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.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This research was financially supported by the National Institute for Allergy and Infectious Diseases (1K01AI182501-01 to Zachary Butzin-Dozier) and a global development grant (OPP1165144) from the Bill & Melinda Gates Foundation to the University of California, Berkeley, CA, USA. Individual authors were supported by the following funding sources: NIMH R01131542 (PI Rena C. Patel), Jerrod Anzalone is supported by the National Institute of General Medical Sciences, U54 GM115458, which funds the Great Plains IDeA-CTR Network. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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This study was approved by the UC Berkeley Office for Protection of Human Subjects (2022-01-14980). The N3C data transfer to NCATS is performed under a Johns Hopkins University Reliance Protocol # IRB00249128 or individual site agreements with NIH. N3C received a waiver of consent from the NIH Institutional Review board and allows the secondary analysis of these data without additional consent
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Data Availability
All analytic code and data are available in the N3C Enclave by request. Access to the N3C Data Enclave is managed by NCATS (https://ncats.nih.gov/research/research-activities/n3c/resources/data-access). Interested researchers must first complete a data use agreement, and next a data use request, in order to access the N3C Data Enclave. Once access is granted, the N3C data use committee must review and approve all use of data and the publication committee must approve all publications involving N3C data.
https://ncats.nih.gov/research/research-activities/n3c/resources/data-access