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Publications

Journal Article Preprint Epublish

PubMed: 40313290 DOI: 10.1101/2025.04.22.25326224

COVID-19 Vaccination Timing, Relative to Acute COVID-19, and Subsequent Risk of Long COVID.

medRxiv

Authors: Zachary Butzin-Dozier, Yunwen Ji, Lin-Chiun Wang, A Jerrod Anzalone, Jeremy Coyle, Rachael V Phillips, Rena C Patel, Jing Sun, Eric Hurwitz, Sarang Deshpande, Junming Seraphina Shi, Andrew Mertens, Mark J van der Laan, John M Colford, Alan E Hubbard

Affiliations

  • School of Public Health, University of California, Berkeley, Berkeley, CA USA.
  • University of Nebraska Medical Center, Omaha, NE USA.
  • University of Alabama at Birmingham, Birmingham, AL USA.
  • Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
  • University of North Carolina at Chapel Hill, Chapel Hill, NC USA.

Abstract

Objectives

Long COVID is a debilitating condition that impacts millions of Americans, but patients and clinicians have little information on how to prevent this disorder. Vaccination is a vital tool in preventing acute COVID-19 and may confer additional protection against Long COVID. There is limited evidence regarding the optimal timing of COVID-19 vaccination (i.e., vaccination schedule) to minimize the risk of Long COVID.

Methods

We applied Longitudinal Targeted Maximum Likelihood Estimation to electronic health record (EHR) data from a retrospective cohort of patients vaccinated against COVID-19 between December 2021 and September 2022. We evaluated the association between binary COVID-19 vaccination status (two or more doses vs. zero doses) and 12-month Long COVID risk among patients diagnosed with acute COVID-19 between December 2021 and September 2022. In addition, we compared the 12-month cumulative risk of Long COVID (ICD-10 code U09.9) among patients diagnosed with acute COVID-19 one to three months after vaccination, three to five months after vaccination, or five to seven months after vaccination while adjusting for relevant high-dimensional baseline and time-dependent covariates.

Results

We analyzed EHR data from a retrospective cohort of 1,558,018 patients. In our binary cohort (n = 519,980), we found that vaccinated patients had a lower risk of Long COVID than unvaccinated patients (adjusted marginal risk ratio 0.84 (0.81, 0.88)). In our longitudinal cohort (n = 1,085,291), we did not find a significant difference in Long COVID risk comparing patients who were diagnosed with acute COVID-19 one to three months after vaccination versus patients who were diagnosed with COVID-19 three to five months (adjusted marginal risk ratio 0.93 (95% CI 0.62, 1.41) or 5 to 7 months (adjusted marginal risk ratio 1.06 (95% CI 0.72, 1.56)) after vaccination.

Conclusions

We found that COVID-19 vaccination before SARS-CoV-2 infection was protective against Long COVID, and we did not find that this protection significantly waned within 7 months after vaccination. These findings suggest that COVID-19 vaccination protects against Long COVID.

MeSH

Vaccines, Vaccination, Covid-19, Odds Ratio, Post-Acute Covid-19 Syndrome