Rate and Risk Factors for Severe/Critical Disease Among Fully Vaccinated Persons With Breakthrough Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection in a High-Risk National Population

Clin Infect Dis. 2022 Aug 24;75(1):e849-e856. doi: 10.1093/cid/ciab1023.


Background: Breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections after vaccination have been reported. Outcomes among persons with breakthrough infection are poorly understood.

Methods: We identified all veterans with a confirmed SARS-CoV-2 infection >14 days after the second dose of an mRNA vaccine between 15 December 2020 and 30 June 2021 and propensity score-matched unvaccinated controls with SARS-CoV-2 infection. The primary outcome was severe/critical disease, defined as admission to an intensive care unit, need for mechanical ventilation, or death within 28 days of diagnosis or during index hospitalization.

Results: Among 502 780 vaccinated and 599 974 unvaccinated persons, there were 2332 (0.5%) breakthrough infections in the vaccinated group and 40 540 (6.8%) infections in the unvaccinated group over a follow-up period of 69 083 person-days in each group. Among these groups, we identified 1728 vaccinated persons with breakthrough infection (cases) and 1728 propensity score-matched unvaccinated controls with infection. Among the former, 95 (5.5%) persons met the criteria for severe/critical disease, while 200 (11.6%) persons met the criteria among the latter group. The incidence rate for severe/critical disease per 1000 person-days (95% confidence interval [CI]) was .55 (.45-.68) among vaccinated persons with breakthrough infection and 1.22 (1.07-1.41) among the unvaccinated matched controls who developed infection (P < .0001). Risk was higher; the hazard ratio (95% CI) with increasing age per 10-year increase was 1.25 (1.11-1.41); for those with >4 comorbidities, it was 2.85 (1.49-5.43), while being vaccinated was associated with strong protection against severe/critical disease (HR, 0.41; 95% CI: .32-.52).

Conclusions: The rate of severe/critical disease is higher among older persons and those with >4 comorbidities but lower among fully vaccinated persons with breakthrough infection compared with unvaccinated controls who develop infection.

Keywords: SARS-CoV-2; breakthrough infection; outcomes; vaccination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • COVID-19* / epidemiology
  • COVID-19* / prevention & control
  • Hospitalization
  • Humans
  • Risk Factors
  • SARS-CoV-2*
  • Vaccination
  • Vaccines, Synthetic
  • mRNA Vaccines


  • Vaccines, Synthetic
  • mRNA Vaccines