Chapter 8 254 might be explained by residual confounding due to variation in clinical severity (ranging from minimal to more substantial symptomatology) within the group classified as having mild disease, given that both antibody titers and PASC are associated with illness severity. Moreover, when we assessed longitudinal serological data, there was also no statistically significant difference in spike- and RBD-binding IgG decay over time between participants with and without PASC. Together, our findings suggest that patients with PASC do not have clearly distinct antibody kinetics during either the acute or convalescent phase, findings which are in line with the lack of effect of vaccination on symptomatology in our study. Future research may wish to investigate potential differences in cell-mediated immunity, also induced by COVID-19 vaccination, between those with and without PASC. Our study’s strengths are its prospective design, hence avoiding bias through selfreferral of PASC patients, detailed prospective symptom data, which minimises recall bias, long follow-up time and representation of the full spectrum of COVID-19 severity. However, our study also has limitations. Although we used a robust statistical method to match cases and controls, vaccination was not randomly assigned and therefore residual confounding may still exist. . In addition, a large proportion of our cohort was vaccinated around 12 months after illness onset after which symptom questionnaires were no longer completed. This greatly reduced the number of participants available for matching, limiting statistical power. Another limitation faced by all PASC studies without SARS-CoV-2-negative controls is that we cannot be sure to what extent the symptoms recorded were causally related to SARS-CoV-2 infection as opposed to either underlying comorbidities (i.e., symptoms were already present before COVID-19) or the psychological and physical effects of the pandemic. This may have resulted in misclassification bias and overestimation of the proportion of participants with PASC. However, there is no reason to believe that this misclassification would be more likely to occur among participants contributing to either the vaccinated or unvaccinated matched follow-up data. Finally, as all participants in our cohort were infected with wild-type or Alpha SARS-CoV-2, results may not be generalisable to those infected with other variants. In summary, we found no evidence of a strong therapeutic effect of SARS-CoV-2 vaccination on the mean number of symptoms among those with PASC over time, nor on odds of full recovery from PASC following first vaccination. Our findings on early and longitudinal serology among those with and without PASC at 3 months after illness onset are consistent with our clinical findings, refuting any immunological basis for a therapeutic effect. There remains a pressing need to understand the underlying biological mechanism of PASC in order to inform effective preventative measures and treatment options.
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