Project 1: Serology

PROJECT 1: SUMMARY As established through decades of research in protective immunity against infectious pathogens, achieving durable immunity against SARS-CoV-2 will require specific functional properties of antibodies, B cells and T cells that need to be defined through detailed repertoire studies. Antibody responses to viral infections in humans are varied and of widely divergent clinical significance. Pre-existing, reactive antibodies or antibodies that are formed early during infection can engage virus particles, forming immune complexes that may neutralize or mediate clearance of the virus. On the other hand, immune complexes can also promote inflammation and exacerbate symptoms of disease. SARS-CoV-2 infections can be asymptomatic or cause disease, COVID-19, which manifests with a spectrum of symptoms ranging from mild to life threatening pneumonia and cytokine dysregulation. The role of antibodies in protection against SARS-CoV-2 infections and whether antibodies may play a role in promoting symptoms of COVID-19 remains unknown. In Project 1, we will define the heterogeneity of antibody responses produced during SARS-CoV-2 infections and test the hypothesis that particular antibody responses, with respect to the target antigen(s), specific epitopes and antibody effector functions, are required for protection against SARS-CoV-2 infections. We will perform studies under the following specific aims: Aim 1: Characterize antibodies elicited by SARS-CoV-2; Aim 2: Define antibody correlates of COVID-19 pathogenesis and protection. These studies will include structure determination by cryo-electron microscopy that will delineate the main binding epitopes and molecular characteristics of antibody recognition against the SARS-CoV-2 spike protein. Further, we will investigate whether there are antibody profiles that correlate with more severe outcomes in COVID-19. Results from these studies will guide the development of safe and effective vaccines and monoclonal antibodies for the prevention and treatment of COVID-19.