Effect of vaccination on time till Long COVID, a comparison of two ways to model effect of vaccination and two outcome definitions

Long COVID, or post-COVID syndrome, is a constellation of symptoms observed in patients at least four weeks after COVID-19 infection. We analyzed the effect of COVID-19 vaccination status on risk of either developing Long COVID symptoms or being diagnosed with Long COVID. In separate analyses we compared the effect of vaccination status at time of COVID-19 infection and the effect of vaccination status as a time-dependent covariate where vaccination could occur at any point with respect to COVID-19 infection. To address this question, we identified a subset of adult patients from Truveta Data who experienced a COVID-19 infection as indicated by a positive laboratory test between 2021-10-01 and 2022-11-31. We considered two distinct ways of modeling the effect of vaccination status (time-independent and time-dependent) and two distinct outcomes of interest (Long COVID symptoms or diagnosis with Long COVID), representing four distinct analyses. The presence of Long COVID symptoms was defined as the presence of one or more new symptoms consistent with COVID-19/Long COVID at least four weeks post COVID-19 infection. Diagnosis of Long COVID was determined by the presence of one or more ICD-10-CM or SNOMED-CT codes explicitly identifying a patient as having been diagnosed with Long COVID. Our analysis focusing on the effect of COVID-19 vaccination status at time of COVID-19 infection found that patients who had completed a primary COVID-19 vaccination sequence or had completed a primary vaccination sequence and received a booster dose at time of COVID-19 infection were on average at lower risk of either developing Long COVID symptoms or being diagnosed with Long COVID than unvaccinated patients (vaccinated versus unvaccinated HR of symptoms 0.9 [0.87-0.94], HR of diagnosis 0.86 [0.74-0.99]; vaccinated and boosted versus unvaccinated HR of symptoms 0.87 [0.83-0.91], HR of diagnosis 0.81 [0.69-0.95]). We do not find evidence that having received a booster dose in addition to having completed a primary vaccination sequence offers additional protection over having completed the primary sequence alone (vaccinated and boosted versus vaccinated HR of symptoms 0.96 [0.91-1.01], HR of diagnosis 0.94-1.13). Our analysis of COVID-19 vaccination status modeled as a time-dependent covariate yielded similar results for patients who had completed a primary COVID-19 vaccination sequence or had completed a primary vaccination sequence and a booster dose. Both groups were on average at lower risk of developing Long COVID symptoms or being diagnosed with Long COVID than patients who where never vaccinated (vaccinated versus unvaccinated HR of symptoms 0.91 [0.88-0.95], HR of diagnosis 0.86 [0.75-0.99]; vaccinated and boosted versus unvaccinated HR of symptoms 0.88 [0.85-0.91], HR of diagnosis 0.77 [0.67-0.9]). As with the time-independent analysis, we also find that having completed a booster dose in addition to a primary COVID-19 vaccination sequence does not provide additional protection from developing Long COVID symptoms or being diagnosed with Long COVID over having completed the primary sequence alone (vaccinated and boosted versus vaccinated HR of symptoms 0.96 [0.92-1.01], HR of diagnosis 0.89 [0.76-1.06]). We find that completing a primary vaccination sequence is associated with a decreased risk of developing Long COVID symptoms or being diagnosed with Long COVID compared with no vaccination regardless of whether vaccination status is modeled as a time-independent or time-dependent covariate. We find a similar protective effect in patients who have completed a primary vaccination sequence and a booster dose when compared to the those who are unvaccinated. However, we do not find evidence for a difference in protective effect between patients who have completed a primary vaccination sequence and a booster dose and those patients who have only completed a primary vaccination sequence. Our results support the growing evidence that having complete a primary vaccination sequence is protective against the development of Long COVID symptoms or the diagnosis of Long COVID. ### Competing Interest Statement All authors are employees of Truveta, Incorporated. ### Funding Statement All authors are employees of Truveta, Incorporated. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data used in this study is available to all Truveta subscribers and may be accessed at studio.truveta.com. The R code used to perform all analyses and generate all tables and figures is available on GitHub at [https://github.com/Truveta/smits\_et\_al\_vaccines\_long_covid][1]. [1]: https://github.com/Truveta/smits_et_al_vaccines_long_covid