The COVID-19 pandemic had a severe impact globally, yet African populations exhibited unexpectedly lower rates of severe disease and mortality. We investigated the potential role of pre-existing immunity in shaping the epidemiology of COVID-19 in Africa. Leveraging paired plasma and peripheral blood mononuclear cells collected from Senegalese female sex workers prior to the COVID-19 pandemic, we observed substantial levels of pre-existing cross-reactive immunity to SARS-CoV-2, stemming from prior exposure to seasonal human coronaviruses (hCoVs). Our antibody analysis revealed a 23.5% (47/200) seroprevalence rate against SARS-CoV-2 nucleocapsid (N). Of these SARS-CoV-2 N-reactives, 85.1% (40/47), 44.7% (21/47), and 95.7% (45/47) showed antibody reactivity against hCoV-229E or hCoV-OC43 spike (S) and/or N or hCoV-HKU1 S. Our analysis of cellular responses also demonstrated cross-reactivity to SARS-CoV-2 with 82.2% (37/45) and 84.4% (38/45) showing IFN-γ responses against S and N, respectively. These findings suggest that prior hCoV exposure may induce cross-reactive adaptive immunity, potentially contributing to protection against COVID-19. A unique pre-pandemic subject had cross-reactive SARS-CoV-2 S antibodies with detectable neutralization and cellular responses. Our study provides unique insights into the dynamics of hCoV and SARS-CoV-2 immunity in West African populations and underscores the importance of understanding the role of pre-existing immunity in shaping COVID-19 outcomes globally.

The authors have declared no competing interest.

This study was funded by a grant to Harvard University, Center for African Studies, Motsepe Presidential Research Accelerator Fund for Africa

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At the time of the original study, all women provided informed consent for the collection and archiving of samples and corresponding data; ethical clearance from the Harvard Institutional Review Board (IRB) and the research ethics committee at Chiekh Anta Diop University, Dakar, Senegal were obtained. All archived samples and corresponding data were anonymized, and as such this secondary analysis did not constitute human subject research by institutional guidelines and regulations which follow the Federal Policy for Protection of Human Subjects.

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