Post COVID-19 condition after Wildtype, Delta, and Omicron variant SARS-CoV-2 infection and vaccination: pooled analysis of two population-based cohorts
Authors: Ballouz Tala , Menges Dominik , Kaufmann Marco , Amati Rebecca , Frei Anja , von Wyl Viktor , Fehr Jan S. , Albanese Emiliano , Puhan Milo A. 
Published: September 2022

AbstractBackgroundPost COVID-19 condition (PCC) is an important complication of SARS-CoV-2 infection, affecting millions worldwide. Further evidence is needed on the risk of PCC after vaccination and infection with newer variants. This study aimed to evaluate the prevalence and severity of PCC across different variants and vaccination histories.MethodsWe used pooled data from 1350 SARS-CoV-2-infected individuals from two representative population-based cohorts in Switzerland, diagnosed between Aug 5, 2020, and Feb 25, 2022. We descriptively analysed the prevalence and severity of PCC, defined as the presence and frequency of PCC-related symptoms six months after infection, among vaccinated and non-vaccinated individuals infected with Wildtype, Delta, and Omicron SARS-CoV-2. We used multivariable logistic regression models to assess the association and estimate the risk reduction of PCC after infection with newer variants and prior vaccination. We further assessed associations with the severity of PCC using multinomial logistic regression. To identify groups of individuals with similar symptom patterns and evaluate differences in the presentation of PCC across variants, we performed exploratory hierarchical cluster analyses.FindingsWe found strong evidence that vaccinated individuals infected with Omicron had a reduced risk of developing PCC compared to non-vaccinated Wildtype-infected individuals (odds ratio 0.42, 95% confidence interval 0.24–0.68). The risk among non-vaccinated individuals was similar after infection with Delta or Omicron compared to Wildtype SARS-CoV-2. We found no differences in PCC prevalence with respect to the number of received vaccine doses or timing of last vaccination. The prevalence of PCC-related symptoms among vaccinated, Omicron-infected individuals was lower across severity levels. In cluster analyses, we identified four clusters of diverse systemic, neurocognitive, cardiorespiratory, and musculoskeletal symptoms, with similar patterns across variants.InterpretationThe risk of PCC appears to be lowered with infection by the Omicron variant and after prior vaccination. This evidence is crucial to guide future public health measures and vaccination strategies.FundingSwiss School of Public Health (SSPH+), University of Zurich Foundation, Cantonal Department of Health Zurich, Swiss Federal Office of Public HealthStudy registrationsISRCTN14990068, ISRCTN18181860Research in contextEvidence before this studyWe searched MEDLINE, EMBASE, and medRxiv for primary studies assessing the prevalence and symptoms associated with post COVID-19 condition (PCC) after infection with different SARS-CoV-2 variants and among infected individuals with and without prior vaccination. We used a specific search strategy limited to the timeframe between Jan 01, 2020, and Aug 29, 2022, without language restriction (reported in Supplementary Table S1). We further searched identified systematic reviews for additional references. We screened 221 unique records and identified four studies investigating the association of Delta or Omicron variant infections and 11 studies investigating the association of prior vaccination with PCC.Current evidence is uncertain whether infection with emerging variants may be associated with a reduction of the risk of developing PCC. Two studies found a decreased risk of PCC with Omicron compared to Delta infection, or to individuals infected during any prior wave. One study found a lower risk of PCC with Alpha compared to Wildtype SARS-CoV-2, but an increased risk among those infected with the Delta or Omicron variant. One study primarily examined symptom clusters across different waves. All identified studies defined PCC as symptoms occurring at ≥4 weeks or ≥12 weeks after infection, and were conducted among hospitalised patients, healthcare workers, or users of the United Kingdom ZOE symptom app.Evidence regarding the preventive effects of vaccination on PCC was of higher certainty, with eight out of 11 studies reporting a substantially reduced PCC incidence with mRNA- and adenovirus vector-based vaccines. The magnitude of the effect in these studies varied, with estimated adjusted odds ratios ranging from 0.22 to 0.85. Nonetheless, three studies found no difference between vaccinated and non-vaccinated infected individuals, including two of three studies evaluating PCC at six months after infection. The third study with a six-month horizon found a higher odds ratio than any other study reporting a reduction at ≥4 weeks or ≥12 weeks. Study populations and designs varied strongly, and only one study evaluated the independent effects of SARS-CoV-2 variants and vaccination.Added value of this studyThis study investigates the association of PCC with infection with Delta and Omicron variants and prior vaccination compared to Wildtype SARS-CoV-2 infection among unvaccinated individuals. We found that infection with the Omicron variant and prior vaccination were associated with a lower risk of developing PCC six months after infection. Compared to previous work, this study is the first to evaluate PCC with a longer-term follow-up, while simultaneously evaluating the risk reduction by Delta and Omicron variants and prior vaccination on PCC. By relying on prospectively collected data from two representative population-based cohorts, we were able to provide an in-depth analysis of the longer-term risk reduction through prior vaccination and novel variants, the severity of PCC-related symptoms, and symptom clusters across pandemic waves between 2020 and early 2022.Implications of all the available evidenceIn conjunction with existing evidence, our study suggests that infection with the Omicron variant and prior vaccination are likely to substantially reduce the risk of developing PCC compared to infection with Wildtype SARS-CoV-2 without prior vaccination. We demonstrate that this risk reduction persists up to six months after infection, and that PCC-related symptoms are reduced to a similar extent across different levels of severity. However, the risk of having mild to even potentially severe PCC six months after infection is not eliminated. Hence, vaccinations will likely continue to be an important mainstay in the management of the further course of the pandemic. The prevention of further infection and PCC may still provide important benefits for public health, even if SARS-CoV-2 further evolves to cause milder infections and becomes endemic. Therefore, information from this study will be crucial to guide vaccination strategies and decisions on timing and enforcement of public health measures worldwide.