COVID-19 Breakthrough Infection Incidence Highest During Omicron Wave

COVID-19 breakthrough infection incidence was highest during the Omicron wave; predictors of severe breakthrough infection included Hispanic ethnicity, obesity, asthma, and hypertension.

COVID-19 breakthrough infection incidence after primary series vaccination was found to be significantly increased during the Omicron wave compared with previous variant-specific waves, according to study results published in The Journal of Infectious Diseases.  

In this ongoing, prospective, population-based sub-study, researchers estimated the incidence and determined significant predictors of COVID-19 breakthrough infection across variant-specific waves. Included participants (N=22,575) were aged 20 years and older at enrollment. Data on infection- and vaccine-induced antibody body status were captured via online questionnaires. Multivariable logistic lasso regression with 5-fold cross-validated regularization was used to evaluate sociodemographic-, behavioral-, and comorbidity-related predictors of COVID-19 breakthrough infection.

Among participants included in this sub-study, 1700 (7.53%) experienced breakthrough infection, with the highest incidence (per 10,000 person-days) occurring during the Omicron wave (incidence rate [IR], 11.2; 95% CI, 8.80-12.95). The incidence of breakthrough infection was comparatively lower during both the pre-Delta (IR, 0.45; 95% CI, 0.38-0.50) and Delta (IR, 2.8; 95% CI, 2.25-3.14) waves.

Factors associated with increased COVID-19 breakthrough infection risk were as follows:

  • Receipt of BNT162b2 (odds ratio [OR], 1.266; 95% CI, 1.138-1.408) or Ad26.COV2.S (OR, 1.496; 95% CI, 1.248-1.792) vs mRNA-1273;
  • Urban vs rural geographic location (OR, 1.383; 95% CI, 1.122-1.704);
  • Daily or limited vs no face-to-face work interactions (OR,2.980; 95% CI, 2.311-3.841); and
  • Hispanic vs non-Hispanic White ethnicity (OR, 1.243; 95% CI, 1.073-1.441).

Comorbidities found to be independently associated with increased breakthrough infection risk included asthma (OR, 1.180; 95% CI, 1.021-1.365), chronic hypertension (OR, 1.233; 95% CI, 1.088-1.397), and immunocompromised status (OR, 1.432; 95% CI, 1.179-1.739).

Further analysis was performed among 1665 participants who reported data on infection severity to determine age-adjusted predictors of severe breakthrough infection. Among these patients, those with a BMI suggestive of obesity had an increased risk for severe breakthrough infection (OR, 2.211; 95% CI, 1.30-3.702).

Future research should focus on breakthrough incidence rates across variants and new variants for which we have not yet had sufficient follow-up time, such as Omicron BA.2.

The remaining results were similar between these participants and the overall cohort, with vaccine type (Ad26.COV2.S vs mRNA-1273), ethnicity (Hispanic vs non-Hispanic White), and the presence of multiple comorbidities (asthma, hypertension, and obesity) associated with increased risk for severe breakthrough infection.

Limitations of this study include potential selection bias and limited generalizability, as well as the inclusion of only participants who developed breakthrough infection within 6 months following primary series vaccination.

According to the researchers, “Future research should focus on breakthrough incidence rates across variants and new variants for which we have not yet had sufficient follow-up time, such as Omicron BA.2.” 


DeSantis SM, Yaseen A, Hao T, et al. Incidence and predictors of breakthrough and severe breakthrough infections of SARS-CoV-2 after primary series vaccination in adults: a population-based survey of 22,575 participants. J Infect Dis. Published online, February 2, 2023. doi:10.1093/infdis/jiad020