Abstract
BACKGROUND: SARS-CoV-2 infections and deaths have been lower in Africa than in other continents, which could be attributed to previous exposure to other pathogens that induce protective cross-immunity or modify the immune phenotype. We aimed to identify and characterise pre-existing cross-reactive immune responses to SARS-CoV-2 in an African population. METHODS: In this cross-sectional study, we determined the prevalence of SARS-CoV-2 serological cross-reactivity of 339 previously collected pre-pandemic (2000–19) serum samples from adults living in four villages in Zimbabwe (Mupfure, Mutoko, Chiredzi, and Murewa). We tested samples with a COVID-19 rapid diagnostic test then screened for cross-reactivity with peptides from the proteomes of seven human coronaviruses. We compared peptide location, coverage, and intensity and matched peptides predicted to be B-cell epitopes to the Human Immune Epitope Database (HIED). FINDINGS: Pre-SARS-CoV-2 serum samples from Mupfure and Murewa showed an overall prevalence of cross-reactivity with the SARS-CoV-2 rapid diagnostic test of 31·9% (95% CI 26·93–37·11). Peptide analysis of samples from all four villages highlighted complex IgM and IgG response profiles against peptides in the spike, nucleocapsid, and polyprotein 1AB proteins across all coronaviruses. Interrogating SARS-CoV-2 peptides recognised by IgG and IgM from the Zimbabwean serum samples against the HIED showed that most were either unique to SARS-CoV-2 or shared only with other betacoronaviruses. However, some SARS-CoV-2 peptides shared motifs with antigens from pathogens endemic to Zimbabwe, including Trypanosoma spp and Plasmodium spp, plant and food immunogens, and human autoantigens. INTERPRETATION: The effect of these cross-reactive antibodies on SARS-CoV-2 infection or COVID-19 is unknown; however, these antibodies should be considered when interpreting SARS-CoV-2 seroepidemiology studies and evaluating outcomes of COVID-19 vaccine trials in Africa. This study also calls for further characterisation of SARs-CoV-2 immune phenotypes and responses in African populations. FUNDING: Scottish Funding Council Global Challenges Research Fund Grant at the University of Edinburgh; UK National Institute for Health Research.