Underlying health biases in previously-infected SARS-CoV-2 vaccination recipients: A cohort study

Uwe Riedmann; Alena Chalupka; Lukas Richter; Dirk Werber; Martin Sprenger; Peter Willeit; Marc Rijksen; Julia Lodron; Tracy Beth Høeg; John Pa Ioannidis; Stefan Pilz

doi:10.1016/j.jinf.2025.106497

Underlying health biases in previously-infected SARS-CoV-2 vaccination recipients: A cohort study

J Infect. 2025 Jun;90(6):106497. doi: 10.1016/j.jinf.2025.106497. Epub 2025 Apr 30.

Authors

Uwe Riedmann¹, Alena Chalupka², Lukas Richter³, Dirk Werber⁴, Martin Sprenger⁵, Peter Willeit⁶, Marc Rijksen⁷, Julia Lodron⁷, Tracy Beth Høeg⁸, John Pa Ioannidis⁹, Stefan Pilz¹⁰

Affiliations

¹ Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria.
² Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria; Institute for Surveillance & Infectious Disease Epidemiology, Austrian Agency for Health and Food Safety (AGES), Vienna, Austria.
³ Institute for Surveillance & Infectious Disease Epidemiology, Austrian Agency for Health and Food Safety (AGES), Vienna, Austria; Institute of Statistics, Graz University of Technology, Graz, Austria.
⁴ Institute for Surveillance & Infectious Disease Epidemiology, Austrian Agency for Health and Food Safety (AGES), Vienna, Austria.
⁵ Institute of Social Medicine and Epidemiology, Medical University Graz, Graz, Austria.
⁶ Institute of Health Economics, Medical University of Innsbruck, Innsbruck, Austria; Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Ignaz Semmelweis Institute, Interuniversity Institute for Infection Research, Vienna, Austria.
⁷ Department of Psychiatry, Psychosomatics and Psychotherapy, Division of Medical Psychology, Psychosomatics and Psychotherapy, Medical University of Graz, Graz, Styria, Austria.
⁸ Sloan School of Management Massachusetts, Institute of Technology, Cambridge, MA, USA; Department of Emergency Medicine, University of California-San Francisco, San Francisco, CA, USA.
⁹ Departments of Medicine, of Epidemiology and Population Health, and of Biomedical Data Science, and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA 94305, USA.
¹⁰ Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria. Electronic address: stefan.pilz@medunigraz.at.

PMID: 40315999
DOI: 10.1016/j.jinf.2025.106497

Abstract

Objectives: Observational studies may over- or under-estimate SARS-CoV-2 vaccine effectiveness (VE) depending on whether healthier (i.e. healthy vaccine effect (HVE)) or more ill individuals are preferentially vaccinated. To evaluate this issue, we compared non-COVID-19 mortality in vaccinated versus unvaccinated individuals.

Methods: This is a nationwide retrospective observational study in the entire adult population in Austria with previously documented SARS-CoV-2 infection, with a follow-up from 2021 to 2023. Cox regression analyses were used to calculate hazard ratios (HRs) according to the number of SARS-CoV-2 vaccinations. We also performed matched analyses, where on each day, newly vaccinated individuals were matched with unvaccinated individuals based on age, sex and nursing home residency.

Results: In 4,324,485 eligible individuals, differences in non-COVID-19 mortality risk between vaccinated and unvaccinated were most prominent in the early periods and decreased thereafter. Matched analyses for the first two weeks after vaccination showed HRs below 0.5 for vaccinated versus unvaccinated individuals, irrespective of vaccination numbers. Similar findings were retrieved for non-COVID-19, all-cause, and cancer deaths. Overall, COVID-19 deaths were significantly reduced in vaccinated individuals (VE of 26 to 53%).

Conclusions: HVE for SARS-CoV-2 vaccines was strong early after vaccination and diminished over time. HVE should be considered when estimating VE.

Keywords: COVID-19; Healthy vaccinee bias; Healthy vaccinee effect; Mortality; National; SARS-CoV-2.

Publication types

Observational Study

MeSH terms

Adult
Aged
Aged, 80 and over
Austria / epidemiology
COVID-19 Vaccines* / administration & dosage
COVID-19 Vaccines* / immunology
COVID-19* / epidemiology
COVID-19* / mortality
COVID-19* / prevention & control
Cohort Studies
Female
Humans
Male
Middle Aged
Retrospective Studies
SARS-CoV-2 / immunology
Vaccination* / statistics & numerical data
Vaccine Efficacy*

Substances

COVID-19 Vaccines