Incidence and Risk Factors of COVID-19 Vaccine Breakthrough Infections: A Prospective Cohort Study in Belgium

Abstract

The objective of this study was to investigate the incidence and risk factors associated with COVID-19 vaccine breakthrough infections. We included all persons ≥18 years that had been fully vaccinated against COVID-19 for ≥14 days, between 1 February 2021 and 5 December 2021, in Belgium. The incidence of breakthrough infections (laboratory confirmed SARS-CoV-2-infections) was determined. Factors associated with breakthrough infections were analyzed using COX proportional hazard models. Among 8,062,600 fully vaccinated adults, we identified 373,070 breakthrough infections with an incidence of 11.2 (95%CI 11.2-11.3)/100 person years. Vaccination with Ad26.COV2.S (HR1.54, 95%CI 1.52-1.56) or ChAdOx1 (HR1.68, 95%CI 1.66-1.69) was associated with a higher risk of a breakthrough infection compared to BNT162b2, while mRNA-1273 was associated with a lower risk (HR0.68, 95%CI 0.67-0.69). A prior COVID-19-infection was protective against a breakthrough infection (HR0.23, 95%CI 0.23-0.24), as was an mRNA booster (HR0.44, 95%CI 0.43-0.45). During a breakthrough infection, those who had a prior COVID-19 infection were less likely to have COVID-19 symptoms of almost all types than naïve persons. We identified risk factors associated with breakthrough infections, such as vaccination with adenoviral-vector vaccines, which could help inform future decisions on booster vaccination strategies. A prior COVID-19 infection lowered the risk of breakthrough infections and of having symptoms, highlighting the protective effect of hybrid immunity.

Keywords: COVID-19; SARS-CoV-2; breakthrough infection; hybrid immunity; mRNA booster vaccine; mRNA vaccines; symptoms; vaccination; viral vector vaccines.

Figure 1

Flow chart of individuals fully vaccinated for at least 14 days on 5 December 2021 in Belgium, with the occurrence of (symptomatic) breakthrough COVID-19 infections. Breakthrough infection = laboratory confirmed COVID-19 infection after at least 14 days after the last vaccine dose; symptomatic breakthrough infection = laboratory confirmed COVID-19 infection after at least 14 days after the last vaccine dose with compatible COVID-19 symptoms.

Figure 2

Daily incidence of breakthrough infections per 100,000 persons during 2021 among fully vaccinated persons (bars) and the weekly positivity rate in the global population (dots). Dashed lines represent the introduction of different primary vaccine brands or of the mRNA booster. Shaded areas represent the occurrence of waves of COVID-19 infections in Belgium.

Figure 3

Cumulative incidence of breakthrough infections among fully vaccinated individuals (A) by different age groups, (B) by brand of primary vaccine and (C) by prior COVID-19 infection. Shaded areas represent 95% confidence intervals.

Figure 4

Symptoms in persons with a breakthrough infection and a prior COVID-19 infection versus persons with a breakthrough infection without a prior COVID-19 infection. Logistic regression models adjusted for age, sex and vaccine brands, and stratified by age group, to assess the association of each type of symptom or of having ≥1 symptom (versus no symptom) with prior COVID-19 infection status. The error bars represent 95% confidence intervals. Persons with a breakthrough infection and having available data on symptoms were taken into account for this analysis.