Among patients with long COVID, the first COVID-19 vaccine injection was associated with a reduction in disease severity and impact on patients’ lives at 120 days after baseline. In particular, our results show that vaccination doubled the remission rate of long COVID symptoms. Beyond remission, vaccination also significantly increased the proportion of patients reporting an acceptable symptom state by 7.5%. Thus for 13 patients with long COVID who are vaccinated, one will experience a notable decrease in the disease's impact on his or her life. Our results also confirm the safety of vaccination for patients with long COVID, with only two (0.4%) patients reporting an adverse effect that required hospitalisation.
As of today, millions of patients experience persistent symptoms after a SARS CoV-2 infection and many more may be at risk in the future. To our knowledge, this is the first study of a pharmacological treatment that could reduce the burden of long COVID on care systems.
Our study provides the answer to “one of the four most urgent questions about long COVID” and does so less than 6 months after the first report of remissions of long COVID after vaccination.8 13 From a public health perspective, these results are critical in times of vaccine hesitancy, especially among patients who have had a SARS-CoV2 infection and who may fear a relapse or worsening in symptoms. These findings may also game-changing for our understanding of the causes underlying the persistence of symptoms after a SARS-CoV 2 infection: for at least some patients, the disease might be related to at least one of the following mechanisms: 1) presence of a persistent viral reservoir; 2) the presence of virus fragments capable of stimulating the immune system; or 3) development of an autoimmune response induced by the infection.7 Future work should explore and describe with precision the symptoms and characteristics of patients who improved after vaccination and could ultimately identify targets for specific therapeutics for long COVID.
From a methodological point of view, our study exemplifies how cohort data can be used to answer comparative effectiveness questions in situations when a randomized trial is not feasible.14 Recruitment for such a trial evaluating vaccination among patients with long COVID would be very difficult — if not impossible — in western countries where most of the population has already been vaccinated.
Our study has some limitations. First, despite the use of robust methods and statistical techniques to draw causal inferences from observational data, treatment was not randomly assigned, and potential unmeasured confounders could bias our results. For example, our data did not allow us to take patients’ motivation to receive COVID-19 vaccination into account, although it may be related to their perception of their long COVID symptoms and this disease's impact, as measured with the long COVID ST and IT. Second, the administration of questionnaires at regular time intervals did not allow to define follow-up relatively to vaccination. In the time-to-event analysis, study baseline was defined as the vaccination date for patients in the vaccination group, and the vaccination date of their matched patient for those in the control group; the treatment effect reported thus directly related to the efficacy of vaccination at 120 days after vaccination. However, for the analysis of the two patient scores (the long covid ST and IT), baseline was defined as patients’ state 120 days before the outcome measurement and up to 60 days before vaccination; the treatment effect reported thus related to the efficacy of vaccination from 60 to 120 days after vaccination. To account for variation in outcome measurement times, we explored how time since vaccination affected the study outcome and found no evidence of an interaction between baseline and time of vaccination on patients’ symptoms and impact (Supplementary material 10).
Third, all patients in our study were infected before May 1, 2021, and thus were not infected with recent variants of concern such as the Delta variant (first confirmed in France in June 2021). The effectiveness of vaccination on persistent symptoms occurring after infection with those variants thus remains unknown.
In conclusion, COVID-19 vaccination reduces the severity and life impact of long COVID among patients with this disease. These results are likely to reduce vaccine hesitancy among patients who have already had COVID-19 and further our knowledge of the mechanisms underlying long COVID.