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

Abstract Background Breakthrough infections of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are well documented. The current study estimates breakthrough incidence across pandemic waves, and evaluates predictors of breakthrough and severe breakthrough infections (defined as those requiring hospitalization). Methods In total, 89 762 participants underwent longitudinal antibody surveillance. Incidence rates were calculated using total person-days contributed. Bias-corrected and age-adjusted logistic regression determined multivariable predictors of breakthrough and severe breakthrough infection, respectively. Results The incidence was 0.45 (95% confidence interval [CI], .38–.50) during pre-Delta, 2.80 (95% CI, 2.25–3.14) during Delta, and 11.2 (95% CI, 8.80–12.95) during Omicron, per 10 000 person-days. Factors associated with elevated odds of breakthrough included Hispanic ethnicity (vs non-Hispanic white, OR = 1.243; 95% CI, 1.073–1.441), larger household size (OR = 1.251 [95% CI, 1.048–1.494] for 3–5 vs 1 and OR = 1.726 [95% CI, 1.317–2.262] for more than 5 vs 1 person), rural versus urban living (OR = 1.383; 95% CI, 1.122–1.704), receiving Pfizer or Johnson & Johnson versus Moderna, and multiple comorbidities. Of the 1700 breakthrough infections, 1665 reported on severity; 112 (6.73%) were severe. Higher body mass index, Hispanic ethnicity, vaccine type, asthma, and hypertension predicted severe breakthroughs. Conclusions Breakthrough infection was 4–25 times more common during the Omicron-dominant wave versus earlier waves. Higher burden of severe breakthrough infections was identified in subgroups. Incidence of breakthrough SARS-CoV-2 infection after primary series vaccination was estimated for Alpha, Delta, and Omicron waves. Breakthrough infections were common; incidence was highest during Omicron. Higher BMI, Hispanic ethnicity, vaccine type, asthma, and hypertension were predictive of severe breakthrough.