Structural vaccinology guided development of a universal CoV vaccine utilizing nucleic acid delivered nanoparticles

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Project Summary In December 2019 a novel coronavirus, named sudden acute respiratory syndrome coronavirus-2 (SARS-CoV- 2). SARS-CoV-2 rapidly spread around the globe causing a pandemic disease termed coronavirus disease of 2019 (COVID-19). There have been more than 80 million infections and close to two million deaths from COVID- 19 to date. SARS-CoV-2 is the third beta coronavirus of zoonotic origin to cause human epidemics. It is similar to, but distinct from, Middle East respiratory syndrome coronavirus (MERS-CoV) and sudden acute respiratory syndrome virus-1 (SARS-CoV-1), both of which have caused outbreaks this century. While several candidate vaccines for SARS-CoV-2 have recently received emergency use authorization, the longevity of vaccine-induced responses, the continued emergency of mutation within SARS-CoV-2 strains, and the disproportionate morbidity and mortality among elderly patient populations present continued challenges to control of SARS-CoV-2. Thus, vaccine modalities which can address these challenges for SARS-CoV-2 vaccines and allow for targeting of multiple potentially pandemic coronaviruses simultaneously are greatly needed. Innovative vaccines which can develop broad immunity against known and newly emergent human coronavirus is a key goal in the field. The effects of antigen epitope diversity, density, valency, duration of antigen availability, and adjuvant- induced cytokine environment on the potency and breadth of vaccine-induced Reponses remains unclear. Nanoparticle vaccine formulations allow the ability to manipulate these variables. We have generated self- assembling synthetic DNA-launched nanoparticle vaccines (DLNPs) which displayed increased immunogenicity compared to matched synthetic DNA launched monomer vaccines or protein-in-adjuvant formulations. We determined that synthetic DNA launched nanoparticles increased both cellular and humoral responses. Recombinant nanoparticle vaccines are thought to mediate their increased immunogenicity by persisting in the lymph nodes for extended periods compared to protein antigens, promoting enhanced antigen presentation by follicular dendritic cells and increasing germinal center formation and humoral immunity. Cell-mediated responses to nanoparticle vaccines are less well understood but similar mechanisms may be at play. We will capitalize on the novel in vivo assembling synDLNP platform we have created to manipulate these variables and determine their effects on acute and long-term responses to CoV antigens in young and aged models.