Inflammatory profiles are associated with long COVID up to 6 months after illness onset: a prospective cohort study of individuals with mild to critical COVID-19 (preprint)

Background After initial COVID-19 disease, immune dysregulation may persist and drive post-acute sequelae of COVID-19 (PASC). We described longitudinal trajectories of cytokines in adults up to 6 months following SARS-CoV-2 infection and explored early predictors of PASC. Methods RECoVERED is a prospective cohort of individuals with laboratory-confirmed SARS-CoV-2 infection between May 2020 and June 2021 in Amsterdam, the Netherlands. Serum was collected at weeks 4, 12 and 24 of follow-up. Monthly symptom questionnaires were completed from month 2 after illness onset onwards; lung diffusion capacity (DLCO) was tested at 6 months. Cytokine concentrations were analysed by human magnetic Luminex screening assay. We used a linear mixed-effects model to study log-concentrations of cytokines over time, assessing their association with socio-demographic and clinical characteristics that were included in the model as fixed effects. Results 186/349 (53%) participants had [≥]2 serum samples and were included. Of these, 101 (54%: 45/101[45%] female, median age 55 years [IQR=45-64]) reported PASC at 12 and 24 weeks after illness onset. We included 37 reference samples (17/37[46%] female, median age 49 years [IQR=40-56]). PASC was associated with raised CRP and abnormal diffusion capacity with raised IL10, IL17, IL6, IP10 and TNF at 24 weeks in the multivariate model. Early (0-4 week) IL-1{beta} and BMI at illness onset were predictive of PASC at 24 weeks. Conclusions Our findings indicate that immune dysregulation plays an important role in PASC pathogenesis, especially among those individuals with reduced pulmonary function. Early IL-1{beta} shows promise as predictors of PASC.

Selection of long COVID symptoms influences prevalence estimates in a prospective cohort (preprint)

Background: Studies on long COVID differ in the selection of symptoms used to define the condition. We aimed to assess to what extent symptom selection impacts prevalence estimates of long COVID. Methods: In a prospective cohort of patients who experienced mild to critical coronavirus disease 2019 (COVID-19), we used longitudinal data on the presence of 20 different symptoms to evaluate changes in the prevalence of long COVID over time when altering symptom selection. Results: Changing symptom selection resulted in wide variation in long COVID prevalence, even within the same study population. Long COVID prevalence at 12 months since illness onset ranged from 39.6% (95%CI=33.4-46.2) when using a limited selection of symptoms to 80.6% (95%CI=74.8-85.4) when considering any reported symptom to be relevant. Conclusions: Comparing the occurrence of long COVID is already complex due to heterogeneity in study design and population. Disparate symptom selection may further hamper comparison of long COVID estimates between populations. Harmonised data collection tools could be one means to achieve greater reproducibility and comparability of results.

Four SARS-CoV-2 vaccines induce quantitatively different antibody responses against SARS-CoV-2 variants (preprint)

BackgroundEmerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants. MethodsIn a prospective cohort of 165 SARS-CoV-2 naive health care workers, vaccinated with either one of four vaccines (BNT162b2, mRNA-1273, AZD1222 or Ad26.COV2.S), we performed a head-to-head comparison of the ability of sera to recognize and neutralize SARS-CoV-2 variants of concern (VOCs; Alpha, Beta, Gamma, Delta and Omicron). Repeated serum sampling was performed 5 times during a year (from January 2021 till January 2022), including before and after booster vaccination with BNT162b2. FindingsFour weeks after completing the initial vaccination series, SARS-CoV-2 wild-type neutralizing antibody titers were highest in recipients of BNT162b2 and mRNA-1273 (geometric mean titers (GMT) of 197 [95% CI 149-260] and 313 [95% CI 218-448], respectively), and substantially lower in those vaccinated with the adenovirus vector-based vaccines AZD1222 and Ad26.COV2.S (GMT of 26 [95% CI 18-37] and 14 [95% CI 8-25] IU/ml, respectively). These findings were robust for adjustment to age and sex. VOCs neutralization was reduced in all vaccine groups, with the largest (9- to 80-fold) reduction in neutralization observed against the Omicron variant. The booster BNT162b2 vaccination increased neutralizing antibody titers for all groups with substantial improvement against the VOCs including the Omicron variant. Study limitations include the lack of cellular immunity data. ConclusionsOverall, this study shows that the mRNA vaccines appear superior to adenovirus vector-based vaccines in inducing neutralizing antibodies against VOCs four weeks after initial vaccination and after booster vaccination.

Cross-reactive antibodies after SARS-CoV-2 infection and vaccination (preprint)

Current SARS-CoV-2 vaccines are losing efficacy against emerging variants and may not protect against future novel coronavirus outbreaks, emphasizing the need for more broadly protective vaccines. To inform the development of a pan-coronavirus vaccine, we investigated the presence and specificity of cross-reactive antibodies against the spike (S) proteins of human coronaviruses (hCoV) after SARS-CoV-2 infection and vaccination. We found an 11 to 123-fold increase in antibodies binding to SARS-CoV and MERS-CoV as well as a 2 to 4-fold difference in antibodies binding to seasonal hCoVs in COVID-19 convalescent sera compared to pre-pandemic healthy donors, with the S2 subdomain of the S protein being the main target for cross-reactivity. In addition, we detected cross-reactive antibodies to all hCoV S proteins after SARS-CoV-2 S protein immunization in macaques, with higher responses for hCoV more closely related to SARS-CoV-2. These findings support the feasibility of and provide guidance for development of a pan-coronavirus vaccine.

Emerging SARS-CoV-2 variants of concern evade humoral immune responses from infection and vaccination (preprint)

Emerging SARS-CoV-2 variants pose a threat to human immunity induced by natural infection and vaccination. We assessed the recognition of three variants of concern (B.1.1.7, B.1.351 and P.1) in cohorts of COVID-19 patients ranging in disease severity (n = 69) and recipients of the Pfizer/BioNTech vaccine (n = 50). Spike binding and neutralization against all three VOC was substantially reduced in the majority of samples, with the largest 4-7-fold reduction in neutralization being observed against B.1.351. While hospitalized COVID-19 patients and vaccinees maintained sufficient neutralizing titers against all three VOC, 39% of non-hospitalized patients did not neutralize B.1.351. Moreover, monoclonal neutralizing antibodies (NAbs) show sharp reductions in their binding kinetics and neutralizing potential to B.1.351 and P.1, but not to B.1.1.7. These data have implications for the degree to which pre-existing immunity can protect against subsequent infection with VOC and informs policy makers of susceptibility to globally circulating SARS-CoV-2 VOC.