PROJECT SUMMARY The COVID-19 pandemic has resulted in vastly different health outcomes for populations in Sub-Saharan Africa as compared to other countries with comparatively higher case numbers and deaths. The comparatively low numbers of cases and deaths reported in the Democratic Republic of Congo (DRC) and Nigeria, as well as throughout sub-Saharan Africa, are likely reflective of poor healthcare infrastructure and limited testing capacity. It is also unclear how the level of transmission of SARS-CoV-2 in urban vs. rural settings may influence COVID- 19 severity and the subsequent identification of cases by testing sites in both countries. Our overarching hypothesis is that prior exposure to related coronaviruses and other pathogens, which partition differentially in urban vs. rural communities, have resulted in significant cross-protective immunity or innate immune priming in the population, which leads to a reduced COVID-19 burden in these countries. We will leverage ongoing longitudinal cohort studies in urban and rural sites in the DRC and Nigeria, to support the characterization of: (i) the incidence of and risk factors for SARS-CoV-2 infection and COVID-19 severity, (ii) the current distribution and severity of respiratory/non-respiratory viral and non-viral pathogens as a cause of non-COVID-19 acute febrile illness, and (iii) role that exposure to syndemic pathogens have on COVID-19 severity. To this end, we propose to describe the incidence and prevalence of SARS-CoV-2 using seroepidemiology and describe factors associated with incidence and recovery (AIM1) and the epidemiology of respiratory and non-respiratory viral or parasitic pathogens viz. acute febrile illness (AFI) during the COVID-19 pandemic (AIM2). Our long-standing relationships through community engagement activities, and direct ties to the Public Health ministries as well as the Africa Centres for Disease Control allow us to obtain and convey accurate data at local resolution. We envision that this multinational surveillance project will provide much needed insight into the epidemiology of SARS-CoV-2 infection and COVID-19 disease in the DRC and Nigeria, elucidating differences in the incidence and disease outcomes across a range of urban vs. rural settings, which in turn can inform public health policy and control measures at country and regional levels.