Immunological drivers of the transition from epidemicity to endemicity of SARS-CoV-2 in a high transmission LMIC setting

PROJECT SUMMARY Although new variants may contribute to surges, we expect SARS-CoV-2 to transition to a new phase where the virus continues to circulate but at lower levels. Sequential immunizing exposures, whether due to infection or vaccination, have transformed the immune status of populations by cumulatively increasing antibody levels and increasing the breadth of antigenic targeting of SARS-CoV-2 by antibodies. The relative role of increased magnitude of antibody responses or broadening of antigenic recognition of SARS-CoV-2 in protecting populations from infection is not known. Strikingly, though mucosal responses have been found to play key roles in protecting individuals from infection, SARS-CoV-2 literature has focused almost exclusively on serological responses. Effective policy and investment in public health measures as the pandemic continues will require information on the relative importance of specific immune responses. Gathering evidence in diverse settings including low and middle income countries (LMIC) is particularly important as the immunizing exposure history in these settings has been different (in terms of infections and vaccine use) and a smaller evidence base is available from these settings. Our proposed work seeks to continue to interrogate SARS-CoV-2 immunity in a cohort residing in an urban slum community in Brazil which we have followed since 2003. We identified an extraordinarily high SARS-CoV-2 attack rate (75%) during two epidemic waves with D614G and Gamma variants. Subsequent vaccination has generated hybrid immunity in a large proportion of our cohort. Our proposed study would investigate the relative role of antibody magnitude and breadth within systemic and mucosal compartments in protecting this population from infection. To accomplish this, we propose to conduct serologic and virologic surveillance in this community and develop tools to interpret serological measures of infection that address a key epidemiological challenge for the world in continued characterization of infection during the next phase of the pandemic. Our proposal leverages a 27-year scientific collaboration with the Brazilian Ministry of Health, an extensive track record of interrogating SARS-CoV-2 immunity, novel assays and analytical methods to infer infection histories and characterize multi-antigen immune responses. Our study will generate key evidence to inform the development of novel vaccines (intranasal, multi-antigen) and a new approach to tracking SARS-CoV-2 infections in populations with pre-existing immunity where symptom-based virologic surveillance may give an insufficient view of viral transmission.