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. 2025 May 26;13(6):564.
doi: 10.3390/vaccines13060564.

Rates of SARS-CoV-2 Breakthrough Infection or Severe COVID-19 and Associated Risk Factors After Primary and Booster Vaccination Against COVID-19 in the Netherlands

Jesse M van den Berg  1   2   3 , Marieke T Blom  2   3 , Jetty A Overbeek  1   2   3 , Sharon Remmelzwaal  2   3   4 , Ron M C Herings  1   3   4 , Petra J M Elders  2   3
Affiliations

Rates of SARS-CoV-2 Breakthrough Infection or Severe COVID-19 and Associated Risk Factors After Primary and Booster Vaccination Against COVID-19 in the Netherlands

Jesse M van den Berg et al. Vaccines (Basel). .

Abstract

Background: The effectiveness of COVID-19 vaccines appears to decline rapidly over time due to waning immunity and immune evasion by emerging variants of concern, and may be reduced in high-risk populations. We aimed to evaluate the rates of SARS-CoV-2 breakthrough infection or severe COVID-19, both in individuals who had completed their primary COVID-19 vaccination, and in those who had received their first booster vaccination. Specifically, we aimed to evaluate whether persons with certain risk factors, such as age, gender, socioeconomic status (SES), and specified comorbidities have an increased risk of either breakthrough infection or severe COVID-19, compared to those without the respective risk factors. Methods: Data on COVID-19 vaccinations, infections, hospitalizations, and deaths were collected from the PHARMO Data Network, consisting of health records from Dutch residents. Two cohorts were established: (1) all persons who have completed their primary COVID-19 vaccination regimen, and (2) those who have received their first booster vaccination. The outcomes were SARS-CoV-2 breakthrough infection, and severe COVID-19, defined as either hospitalization or death following SARS-CoV-2 infection. Incidence rates of these outcomes were calculated in both cohorts. The adjusted incidence rate ratios of these outcomes in persons with certain risk factors were calculated, using generalized linear models with a Poisson distribution. Results: In 2021, a total of 1,090,567 individuals received either two doses of BNT162b2, AZD1222, or mRNA-1273, or one dose of Ad26.COV2.S and were included in the primary vaccination cohort, of which 344,153 (31.6%) received a booster vaccination. Overall incidence rates of SARS-CoV-2 breakthrough infection and severe COVID-19 after primary vaccination were 29.9 and 3.1 per 1000 person-years, respectively, and after booster vaccination were 256.4 and 2.3, respectively. Male gender, older age, lower SES, history of COVID-19, and recent hospitalization were factors associated with a lower risk of breakthrough infection after primary vaccination, and a higher risk of severe COVID-19. The risk of severe COVID-19 after primary vaccination was increased in persons with several comorbidities, compared to those without, and remained elevated after booster vaccination in persons with diabetes or lung disease. Conclusions: Our study emphasizes the crucial role of boosters in reducing breakthrough infections, particularly in high-risk populations. The varied impact on severe outcomes in individuals with comorbidities underscores the need for ongoing surveillance and tailored vaccination strategies.

Keywords: COVID-19; SARS-CoV-2; comorbidities; coronavirus; risk factors; vaccination; vaccine effectiveness.

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Conflict of interest statement

Jesse M. van den Berg and Jetty A. Overbeek are employees and Ron M. C. Herings is scientific director of the PHARMO Institute for Drug Outcomes Research. This independent research institute performs financially supported studies for the government, related healthcare authorities, and several pharmaceutical companies. The other authors have declared no competing interests.

Figures

Figure 1
Figure 1
Study diagram with description of cohorts, including assessment windows of exclusions, covariates, and outcomes for both the primary vaccination cohort and the booster vaccination cohort. Persons with ≤1 dose were excluded (except for Ad26.COV2.S vaccine). Censoring of cohort 1 occurred at either SARS-CoV-2 breakthrough infection, COVID-19 related hospitalization, death, end of follow-up, or date of booster vaccination, whichever came first. Censoring of cohort 2 occurred at either SARS-CoV-2 breakthrough infection, COVID-19 related hospitalization, end of follow-up, death, or end of study period, whichever came first. CED, cohort entry date; SES, socioeconomic status.
Figure 2
Figure 2
Forest plot of incidence rate ratios (IRRs) of SARS-CoV-2 breakthrough infection after primary vaccination, and after booster vaccination. Primary vaccination is defined as having received two doses of BNT162b2, mRNA-1273 or AZD1222, or one dose of Ad26.COV2.S. Booster vaccination is defined as having received a third dose, being either BNT162b2 or mRNA-1273. Corresponding IRRs are reported in Table 2.
Figure 3
Figure 3
Forest plot of incidence rate ratios (IRRs) of severe COVID-19 after primary vaccination, and after booster vaccination. Primary vaccination is defined as having received two doses of BNT162b2, mRNA-1273 or AZD1222, or one dose of Ad26.COV2.S. Booster vaccination is defined as having received a third dose, being either BNT162b2 or mRNA-1273. Corresponding IRRs are reported in Table 2.
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