{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T19:13:50Z","timestamp":1792005230945,"version":"4.4.0"},"reference-count":32,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/vaccines13060564","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T04:49:52Z","timestamp":1748234992000},"page":"564","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["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"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3270-6641","authenticated-orcid":false,"given":"Jesse M.","family":"van den Berg","sequence":"first","affiliation":[{"name":"PHARMO Institute for Drug Outcomes Research, 3528 AE Utrecht, The Netherlands"},{"name":"Department of General Practice, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health Research Institute, Health Behaviors and Chronic Diseases, 1105 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8088-1105","authenticated-orcid":false,"given":"Marieke T.","family":"Blom","sequence":"additional","affiliation":[{"name":"Department of General Practice, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health Research Institute, Health Behaviors and Chronic Diseases, 1105 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0935-5193","authenticated-orcid":false,"given":"Jetty A.","family":"Overbeek","sequence":"additional","affiliation":[{"name":"PHARMO Institute for Drug Outcomes Research, 3528 AE Utrecht, The Netherlands"},{"name":"Department of General Practice, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health Research Institute, Health Behaviors and Chronic Diseases, 1105 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3399-5836","authenticated-orcid":false,"given":"Sharon","family":"Remmelzwaal","sequence":"additional","affiliation":[{"name":"Department of General Practice, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health Research Institute, Health Behaviors and Chronic Diseases, 1105 HV Amsterdam, The Netherlands"},{"name":"Department of Epidemiology and Data Science, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ron M. C.","family":"Herings","sequence":"additional","affiliation":[{"name":"PHARMO Institute for Drug Outcomes Research, 3528 AE Utrecht, The Netherlands"},{"name":"Amsterdam Public Health Research Institute, Health Behaviors and Chronic Diseases, 1105 HV Amsterdam, The Netherlands"},{"name":"Department of Epidemiology and Data Science, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra J. M.","family":"Elders","sequence":"additional","affiliation":[{"name":"Department of General Practice, Amsterdam UMC Location Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Public Health Research Institute, Health Behaviors and Chronic Diseases, 1105 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1056\/NEJMoa2101544","article-title":"Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against COVID-19","volume":"384","author":"Sadoff","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0140-6736(20)32661-1","article-title":"Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: An interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK","volume":"397","author":"Voysey","year":"2021","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1056\/NEJMoa2200797","article-title":"Effect of mRNA Vaccine Boosters against SARS-CoV-2 Omicron Infection in Qatar","volume":"386","author":"Chemaitelly","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1056\/NEJMoa2119451","article-title":"COVID-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant","volume":"386","author":"Andrews","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e072141","DOI":"10.1136\/bmj-2022-072141","article-title":"Waning of vaccine effectiveness against moderate and severe COVID-19 among adults in the US from the VISION network: Test negative, case-control study","volume":"379","author":"Ferdinands","year":"2022","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yan, Z., Yang, M., and Lai, C.L. (2021). COVID-19 Vaccinations: A Comprehensive Review of Their Safety and Efficacy in Special Populations. Vaccines, 9.","DOI":"10.3390\/vaccines9101097"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/10408363.2022.2038539","article-title":"Effects of age, sex, serostatus, and underlying comorbidities on humoral response post-SARS-CoV-2 Pfizer-BioNTech mRNA vaccination: A systematic review","volume":"59","author":"Notarte","year":"2022","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Petras, M., Macalik, R., Janovska, D., Celko, A.M., Danova, J., Selinger, E., Dolecek, J., Neradova, S., Franklova, M., and Dlouhy, P. (2022). Risk factors affecting COVID-19 vaccine effectiveness identified from 290 cross-country observational studies until February 2022: A meta-analysis and meta-regression. BMC Med., 20.","DOI":"10.1186\/s12916-022-02663-z"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Van den Berg, J.M., Remmelzwaal, S., Blom, M.T., van Hoek, B., Swart, K.M.A., Overbeek, J.A., Burchell, G.L., Herings, R.M.C., and Elders, P.J.M. (2022). Effectiveness of COVID-19 Vaccines in Adults with Diabetes Mellitus: A Systematic Review. Vaccines, 11.","DOI":"10.3390\/vaccines11010024"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"343","DOI":"10.5306\/wjco.v14.i9.343","article-title":"Effectiveness and safety of COVID-19 vaccines in patients with oncological diseases: State-of-the-art","volume":"14","author":"Ivanov","year":"2023","journal-title":"World J. Clin. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1093\/ckj\/sfac166","article-title":"BNT162b2 vaccine effectiveness in chronic kidney disease patients-an observational study","volume":"15","author":"Bielopolski","year":"2022","journal-title":"Clin. Kidney J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"418","DOI":"10.2215\/CJN.0000000000000376","article-title":"Vaccine Effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA.2 in CKD","volume":"19","author":"Cheng","year":"2024","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kopel, H., Nguyen, V.H., Boileau, C., Bogdanov, A., Winer, I., Ducruet, T., Zeng, N., Bonafede, M., Esposito, D.B., and Martin, D. (2023). Comparative Effectiveness of Bivalent (Original\/Omicron BA.4\/BA.5) COVID-19 Vaccines in Adults. Vaccines, 11.","DOI":"10.3390\/vaccines11111711"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/oxfordjournals.epirev.a017990","article-title":"Design and interpretation of vaccine field studies","volume":"21","author":"Halloran","year":"1999","journal-title":"Epidemiol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7286","DOI":"10.1016\/j.vaccine.2018.04.016","article-title":"A framework for research on vaccine effectiveness","volume":"36","author":"Crowcroft","year":"2018","journal-title":"Vaccine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1056\/NEJMe2113151","article-title":"COVID-19 Vaccine Effectiveness and the Test-Negative Design","volume":"385","author":"Dean","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"134","DOI":"10.5644\/ama2006-124.383","article-title":"On Measuring Vaccine Effectiveness with Observational Study Designs","volume":"51","author":"Habibzadeh","year":"2022","journal-title":"Acta Med. Acad."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1097\/EDE.0000000000001366","article-title":"Theoretical Framework for Retrospective Studies of the Effectiveness of SARS-CoV-2 Vaccines","volume":"32","author":"Lewnard","year":"2021","journal-title":"Epidemiology"},{"key":"ref_21","unstructured":"WHO (2025, May 03). Guidance on Conducting Vaccine Effectiveness Evaluations in the Setting of New SARS-CoV-2 Variants. Addendum to Evaluation of COVID-19 Vaccine Effectiveness: Interim Guidance. Available online: https:\/\/iris.who.int\/bitstream\/handle\/10665\/343173\/WHO-2019-nCoV-vaccine-effectiveness-variants-2021.1-eng.pdf?sequence=1."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"415","DOI":"10.2147\/CLEP.S247575","article-title":"Existing Data Sources for Clinical Epidemiology: The PHARMO Database Network","volume":"12","author":"Kuiper","year":"2020","journal-title":"Clin. Epidemiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/CLEP.S389598","article-title":"Completeness and Representativeness of the PHARMO General Practitioner (GP) Data: A Comparison with National Statistics","volume":"15","author":"Overbeek","year":"2023","journal-title":"Clin. Epidemiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1002\/pds.5436","article-title":"Categorization of COVID-19 severity to determine mortality risk","volume":"31","author":"Garry","year":"2022","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Harris, M., Hart, J., Bhattacharya, O., and Russell, F.M. (2023). Risk factors for SARS-CoV-2 infection during the early stages of the COVID-19 pandemic: A systematic literature review. Front. Public Health, 11.","DOI":"10.3389\/fpubh.2023.1178167"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1056\/NEJMoa2114255","article-title":"Protection of BNT162b2 Vaccine Booster against COVID-19 in Israel","volume":"385","author":"Goldberg","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/14760584.2023.2143347","article-title":"Expert review of global real-world data on COVID-19 vaccine booster effectiveness and safety during the omicron-dominant phase of the pandemic","volume":"22","author":"Solante","year":"2023","journal-title":"Expert Rev. Vaccines"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/S1473-3099(22)00345-0","article-title":"Vaccine effectiveness of one, two, and three doses of BNT162b2 and CoronaVac against COVID-19 in Hong Kong: A population-based observational study","volume":"22","author":"McMenamin","year":"2022","journal-title":"Lancet Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e069761","DOI":"10.1136\/bmj-2021-069761","article-title":"Clinical severity of, and effectiveness of mRNA vaccines against, COVID-19 from omicron, delta, and alpha SARS-CoV-2 variants in the United States: Prospective observational study","volume":"376","author":"Lauring","year":"2022","journal-title":"BMJ"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"139","DOI":"10.15585\/mmwr.mm7104e3","article-title":"Effectiveness of a Third Dose of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance\u2014VISION Network, 10 States, August 2021-January 2022","volume":"71","author":"Thompson","year":"2022","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_31","unstructured":"RIVM (2025, March 25). Risk Groups and COVID-19, Available online: https:\/\/www.rivm.nl\/en\/coronavirus-covid-19\/risk-groups."},{"key":"ref_32","unstructured":"RIVM (2024, January 31). Deelname COVID-19-Vaccinatie in Nederland, Available online: https:\/\/www.rivm.nl\/sites\/default\/files\/2022-01\/COVID-19_Vaccinatie_Schattingen_WebSite_rapport_20220103_1259_def.pdf."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/6\/564\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:40:21Z","timestamp":1760031621000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/6\/564"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,26]]},"references-count":32,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["vaccines13060564"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13060564","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,26]]}}}