Investigation of sarbecovirus exposure patterns and development of pan-SARS-CoV-2 neutralizing antibody responses in high-risk cohorts in Myanmar

PROJECT SUMMARY Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a global challenge to the effectiveness of existing and future vaccines. This project will address questions surrounding the immunological response to different sarbecovirus exposure patterns with implications for vaccine development by conducting longitudinal repeated surveillance of unique human populations, previously determined to be highly exposed to a diversity of SARS-CoV-2-related coronaviruses in Myanmar. There is a timely opportunity to follow these communities, particularly immediately following SARS-CoV-2 infection and/or vaccination to understand which previous sarbecovirus exposure patterns expand the likelihood of development of pan-sarbecovirus neutralizing antibodies. We will evaluate the impact of diverse patterns of natural and vaccination-based sarbecovirus exposure on development of pan- sarbecovirus neutralizing antibodies by following three specific human cohorts: (1) elephant loggers engaged in bushmeat hunting (including bats and pangolins) during the process of active deforestation of Myanmar's remaining teak forests, (2) bat guano harvesting communities surrounding HpaAn cave systems in Kayin State and (3) a previously uninvestigated population engaged in religious activities within the Karst cave systems in the Northern Dawna range. Waxing and waning of specific antibody responses will be followed over time through use of pre-pandemic archived specimens from these populations and repeated prospective sampling. We will utilize a novel Luminex bead-based multi-plex sarbecovirus assay, capable of simultaneously detecting neutralizing antibodies against 21 different hACE2-binding sarbecoviruses. Exposure patterns to specific sarbecoviruses will be identified and viral characteristics evaluated for their contribution to the likelihood of developing pan-sarbecovirus antibody responses, including viral genetic and functional phenotypic similarity and host plasticity (breadth of host species a virus is known to infect). Patterns of prior natural sarbecovirus exposure coupled with natural SARS-COV-2 infection and / or vaccination will then be evaluated for contributions to broadly reactive antibody responses. Data generated through this project will inform on potential cross sarbecovirus clade vaccination strategies that could protect against both known and future emerging SARS-CoV-2 variants. We will also conduct an in-depth investigation of behavioral risk factors contributing to zoonotic sarbecovirus spillover that will aid in mitigation strategies in this critically important ecological region for coronavirus emergence.