Longitudinal tracking of B cell and functional antibody responses to SARS-CoV-2 and other human coronaviruses in Africa

Background and Rationale: In contrast to soaring COVID-19 case numbers during pandemic waves in the Americas and Europe, large parts of Africa have reported relatively low numbers of SARS-CoV-2 infections and COVID-19-related deaths. Hypotheses to explain this observation include differential innate and adaptive immune mechanisms of protection in different populations. Cross-protective immunity from prior exposure to endemic coronaviruses (HCoVs) and "trained" immunity from other pathogen exposures in Africa are suspected, but data are limited. Much has been learnt about immune responses to SARS-CoV-2 in U.S. and European COVID-19 patients, contributing to the development of effective vaccines. Similar studies in African populations with different immunological backgrounds are urgently required to define shared and distinct, potentially beneficial features of immune responses to SARS-CoV-2 and to investigate the nature and longevity of infection- and vaccine-induced immunity.Goal and Specific Objectives: The goal of this project is to characterize immune responses of rural and urban populations in Ghana to SARS-CoV-2 and HCoVs, and to COVID-19 vaccination. Results will be compared to available data from U.S. COVID-19 patients and vaccinees. Specific objectives are (i) to determine the point prevalence and longitudinal development of serum and saliva antibodies to SARS-CoV-2 and HCoVs in individuals from rural and urban areas, (ii) to conduct a detailed analysis of antibody specificities and effector functions in serum and saliva from study participants who had been infected with SARS-CoV-2, and/or HCoVs, and/or received COVID-19 vaccines, (iii) to analyze clonal B cell lineages in study participants to identify specific characteristics of class switching, immunoglobulin heavy (IGH) chain gene segment usage, and IGH complementarity-determining region-3 length and somatic hypermutation, and (iv) to develop monoclonal antibody (mAb)-based point of care (POC) tools to identify SARS-CoV-2 variant and HCoV infections.Methods: Study participants will be enrolled in rural and urban Ghana with longitudinal blood, saliva, and nasopharyngeal swab collection. We will use enzyme-linked immunosorbent-, Luminex-, and cell-based assays to examine functional properties of antibodies and high-throughput sequencing of B cell receptor (BCR) rearrangements combined with computational analysis pipelines to study clonal B cell lineages. Mouse and human mAbs will be generated using hybridoma technology and antigen-specific single B cell sorting.Expected Results: Results will shed light on SARS-CoV-2 and HCoV infection prevalence in rural and urban Ghana and give insights into the effects of HCoV immunity on the susceptibility of populations to SARS-CoV-2. Analysis of functional humoral and mucosal antibody responses and BCR repertoires will reveal characteristics of African immune responses and improve understanding of the potential interplay of local and systemic antibody-mediated immunity. SARS-CoV-2 variant- and HCoV-specific POC assays will provide tools for epidemiological studies on the prevalence and types of coronavirus infections.Impact: Comparative study of pre-existing and SARS-CoV-2 infection-elicited functional antibody responses and BCR repertoire features in Ghanaian versus other populations have the potential to reveal correlates of protection that may help explain differences in the impact of the COVID-19 pandemic on different continents. Analysis of antibody and B cell responses to COVID-19 vaccination will provide valuable information on characteristics and potential impairments of vaccine-elicited immunity in rural versus urban populations to inform public health action.