Multiple SARS-CoV-2 Immunizations of an Unvaccinated Population Lead to Complex Immunity. A T Cell Reactivity Study of Blood Donors in Antananarivo

Madagascar has undergone five COVID-19 waves since March 2020. The immunological background developed by the population following multiple exposures to different variants in a context of extremely poor overall vaccination has not been described, but is essential to better apprehend the impact of future outbreaks.In this study, serological analysis and specific T cell response descriptions were used to describe the history of exposures of the capital’s blood donors to SARS-CoV-2 and its VOCs. Samples were collected between January and April 2022 at the regional blood transfusion centre in Madagascar’s Capital Antananarivo. Pools of multiple strains of SARS-CoV-2 immunogenic peptides were used in an IFN-γ secretion ELISPOT assay to characterize the specific T cell immunity developed by the Capital’s blood donors to these potential epitopes.Multiple waves have led to 92·1% of donors have detectable antibodies developed against SARS-CoV-2 and 94·8% have developed specific T cell lymphocytes to SARS-CoV-2. Heterogeneous reactivities to different strain-derived peptides were found suggesting multiple immunological backgrounds in the study population. These backgrounds include 16·1% of individuals exposed at least once to a unique SARS-CoV-2 strain, 27·1% at least once to 2 strains, 28·5% at least once to 3 strains, and 23·1% at least once to four distinct strains.Cross-reactivity increased with multiple exposures but did not decrease the risk of infection by another strain. These results describe how multiple natural immunizations lead to an extremely complex immunological background.Funding: This work was supported by UNICEF and by the French Ministry for Europe and Foreign Affairs through the REPAIR COVID-19-Africa project coordinated by the Pasteur International Network association.Declaration of Interest: The authors declare that they have no competing interest.Ethical Approval: This study is part of the surveillance of SARS-CoV-2 conducted by the Pasteur Institut of Madagascar with the Ethics and Biomedical Research Committee of the Ministry of Public Health approval (CERBM: IORG0000851).