Much of sub-Saharan Africa has fared the SARS-CoV-2 pandemic with reduced disease and death even with low uptake of vaccines, little to no infection mitigation strategies, and clear serologic evidence of infection. While warmer weather, a youthful population, and microbiome have been posited to explain the differences in Africa compared to Americas, we aimed to determine if there was a unique humoral immune response to SARS-CoV-2. To do this, we analyzed SARS-CoV-2 seropositive and seronegative samples from Nairobi, Kenya and compared to a cohort collected in the US in late 2020. We measured the levels of antibodies (Abs) against SARS-CoV-2 Spike [S], receptor binding domain [RBD], and nucleocapsid [N] and hCoVs (229E, NL63, OC43, HKU1) S using a multiplexed Luminex-based assay, and we measured induction of antiviral Ab functions including Ab-dependent cellular phagocytosis (ADCP), neutrophil phagocytosis (ADNP), neutralization, NK cell activation (ADNKA), and complement deposition (ADCD). Correlation network analysis revealed that Ab effector functions were strongly associated with SARS-CoV-2 S, RBD and N-specific Abs in both Kenyan- and US-based cohorts. Surprisingly, we observed that hCoV-specific Abs were correlated with the effector functions against SARS-CoV-2 in the Kenyan samples, but not in the US samples. A subset of Kenyan seronegative subjects displayed ADCP and ADNP against SARS-CoV-2, which was reduced when HKU1-specific IgG was depleted from samples, suggesting cross-reactive Ab responses from hCoVs may augment SARS-CoV-2 immunity. Thus, together these data suggests that unique Ab-mediated functions induced by hCoVs in Africa may help explain the disparity in COVID- 19 severity observed across the globe.
