Discovering Durable Pan-Coronavirus Immunity

OVERALL SUMMARY Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a devastating human threat. While successful vaccine programs are underway, genetic drift and immune escape have already begun to subvert immunity, with more variants likely to continue to emerge. Moreover, the rates of zoonotic CoV transmission have increased over the past two decades-indicating that it may not be long before another CoV breaches host-species barriers into humans. Next generation vaccine design strategies that are able to provide robust protection against evolving SARS-CoV-2 strains in addition to other CoVs are urgently needed. The overall goal of this program is to produce critical information necessary for the design and testing of next generation vaccine strategies that provide protective efficacy with the greatest possible breadth across the CoV family. The overall Program hypothesis is that immunological discernment of heterogeneity in human responses to SARS-CoV-2 infection and vaccination will illuminate factors that can impact efficacy and breadth of CoV vaccine strategies. This hypothesis is supported by recent publications and preliminary data from our team. In this regard, although hundreds of vaccines are under development, the targets most relevant for pan- CoV immunity may defy the simple need for the induction of neutralizing antibody responses, which largely bind to non-conserved areas in the S1 region of the viral Spike (S) protein-susceptible to viral escape. Emerging evidence from our team points to the importance of the S2 region, which is more conserved across CoVs. Our team has found that rapid induction of anti-S2 antibodies is connected to less death in severe disease, more cross-reactive memory B cell responses, swift healing in mild disease, and improved antibody durability after disease resolution. The factors underlying why some people develop better-clinical-outcome- associated crossreactive anti-S2 immune responses remains to be fully defined. We have assembled a multidisciplinary team with expertise in immunology, virology, genetics, medicine, biochemistry, structural biology and mathematics to achieve the overall Program goal. The complementary and integrative expertise of the team will come together to: 1) finely map the humoral and cellular responses to SARS-CoV-2 variants and coronaviral relatives that emerge after natural infection or vaccination, 2) define the mechanism(s) by which these responses confer protection, and 3) utilize these mechanistic correlates of immunity to inspire cutting edge, structurally stable native-like S antigens that will be used in a step-wise improvement approach in vaccination and protection studies. Collectively, the data generated by this team will (a) identify immunological correlates of anti-CoV breadth expected to inform vaccine design; (b) define the most conserved targets on CoV S accessible to the human adaptive immune system and mechanistic insights into their recognition; (c) generate novel immunogens incorporating B and T cell strategies informed by (a-c) above; and (d) test them in the context of Program-optimized delivery methods to maximize breadth of protective, durable CoV immunity.