COVID Transmission and Morbidity in Malawi (COVID-TMM)

PROJECT SUMMARY SARS-CoV-2 transmission was expected to have a devastating impact in sub-Saharan African countries. Instead, morbidity and mortality rates in nearly the whole region are an order of magnitude lower than in Europe and the Americas. To identify what is different requires a better understanding of the underlying immunological substrate of the population, and how these factors affect susceptibility to infection, progression of symptoms, transmission, and responses to SARS-CoV-2 vaccination. These populations are assaulted by many infectious diseases, including malaria. Exposure to these pathogens can produce long-lasting changes in the innate immune system, which may confer decreased susceptibility to heterologous infections. By generating rapid responses to the virus, the innate immune system can decrease the susceptibility to SARS-CoV-2 infection and the risk of progression from infection to disease. On the other hand, malaria infections and helminthiasis can impair the acquisition and longevity of antibody (Ab)- induced immunity through several mechanisms, including tolerogenic innate immune responses. In addition to malaria, other co-morbidities, e.g., anemia and chronic undernutrition, are likely to affect Ab-mediated immunity. We hypothesize that malaria and helminthiasis affect morbidity of SARS-CoV-2 in sub-Saharan Africa. Compared to Western populations, both uninfected and infected-but-asymptomatic subjects will have enhanced innate immune phenotypes. Most infections will be asymptomatic. Once infected, though, malaria, infections with intestinal parasites, anemia, and mild undernutrition will decrease the acquisition and longevity of Ab responses, increasing the risk of re-infection. These comorbidities will also reduce longevity of Ab responses elicited by the Astrazeneca vaccine. To test these hypotheses, we will enroll 200 symptomatic individuals (index cases), their household contacts, and 300 vaccinees. We will assess the specific innate immune phenotypes that differentiate uninfected Malawians from Western controls and whether those responses are protecting Malawians from infection and/or progression of disease. We will follow infected participants and vaccinees for 1.5 years to assess acquisition and longevity of Ab responses and memory B cells. The work will be supported by a platform established on the basis of long-term collaborations with the Ministry of Health and the University of Malawi. As global vaccination campaigns launch, data to optimize vaccination in sub-Saharan countries are urgently needed. Identifying groups at high risk of infection and disease and understanding the susceptibility of the local population will help to define optimal vaccination policies to control transmission. Identifying "hypo- responders" and those whose Ab responses wane more quickly will help to optimize vaccination regimen. In summary, data generated by this study will improve our general understanding of SARS-CoV-2 transmission and pathogenesis and will allow regional vaccination programs to be designed for maximum effectiveness.