Cross-Protective Humoral Immunity to Coronavirus

PROJECT 1 SUMMARY Global establishment of Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a continued human threat. While successful vaccine programs are well underway, genetic drift and immune escape have already begun to subvert immunity. In addition, related zoonotic coronaviruses threaten transition into the human population. CoVs can be highly transmissible and highly lethal, posing a grave threat to human lives and world economies. In this light, developing pan-CoV vaccine options in preparation for the expected broad range of SARS-CoV-2 variants and future emergent coronaviruses could save millions of lives and prevent future global catastrophes. While current SARS-CoV-2 vaccines targeting the virus spike (S) protein hold great promise in providing protection against current circulating strains, research is urgently needed to understand breadth and durability of immunity across the CoV family and to translate this information into next generation vaccines with increased breadth to cover SARS-CoV-2 escape mutants as well as to address emergent CoVs. The overall goal of this program is to produce critical information necessary for the design and testing of next generation CoV vaccine strategies with the greatest possible breadth across the CoV family. The Program team will identify humoral, cellular, and structural immunologic features influencing clinical outcomes and immune recognition breadth in human SARS-CoV-2 infection and human vaccination cohorts to fuel design and pre-clinical testing of protective coronavirus vaccine strategies to identify those with the greatest possible breadth. Project 1's goal in this process is to define B cell/serologic properties of broad CoV immunity and identify vaccine delivery conditions that can best support them. Preliminary discoveries from Project 1 together with recent literature support the working hypothesis that aspects of vaccine strategy such as antigen choice, delivery timing, dose, and valency will influence CoV recognition breadth and effectiveness. Knowledge gained from strategic analysis of the heterogeneity of active human SARS-CoV-2 convalescent and vaccine cohorts will generate new hypotheses to integrate into pre-clinical vaccine testing approach. In particular, recent work from Project 1 investigators has identified the conserved S2 domain as promising target for broad CoV immunity in humans. Program 1's roles in evaluating these hypotheses are to: 1) identify immune correlates of convalescent COVID-19 patients and vaccinees that exhibit superior durability and cross-reactivity; 2) define the mechanisms of cross-reactive monoclonal mediated protection against CoVs in vivo; and 3) evaluate the efficacy of novel vaccine immunogens to induce protective B cell/functional serological responses in animals. Supported by Core B, results from Project 1 will provide strategic antibody, serological and memory B cell analysis in the context of an integrative programmatic approach in synergy with Projects 2 and 3 approach to generate vaccine strategies with maximal breadth and effectiveness.