In this large register-based cohort study, including 589 722 residents from two of Sweden’s largest regions, we found a strong association between vaccination before first registering Covid-19 and a lower likelihood of receiving a PCC diagnosis. In the study population, unvaccinated individuals had four times more PCC diagnoses compared to those who had been vaccinated (1.4%). No 0.4%) We found a vaccine efficacy of 58% against PCC given before primary infection. Vaccine efficacy increased with each successive dose: 21% for one dose, 59% for two doses, and 73% for three or more doses.
Findings in context
The few previous studies on vaccine efficacy have shown mostly protective effects on the long-term effects of Covid-19, with many estimates of effect;2627 But some of them could not show a general protective effect.2829 The methods and data included in previous studies were varied and had limitations. A study population is rarely population-based and often includes a small number of participants.3031 Analyzes of the differential effects of different vaccine doses have not always been done prior to Covid-19.2732 Vaccination during follow-up is usually not a criterion for censoring, so both vaccinated and unvaccinated individuals were included in the unvaccinated group. In the present study, we analyzed the effectiveness of vaccination for any dose, one dose, two doses, and three or more doses, by censoring 589 722 individuals in a population-based population, either by vaccination or reinfection. Previous studies have generally shown that PCC They have no clear definition, and symptoms are often self-reported.29303133 Based on the results, we used clinical diagnoses of PCC. In addition, the follow-up duration in previous studies was often short;29 In our study, the median follow-up was 28 days after the first recorded infection and 129 days. A recent systematic review concluded that vaccination against covid-19 before infection had a protective effect on PCC in 10 of 12 studies.11 No meta-analysis was performed due to high heterogeneity between studies and low certainty of evidence. In other systematic reviews, meta-analyses have included many of these studies, but the results should be interpreted with caution.3435 One of these meta-analyses concluded that receiving two vaccinations prior to covid-19 was associated with a lower risk of PCC compared with vaccination.34 and the odds ratio was 0.71 for at least one dose prior to the disease.35
Using data from the general population of adults in the two largest regions of Sweden, we showed that pre-vaccination for Covid-19 was associated with a reduced likelihood of PCC diagnosis. When we determined the median interval between vaccination and infection (126 days), to assess the potential differential effects of recent vaccinations, we found that receiving the last dose of vaccine more than 126 days before exposure to VV-19 was still associated with a relatively high risk. The effectiveness of vaccination against PCC, and only slightly less than the original analysis. We also restricted the vaccinated population to those who received their last dose more than 14 days before covid-19 in a sensitivity analysis to ensure sufficient time between vaccination and acute infection, and the estimated vaccination effect did not change significantly. The main analysis. In addition, in the main analyses, we only considered the first PCC diagnosis at least 28 days after the infection, but in the sensitivity analyzes we required a minimum of 90 days after the infection, with similar results.
Research shows that women may have a greater immune response to vaccines than men.36 Although this does not necessarily mean better protection against the disease. In our study, men showed greater efficacy of vaccination against PCC than women. Whether PCC is more likely to occur with specific variants is not yet fully established. However, available data suggest that individuals with the micron variant are less likely to experience long-term effects of Covid-19 than those with other variants.373839 However, it is difficult to determine whether this lower risk is related to a specific difference or a protective effect of past infections or vaccinations or a shorter follow-up period. A small study evaluating the protective effect of Covid-19 vaccines on PCC did not show significantly different results between the variants, including individuals with omicron time and earlier infections.30 In the current study, the study population included those infected during the pre-alpha and omicron periods when alpha and delta variants predominated. Although the vaccine coverage was not evenly distributed during these periods, the simplification of the prime differentiation period during the virus phase showed a slightly lower vaccine efficacy against PCC in the omicron period than in the pre-alpha and alpha periods. Because we did not have access to viral sequence data in our analysis, we used the duration of infection as a surrogate proxy. Therefore, the difference in acute infection in some study individuals may have been misclassified.
The pathogenesis of PCC has not yet been elucidated, but several mechanisms associated with different symptoms have been proposed and it has become clear that patients with PCC are a heterogeneous group. Possible mechanisms include organ damage, abnormal immune activity during acute infection, reintroduction of other viruses, alteration of the systemic immune system, autoimmunity, and immune activation due to viral persistence.40 Determining the pathogen may suggest possible pathways for the protective effect of the vaccines – for example, a reduction in viral load during acute infection after vaccination may reduce the ability of the virus to provide lasting immunity. Different sets of PCC symptoms may have different mechanisms for the effect of the vaccine because they may have different pathogens. We showed that approximately 37% of patients with Covid-19 treated in the ICU had a diagnosis of PCC.16 The covid-19 vaccines have been shown to prevent hospital admissions with covid-19.41 It may be one way for the vaccines to have a protective effect on PCC. In our analysis, the effectiveness of vaccination against PCC appears to be only partially explained by the reduced risk of hospitalization. Furthermore, analyzes stratified by acute illness severity as indicated by the importance of hospitalization showed that vaccine efficacy was similar in both the no-ICU hospitalization group and the no-hospitalization group. In addition, one study found that people who were vaccinated after Covid-19 had a lower risk of developing PCC in the 12 weeks after Covid-19 than those who were not vaccinated.26 This, together with the findings of the current study, supports the hypothesis that the protective effect of Covid-19 vaccines on PCC goes beyond the protective effect on hospitalization. It is also important to note that PCC symptoms frequently occur not only in patients with confirmed covid-19 but also in those with positive SARS-CoV-2 PCR test results.42
Strengths and limitations of this study
The present study has several strengths. First, we used registry-based data collected from a high-quality registry, with essentially no loss to follow-up and low self-report bias. In Sweden, it is mandatory and statutory to record each dose of the Covid-19 vaccine in the national vaccination register. Therefore exposure data (vaccination) is particularly comprehensive and precisely measured. Second, we obtained individual-level data from primary health care as well as inpatient and outpatient specialist health care. This is important when studying the diagnosis of PCC, as we have previously shown that the majority (>85%) of patients with PCC in Sweden received a primary health care diagnosis.16 Additionally, to fully account for health-seeking behavior and the fact that the PCC group is a biased group of health-care seekers, the number of health-care contacts in 2019 was included as a confounder in the full model. In addition, the study is population-based and covers the two largest Swedish regions (region Stockholm and Vastra Gotaland, 40% of the total Swedish population). Finally, most previously published studies examining the protective effect of PCC given before Covid-19 failed to take into account vaccinations given after the disease. Without taking these vaccines into account, the overall protective effect on PCC may be reduced because the groups are more similar to each other. Using survival data combined with vaccinations from the National Immunization Registry, we were able to censor individuals with vaccinations after acute infection.
Limitations of the current study include that both PCC and the ICD-10 diagnosis code, U09.9, are relatively new and the code has not yet been validated in the Swedish setting. PCC may be overdiagnosed or underdiagnosed, which may affect the sensitivity and specificity of PCC as an outcome measure. If this affects both unvaccinated and vaccinated individuals equally, this will lead to differential misclassification of results, resulting in some bias toward the null on average. However, we cannot completely rule out the possibility that vaccinated individuals are less likely to have PCC than undiagnosed individuals based on expectations from patients and health care providers about the protective effect of vaccination—although this bias is unlikely to increase with increasing vaccination rates and the strong dose-response association in our results. . A recent paper from Sweden examining post-Covid-19 health care utilization in patients with PCC diagnosis codes compared with age, sex, and number of health care contacts showed that the pre-PCC group had significantly more post-Covid-19 health care contacts. -19.24 Therefore, we believe that the difference in PCC diagnostic codes may be good, but the sensitivity remains less clear. In addition, vaccine effectiveness may be different for patients with a specific symptom compared to those with another symptom in the PCC spectrum. However, if the vaccine’s protective effect is only valid for certain specific symptoms in the PCC spectrum, the relatively strong effect we see in this study on PCC diagnosis would be unlikely. A few studies have examined the effect of the vaccine on current PCC, showing both no effect and alleviation and exacerbation of PCC symptoms.434445 Because the registry data used in this study had limited information on symptoms, it would be difficult to assess changes in symptoms of pre-existing PCC. Moreover, even if PCC is diagnosed on a specific date, the condition and symptoms are usually discovered before the date of diagnosis. Finally, our results are based on initial SARS-CoV-2 infections, but reinfections may represent the majority of infections today. The impact of reinfections on the efficacy of the covid-19 PCC vaccine remains to be elucidated.