RESUMO
Post-acute sequelae of COVID-19 (PASC) are long-term consequences of SARS-CoV-2 infection that can substantially impair quality of life. Underlying mechanisms ranging from persistent virus to innate and adaptive immune dysregulation have been discussed. Here, we profiled plasma of 181 individuals from the cohort study for digital health research in Germany (DigiHero) including individuals after mild to moderate COVID-19 with or without PASC and uninfected controls. We focused on soluble factors related to monocyte/macrophage biology and on circulating SARS-CoV-2 spike (S1) protein as potential biomarker for persistent viral reservoirs. At a median time of eight months after infection, we found pronounced dysregulation in almost all tested soluble factors including both pro-inflammatory and pro-fibrotic cytokines. These perturbations were remarkably independent of ongoing symptoms, but further correlation and regression analyses suggested PASC specific patterns involving CCL2/MCP-1 and IL-8 as well as long-term persistence of high IL-5 and IL-17F levels. None of the analyzed factors correlated with the detectability or levels of circulating S1 indicating that this represents an independent subset of patients with PASC. This data confirms prior evidence of immune dysregulation and persistence of viral protein in PASC and illustrates its biological heterogeneity that still awaits correlation with clinically defined PASC subtypes.
RESUMO
High antibody affinity against the ancestral SARS-CoV-2 strain seems to be necessary (but not always sufficient) for the control of emerging immune-escape variants. Therefore, aiming at strong B cell somatic hypermutation - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naive, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the booster, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529. Brief summaryPriming SARS-CoV-2 vaccinations generate antibodies from low-level matured B cells while the third vaccination strongly boosts somatic hypermutation potentially explaining different protection from immune-escape variants.
RESUMO
Post-acute sequelae of COVID-19 (PASC) emerge as a global problem with unknown molecular drivers. In a digital epidemiology approach, we rapidly recruited 8,077 individuals out of 129,733 households in Halle (Saale) to the cohort study for digital health research in Germany (DigiHero). These responded to a basic questionnaire followed by a PASC-focused survey and blood sampling in case of prior positive SARS-CoV-2 testing in their household. The presented analysis is based on the first 318 DigiHero participants, the majority thereof after mild infections. PASC were reported in 67.8% of cases, consisted predominantly in fatigue, dyspnea and concentration deficit, persisted in 60% over the follow-up period of on average eight months and their resolution was unaffected by post-infection vaccination. PASC was not associated with post-COVID-19 autoantibodies, but with elevated levels of IL-1{beta}, IL-6 and TNF-. Blood profiling and single-cell data from validation cohorts with early infection suggested the induction of these cytokines in COVID-19 lung pro-inflammatory macrophages creating a self-sustaining feedback loop. Our data indicate a long-lasting cytokine triad -potentially underlying PASC symptoms - to be driven by macrophage primed during infection. We demonstrate how the combination of digital epidemiology with selective biobanking can rapidly generate hints towards disease mechanisms.
RESUMO
Nearly all mass gathering events (MGEs) worldwide have been banned since the outbreak of SARS-CoV-2 as they are supposed to pose a considerable risk for transmission of COVID-19. We investigated transmission risk of SARS-CoV-2 by droplets and aerosols during an experimental indoor MGE (using N95 masks and contact tracing devices) and conducted a simulation study to estimate the resulting burden of disease under conditions of controlled epidemics. The number of exposed contacts was <10 for scenarios with hygiene concept and good ventilation, but substantially higher otherwise. Of subsequent cases, 0%-23% were attributable to MGEs. Overall, the expected additional effect of indoor MGEs on burden of infections is low if hygiene concepts are applied and adequate ventilation exists. One Sentence SummarySeated indoor events, when conducted under hygiene precautions and with adequate ventilation, have small effects on the spread of COVID-19.
