Seroprofiling of antibodies against endemic human coronaviruses and SARS-CoV-2 in an HIV cohort in Lesotho: correlates of antibody response and seropositivity.

BACKGROUND: Serological data on endemic human coronaviruses (HCoVs) and SARS-CoV-2 in southern Africa are scarce. Here, we report on i) endemic HCoV seasonality, ii) SARS-CoV-2 seroprevalence, and iii) predictive factors for SARS-CoV-2 seropositivity and strength of SARS-CoV-2 and HCoV serological response during a 17-month period at the start of the COVID-19 pandemic among adults living with HIV. METHODS: Plasma samples were collected from February 2020 to July 2021 within an outpatient HIV cohort in Lesotho. We used the ABCORA multiplex immunoassay to measure antibody responses to endemic HCoV (OC43, HKU1, NL63, and 229E) and SARS-CoV-2 antigens. RESULTS: Results of 3'173 samples from 1'403 adults were included. Serological responses against endemic HCoVs increased over time and peaked in winter/spring. SARS-CoV-2 seropositivity reached >35% among samples collected in early 2021 and was associated with female sex (p = 0.004), obesity (p < 0.001), working outside the home (p = 0.02), and recent tiredness (p = 0.005) or fever (p = 0.007). Positive correlations were observed between the strength of response to endemic HCoVs and to SARS-CoV-2, and between older age or obesity and the IgG response to SARS-CoV-2. CONCLUSIONS: These results add to our understanding of the impact of biological, clinical, and social/behavioural factors on serological responses to coronaviruses in southern Africa.

Antibody response to a third SARS-CoV-2 vaccine dose in recipients of an allogeneic haematopoietic cell transplantation.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.

Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response.

BACKGROUNDNeutralizing 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.METHODSWe 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.RESULTSIn 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).CONCLUSIONOur 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 REGISTRATIONClinicalTrials.gov NCT04869072.FUNDINGThis 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.

Determinants of antibody response to severe acute respiratory syndrome coronavirus 2 mRNA vaccines in people with HIV.

We identified determinants of SARS-CoV-2 mRNA vaccine antibody response in people with HIV (PWH). Antibody response was higher among PWH less than 60 years, with CD4+ cell count superior to 350 cells/µl and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response. Elderly PWH and those with low CD4+ cell count should be prioritized for booster vaccinations.

Antibody Response to SARS-CoV-2 Vaccination in Patients following Allogeneic Hematopoietic Cell Transplantation.

Vaccines against SARS-CoV-2 have been rapidly approved. Although pivotal studies were conducted in healthy volunteers, little information is available on the safety and efficacy of mRNA vaccines in immunocompromised patients, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). Here we used a novel assay to analyze patient- and transplantation-related factors and their influence on immune responses to SARS-CoV-2 vaccination over an extended period (up to 6 months) in a large and homogenous group of allo-HCT recipients at a single center in Switzerland. We examined longitudinal antibody responses to SARS-CoV-2 vaccination with BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna) in 110 allo-HCT recipients and 86 healthy controls. Seroprofiling recording IgG, IgA, and IgM reactivity against SARS-CoV-2 antigens (receptor-binding domain, spike glycoprotein subunits S1 and S2, and nucleocapsid protein) was performed before vaccination, before the second dose, and at 1, 3, and 6 months after the second dose. Patients were stratified to 3 groups: 3 to 6 months post-allo-HCT, 6 to 12 months post-allo-HCT, and >12 months post-allo-HCT. Patients in the 3 to 6 months and 6 to 12 months post-allo-HCT groups developed significantly lower antibody titers after vaccination compared with patients in the >12 months post-allo-HCT group and healthy controls (P < .001). Within the cohort of allo-HCT recipients, patients age >65 years (P = .030), those receiving immunosuppression for prevention or treatment of graft-versus-host disease (GVHD) (P = .033), and patients with relapsed disease (P = .014) displayed low humoral immune responses to the vaccine. In contrast, the intensity of the conditioning regimen, underlying disease (myeloid/lymphoid/other), and presence of chronic GVHD had no impact on antibody levels. Antibody titers achieved the highest levels at 1 month after the second dose of the vaccine but waned substantially in all transplantation groups and healthy controls over time. This analysis of long-term vaccine antibody response is of critical importance to allo-HCT recipients and transplant physicians to guide treatment decisions regarding revaccination and social behavior during the SARS-CoV-2 pandemic.

Multifactorial seroprofiling dissects the contribution of pre-existing human coronaviruses responses to SARS-CoV-2 immunity.

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.

Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19.

Immune response dynamics in coronavirus disease 2019 (COVID-19) and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163+ monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.

Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis.

Immune responses to respiratory viruses like SARS-CoV-2 originate and function in the lung, yet assessments of human immunity are often limited to blood. Here, we conducted longitudinal, high-dimensional profiling of paired airway and blood samples from patients with severe COVID-19, revealing immune processes in the respiratory tract linked to disease pathogenesis. Survival from severe disease was associated with increased CD4 + T cells and decreased monocyte/macrophage frequencies in the airway, but not in blood. Airway T cells and macrophages exhibited tissue-resident phenotypes and activation signatures, including high level expression and secretion of monocyte chemoattractants CCL2 and CCL3 by airway macrophages. By contrast, monocytes in blood expressed the CCL2-receptor CCR2 and aberrant CD163 + and immature phenotypes. Extensive accumulation of CD163 + monocyte/macrophages within alveolar spaces in COVID-19 lung autopsies suggested recruitment from circulation. Our findings provide evidence that COVID-19 pathogenesis is driven by respiratory immunity, and rationale for site-specific treatment and prevention strategies.

Analysis of respiratory and systemic immune responses in COVID-19 reveals mechanisms of disease pathogenesis (preprint)

Immune responses to respiratory viruses like SARS-CoV-2 originate and function in the lung, yet assessments of human immunity are often limited to blood. Here, we conducted longitudinal, high-dimensional profiling of paired airway and blood samples from patients with severe COVID-19, revealing immune processes in the respiratory tract linked to disease pathogenesis. Survival from severe disease was associated with increased CD4+T cells and decreased monocyte/macrophage frequencies in the airway, but not in blood. Airway T cells and macrophages exhibited tissue-resident phenotypes and activation signatures, including high level expression and secretion of monocyte chemoattractants CCL2 and CCL3 by airway macrophages. By contrast, monocytes in blood expressed the CCL2-receptor CCR2 and aberrant CD163+ and immature phenotypes. Extensive accumulation of CD163+monocyte/macrophages within alveolar spaces in COVID-19 lung autopsies suggested recruitment from circulation. Our findings provide evidence that COVID-19 pathogenesis is driven by respiratory immunity, and rationale for site-specific treatment and prevention strategies.