Clinical manifestations of COVID-19 breakthrough infections: A systematic review and meta-analysis

J Med Virol. 2022 Sep;94(9):4234-4245. doi: 10.1002/jmv.27871. Epub 2022 Jun 1.


To provide a comparative meta-analysis and systematic review of the risk and clinical outcomes of coronavirus 2019 (COVID-19) infection between fully vaccinated and unvaccinated groups. Eighteen studies of COVID-19 infections in fully vaccinated ("breakthrough infections") and unvaccinated individuals were reviewed from Medline/PubMed, Scopus, Embase, and Web of Science databases. The meta-analysis examined the summary effects and between-study heterogeneity regarding differences in the risk of infection, hospitalization, treatments, and mortality between vaccinated and unvaccinated individuals. he overall risk of infection was lower for the fully vaccinated compared to that of the unvaccinated (relative risk [RR] 0.20, 95% confidence interval [CI]: 0.19-0.21), especially for variants other than Delta (Delta: RR 0.29, 95% CI: 0.13-0.65; other variants: RR 0.06, 95% CI: 0.04-0.08). The risk of asymptomatic infection was not statistically significantly different between fully vaccinated and unvaccinated (RR 0.56, 95% CI: 0.27-1.19). There were neither statistically significant differences in risk of hospitalization (RR 1.06, 95% CI: 0.38-2.93), invasive mechanical ventilation (RR 1.65, 95% CI: 0.90-3.06), or mortality (RR 1.19, 95% CI: 0.79-1.78). Conversely, the risk of supplemental oxygen during hospitalization was significantly higher for the unvaccinated (RR 1.40, 95% CI: 1.08-1.82). Unvaccinated people were more vulnerable to COVID-19 infection than fully vaccinated for all variants. Once infected, there were no statistically significant differences in the risk of hospitalization, invasive mechanical ventilation, or mortality. Still, unvaccinated showed an increased need for oxygen supplementation. Further prospective analysis, including patients' risk factors, COVID-19 variants, and the utilized treatment strategies, would be warranted.

Keywords: COVID-19; Delta variant; breakthrough infection; clinical manifestations; vaccine effectiveness.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • COVID-19 Vaccines
  • COVID-19*
  • Coronavirus Infections*
  • Humans
  • SARS-CoV-2


  • COVID-19 Vaccines

Supplementary concepts

  • COVID-19 breakthrough infections
  • SARS-CoV-2 variants