Magdalena Schwarzmüller

Despite suppressive antiretroviral therapy, many people with HIV (PWH) retain chronic interferon-associated immune dysregulation. Observational data from the Swiss HIV Cohort Study linked asymptomatic mycobacterial exposure to lower viral set points, reduced interferon-associated activity, and attenuated HIV-specific antibody responses, a pattern sharing features with HIV elite controllers and natural hosts of primate lentiviruses. We therefore examined whether Bacillus Calmette-Guérin (BCG) vaccination could induce a related immune configuration in ART-treated PWH. Using longitudinal systems-level profiling within the BELIEVE trial, we found that BCG reduced constitutive NK cell IFN-γ production and PBMC-mediated direct cytotoxicity without impairing inducible cytokine responses or antibody-dependent cellular cytotoxicity. Multiomic and proteomic analyses showed reduced interferon- and activation-associated programs, while adaptive immune parameters remained largely stable and follow-up revealed no obvious adverse clinical pattern. This configuration, reduced baseline interferon activity coexisting with preserved Fc-dependent effector function, shares selected features with immune states described in natural lentiviral control and provides a rationale for testing BCG in combination with antibody-based HIV interventions.

BACKGROUND. Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated. METHODS. We conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7–11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends. RESULTS. In this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and 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, 3.0; 95% CI, 1.1–8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1–11; P = 0.034). CONCLUSION. Our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT04869072. FUNDING. This study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program “Comprehensive Genomic Pathogen Detection” of the University of Zurich.

Determination of SARS-CoV-2 antibody responses in the context of pre-existing immunity to circulating human coronavirus (HCoV) is critical for understanding protective immunity. Here we perform a multifactorial analysis of SARS-CoV-2 and HCoV antibody responses in pre-pandemic (N = 825) and SARS-CoV-2-infected donors (N = 389) using a custom-designed multiplex ABCORA assay. ABCORA seroprofiling, when combined with computational modeling, enables accurate definition of SARS-CoV-2 seroconversion and prediction of neutralization activity, and reveals intriguing interrelations with HCoV immunity. Specifically, higher HCoV antibody levels in SARS-CoV-2-negative donors suggest that pre-existing HCoV immunity may provide protection against SARS-CoV-2 acquisition. In those infected, higher HCoV activity is associated with elevated SARS-CoV-2 responses, indicating cross-stimulation. Most importantly, HCoV immunity may impact disease severity, as patients with high HCoV reactivity are less likely to require hospitalization. Collectively, our results suggest that HCoV immunity may promote rapid development of SARS-CoV-2-specific immunity, thereby underscoring the importance of exploring cross-protective responses for comprehensive coronavirus prevention.

Importance: Understanding transmission and impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in school children is critical to implement appropriate mitigation measures. Objective: To determine the variation in SARS-CoV-2 seroprevalence in school children across districts, schools, grades, and classes, and the relationship of SARS-CoV-2 seroprevalence with self-reported symptoms. Design: Cross-sectional analysis of baseline measurements of a longitudinal cohort study (Ciao Corona) from June-July 2020. Setting: 55 randomly selected schools and classes stratified by district in the canton of Zurich, Switzerland (1.5 million inhabitants). Participants: Children, aged 6-16 years old, attending grades 1-2, 4-5 and 7-8. Exposure: Exposure to circulating SARS-CoV-2 between February and June 2020 including public lock-down and school closure (March 16-May 10, 2020). Main Outcomes and Measures: Variation in seroprevalence of SARS-CoV-2 in children across 12 cantonal districts, schools, and grades using a Luminex-based antibody test with four targets for each of IgG, IgA and IgM. Clustering of cases within classes. Analysis of associations of seropositivity and symptoms. Comparison of seroprevalence with a randomly selected adult population, based on Luminex-based IgG and IgA antibody test of Corona Immunitas. Results: In total, 55 schools and 2585 children were recruited (1337 girls, median age 11, age range 6-16 years). Overall seroprevalence was 2.8 % (95% CI 1.6–4.1%), ranging from 1.0% to 4.5% across districts. Seroprevalence was 3.8% (1.9-6.1%) in grades 1-2, 2.5% (1.1-4.2%) in grades 4-5, and 1.5% (0.5-3.0%) in grades 7–8. At least one case was present in 36/55 tested schools and in 43/128 classes with ≥50% participation rate and ≥5 children tested. 73% of children reported COVID-19 compatible symptoms since January 2020, but none were reported more frequently in seropositive compared to seronegative children. Seroprevalence of children was very similar to seroprevalence of randomly selected adults in the same region in June-July 2020, measured with the same Corona Immunitas test, combining IgG and IgA (3.1%, 95% CI 1.4-5.4%, versus 3.3%, 95% CI 1.4-5.5%). Conclusions and Relevance: Seroprevalence was inversely related to age and revealed a dark figure of around 90 when compared to 0.03% confirmed PCR+ cases in children in the same area by end of June. We did not find clustering of SARS-CoV-2 seropositive cases in schools so far, but the follow-up of this school-based study will shed more light on transmission within and outside schools. Trial registration: http://ClinicalTrials.gov Identifier: NCT04448717 , registered June 26, 2020. https://clinicaltrials.gov/ct2/show/NCT04448717 Key Points: Question: What is the variation in seroprevalence of SARS-CoV-2 cases in school children across districts, schools and classes? Findings: Among 55 randomly selected schools and 2585 children, 2.8 % (95% CI 1.6-4.1%) of children had SARS-CoV-2 antibodies, similar to the seroprevalence in the adult population in the same region but showing a much higher dark figure (89 versus 12 in adults). A third of tested classes had at least one SARS-CoV-2 case, and higher seroprevalence was observed in lower grades. Seropositive children did not report SARS-CoV-2 infection symptoms more often than seronegative children. Meaning: The results so far do not suggest substantial transmission within schools. In contrast to the current literature, younger children seem to be infected slightly more often; the striking dark figure of 89 could be partly due to the fact that symptoms compatible with COVID - 19 were highly prevalent in children and do not help to differentiate between seropositive and seronegative children.