Mechanisms and Duration of Immunity to SARS-CoV-2 - Supplement Application for Sept 2024-Aug 2025

SUMMARY The Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) has remained true to its original goals as a member of the SeroNet consortium organized to address the urgent need for better understanding of human immune responses to the SARS-CoV-2 coronavirus in the Covid-19 pandemic. We have incorporated new facts into our research plans as they arose during the pandemic, including the availability of mRNA vaccines, the development of long Covid by a subset of infected individuals, and rare reactions towards vaccines. The preponderance of our work has been toward understanding the adaptive immune responses to SARS-CoV-2 and its variants in the context of infection or vaccination, with emphasis on responses occurring in non-blood tissue sites, and analyses of diverse populations. In the proposed Supplement funding for this award, we will carry out further investigations into SARS-CoV-2-specific responses in pregnancy; multi-antigen variant B cell sorting and single-cell transcriptome and B cell receptor sequencing experiments to deeply characterize the evolution of B cell memory through the pandemic; structural studies of protective antibodies bound to their antigens; extensive analysis of class I epitope presentation of SARS-CoV-2 across human HLA alleles; and in- depth T cell and B cell lineage analysis in patients with long Covid. The combined impact of these studies will be to extend understanding of the cellular and molecular mechanisms affecting immune responses to the continuing evolving SARS-CoV-2 viral populations in individuals with different prior exposure histories, and in some populations such as pregnant individuals or long Covid patients who have altered immunity.