speed and Scope of Diffusion of COVID-19 Therapeutics in a Nationwide Healthcare Setting: A Mixed Methods Investigation

Limited empiric data are available regarding factors associated with rapid dissemination and diffusion in healthcare. The wealth of VA national data provides an opportunity to evaluate factors associated with the speed and scope of diffusion of practice change. In this national study, investigators found that the adoption of first-in-class therapeutics occurred rapidly and was sustained, after press releases, coverage by traditional and social media outlets, and pre-prints – and prior to peer-reviewed publication and guideline updates. High-quality evidence generated later had a slower rise and lower peak uptake, indicating practice change is harder after a clinical niche has been filled. These data were used to create an adapted Speed and Scope of Diffusion Matrix that can be applied in other settings to predict the speed and spread of novel therapeutics.


The history of the COVID-19 pandemic indicates that these study results will continue to be relevant in future waves of multiple countries with different variants – and in populations with different degrees of immunity from vaccination and/or prior infection. For example, the 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.


  1. Li, L, Zheng C, La J, Do N, Monach PM, Strymish JM, Fillmore NF, Branch-Elliman W. Impact of prior SARS-CoV-2 infection on hospitalization and adverse events following mRNA SARS-CoV-2 vaccination: A nationwide, retrospective cohort study. Vaccine. February 16, 2022;40(8):1082-1089.
  2. Fillmore N, La J, Zheng C, et al. The COVID-19 hospitalization metric in the pre- and post-vaccination eras as a measure of pandemic severity: A retrospective, nationwide cohort study. Infection Control & Hospital Epidemiology. January 11, 2022;1-6.
  3. Corrigan J, La J, Fillmore N, et al. Coronavirus disease 2019 (COVID 19) hospitalization metrics that do not account for disease severity underestimate protection provided by severe acute respiratory coronavirus 2 (SARS-CoV-2) vaccination and boosting: A retrospective cohort study. Infection Control and Hospital Epidemiology. May 2022;23:1-3.
  4. Vo A, La J, Wu J, et al. Factors associated with severe COVID-19 despite vaccination: A nation-wide, retrospective cohort study. Research Square.
  5. Schechter-Perkins E, Doron S, Johnston R, et al. A test-to-stay modified quarantine program for COVID-19 in schools. Pediatrics. May 1, 2022;149(5):e2021055727.
  6. Massachusetts Department of Public Health. Hospitalizations from COVID-19. 2022.
  7. Jones M, Khader K, and Branch-Elliman W. Estimated impact of the US COVID-19 vaccination campaign – Getting to 94% of deaths prevented. JAMA Network Open. July 6, 2022;5(7):e2220391.

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