ABSTRACT
Background: SARS-CoV-2 infection leads to a broad range of clinical manifestations, from no symptoms to critical illness. Pre-stimulated innate defenses, rapid induction of SARS-CoV-2 responses and pre-existing crossreactive immunity to circulating human coronaviruses (HCoV) may early dampen SARS-CoV-2 infection, preventing symptomatic disease. Here we explore SARS-CoV-2 and HCoV antibody impact on asymptomatic infection in individuals first encountering SARS-CoV-2 in March 2020-March 2021 participating in a longitudinal pediatric cohort (n=2917) and a cross-sectional adult and children diagnostic cohort (n=882) in Switzerland. Method(s): Antibodies (Ab) to S1 of the four HCoV strains and SARS-CoV-2 antigens S1, RBD, S2 and N were determined in saliva (n=4993) and serum (n=7486) samples. Mucosal and systemic neutralization activity against wildtype SARS-CoV-2-Wuhan, and Alpha, Delta and Omicron (BA.2) variants of concerns (VoC) was assessed by pseudovirus neutralization in a subset of individuals. Result(s): Analysis of simultaneously sampled saliva and plasma revealed a strong correlation of mucosal and systemic SARS-CoV-2 anti-spike responses in recent infection. Notably, pre-existing high HCoV antibody response was significantly associated with higher systemic (IgG, IgA, and IgM, p< 0.001) and mucosal (IgG, p=0.03) SARS-CoV-2 responses following SARS-CoV-2 infection. Adjusting for age and sex, we found four saliva SARS-CoV-2 Ab parameters, namely total Ig S2, total Ig S1, IgA S2 and IgM S1 (p< 0.001, p< 0.001, p=0.02, p=0.01 respectively), inversely associated with salivary viral load highlighting the impact of mucosal Ab response on viral suppression. Saliva neutralization activity was modest but surprisingly broad, retaining same level activity against Wuhan, Alpha and Delta, but not Omicron BA.2, whereas plasma neutralization activity showed the typical decrease for all three VoCs compared to Wuhan. Most interestingly, asymptomatic individuals presented with higher IgG S2 antibody reactivity in saliva (p=0.03) and higher pre-existing HCoV-S1 IgG activity in plasma (HKU1, p=0.04) and saliva (total hCoV, p=0.02) suggesting immune factors that restrict disease severity. Conclusion(s): Focusing on a SARS-CoV-2 infection and vaccine naive population, our study reveals interdependencies of systemic and mucosal SARS-CoV-2 and HCoV immunity following primary SARS-CoV-2 infection and locates reactivities linked with reduced viral load and asymptomatic infection.
ABSTRACT
Background: Despite favorable vaccine responses of people with HIV (PWH), susceptibility to SARS-CoV-2 (SCv2) infection and increased risk of COVID-19 in immunocompromised PWH continue to be of concern. Here, we searched the Swiss HIV Cohort Study (SHCS) with>9500 actively enrolled, optimally treated PWH to identify factors associated with SCv2 infection in the pre-and postvaccination area. Method(s): We utilized information on SCv2 events reported to the SHCS in 2020 -2021. To detect asymptomatic infection, we screened pre-pandemic (2019) and pandemic (2020-2021) bio-banked plasma for SCv2 antibodies (Ab). SCv2+ and matched SCv2- PWH were additionally screened for Abs to circulating human coronaviruses (HCoV). Data were compared to HIV negative (HIV-) controls. SCv2 data and >26 behavioral, immunologic and disease-parameters available in the SHCS data base were analyzed by logistic regression, conditional logistic regression, and Bayesian multivariate regression. Result(s): Considering information on the SCv2 status of 6270 SHCS participants, neither HIV-1 viral load nor CD4+ T cell levels were linked with increased SCv2 infection risk. COVID-19-linked hospitalization (87/982) and case fatality rates (8/982) were low, but slightly higher than in the general Swiss population when stratified by age. Compared to HIV-, PWH had lower SCv2 IgG responses (median effect size= -0.48, 95%-Credibility-Interval=[-0.7, -0.28]). Consistent with earlier findings, high HCoV Abs pre-pandemic (2019) were associated with a lower risk of a subsequent SCv2-infection and, in case or infection, with higher Ab responses. Examining behavioral factors unrelated to the HIV-status, people living in single-person households were less at risk of SCv2 infection (aOR= 0.77 [0.66,0.9]). We found a striking, highly significant protective effect of smoking on SCv2 infection risk (aOR= 0.46 [0.38,0.56], p=2.6*10-14) which was strongest in 2020 prior to vaccination and was even comparable to the effect of early vaccination in 2021. This impact of smoking was highly robust, occurred even in previous smokers and was highest for heavy smokers. Conclusion(s): Our unbiased cohort screen identified two controversially discussed factors, smoking and cross-protection by HCoV responses to be linked with reduced susceptibility to SCv2, validating their effect for the general population. Overall weaker SCv2 Ab responses in PWH are of concern and need to be monitored to ensure infection- and vaccine-mediated protection from severe disease.
ABSTRACT
Background: Since January 2021, the two in Switzerland approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines tozinameran (Pfizer/Biontech) and elasomeran (Moderna) have been used to vaccinate the Swiss population. These vaccines were found to be safe in licensing trials with excellent efficacy of 95% and 94% in terms of preventing COVID-19 illness 14 days after the second vaccination. However, randomized evidence on the comparative effectiveness of both vaccines in immunocompromised patients is currently lacking. Methods: We conducted a parallel, two-arm (allocation 1:1) open-label, non-inferiority randomized clinical trial (RCT) nested into the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS). Patients living with HIV and solid organ transplant recipients (i.e. lung and kidney) from these cohorts were randomized to receive either tozinameran or elasomeran. The primary endpoint was an antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain using Elecsys® Anti-SARS-CoV-2 S assay from Roche (binary, cut-off ≥0.8 Units/ml) 12 weeks after first vaccination (8 weeks after second vaccination). Secondary outcomes were immune response measured with the Antibody CORonavirus Assay (ABCORA), clinical and safety outcomes. Results: A total of 430 patients were randomized and 412 were included in the intention-to-treat analysis (341 HIV patients and 71 solid organ transplant recipients). Antibody response was for elasomeran 92.1% (95% CI 88.4-95.8%;186/202) and for tozinameran 94.3% (95% CI 91.2-97.4%;198/210;difference:-2.2%;95% CI-7.1-2.7%), fulfilling non-inferiority of elasomeran. Overall, neutralization activity to SARS-CoV-2 Wuhan HU-1 strain was estimated to 96.5% (95% CI 94.5-98.4%) in HIV patients and 21.1% (95% CI 11.6-30.6%) in solid organ transplant recipients. 5 SARS-CoV-2 infections occurred (3 elasomeran;2 tozinameran) and 18 serious adverse event occurred (9 elasomeran;9 tozinameran). Conclusion: In immunocompromised patients the antibody response of elasomeran was comparable to tozinameran. People living with HIV had in general a sufficient immune response while a high proportion of transplant recipients had no immune response. Nearly 80% of patients with solid organ transplant have not developed neutralizing activity and need booster vaccination.
ABSTRACT
Background: Neutralizing antibodies are recognized as a principal correlate for protection induced by SARS-CoV-2 vaccines and have been considered for antiviral treatment as an active component in convalescent plasma therapy (CPT) and as monoclonal antibody therapeutics. However, unless used at a very early stage of infection, antibody-based SARS-CoV-2 therapies have not achieved the substantial disease-modulating effect hoped for. Methods: Here, we conducted a proof-of-principle study of CPT based on a phase I trial in thirty hospitalized COVID-19 patients with a median interval between the onset of symptoms and the first transfusion of 9 days (IQR, 7-11.8 days). A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients in conjunction with detailed post-hoc seroprofiling of transfused convalescent plasma allowed deciphering of parameters on which plasma therapy efficacy depends. Results: In this study, CPT was safe as evidenced by the absence of transfusion-related adverse events. We also observed an overall low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (p = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio (HR) = 3.0 [95% confidence interval (CI) 1.1;8.1], p = 0.026) (Figure 1). Endogenous immunity had strong effects on virus control. Lack of endogenous neutralizing activity at baseline was associated with a higher risk of systemic viremia. The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their endogenous neutralization status recipients benefitted from plasma therapy with high neutralizing antibodies (HR= 4.0 [95% CI 1.3;13], p = 0.017). Conclusion: In summary, our data demonstrate a clear impact of neutralizing antibody therapeutics on the rapid clearance of viremia and with this provide directions for improved efficacy evaluation of current and future SARS-CoV-2 therapies beyond antibody-based interventions. In particular, incorporating an assessment of the endogenous immune response and its dynamic interplay with viral production is critical for determining therapeutic effect.
ABSTRACT
Background: Remdesivir (RDV), an RNA-dependent RNA polymerase inhibitor of SARS-CoV-2, and its intravenous formulation excipient, cyclodextrin, are renally cleared. We sought to characterize whether RDV was associated with worsening renal function in hospitalized patients with moderate COVID-19. Methods: We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, oxygen saturation >94% on room air and eGFR ≥50 mL/ min/1.73m2. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone. Also included in this analysis were patients who enrolled in an extension phase of the trial, receiving 10d of RDV. RDV was dosed intravenously at 200 mg on d1 and 100 mg daily thereafter. Acute kidney injury (AKI) was defined as an increase in serum creatinine from baseline and classified as Stage 1 (increase > 0.3 and % change ≤25%, or % change >25% and ≤ 100%), Stage 2 (% change >100% and ≤200%), Stage 3 (% change >200%). For AKI development (ever/never for stage 1 or greater), age-adjusted risk ratios (RR) and 95% Wald confidence intervals (CI) were reported. Results: 1005 patients (822 [83%] RDV, 183 [17%] SoC) with creatinine values collected through d14 were evaluated. Baseline patient demographics, creatinine, and eGFR were mostly similar between RDV vs SoC arms. Worsening renal function was observed less frequently in patients receiving RDV vs SOC (7% vs 10%, p=0.03, Table). After adjustment for age, there was no significant association of RDV with risk of AKI relative to SoC (RR=0.66;95% CI 0.40, 1.09). Most AKI events were observed in patients with baseline eGFR >90 mL/min, with few events occurring in patients with a baseline eGFR 50-59 mL/min. In patients who developed Stage 3 AKI, those treated with RDV (n=2, 0.2%) returned to baseline creatinine values while those on SOC (n=4, 2%) remained elevated to d14. No difference in AKI between treatment arms was observed in patients with a history of chronic kidney disease (CKD;RDV: n=6 [12%] vs SOC: n=2 [40%] p=0.14). Older age, history of CKD, and eGFR status at baseline were independently associated with worsening renal function. Conclusion: AKI events were observed less frequently in patients with moderately severe COVID-19 patients treated with RDV compared to SoC.