Project 2: Structure-based antigen and nanoparticle vaccine design

PROJECT SUMMARY - PROJECT 2: Structure-based antigen and nanoparticle vaccine design Project 2 is focused on the design, production, and characterization of novel stabilized antigens and broadly protective nanoparticle vaccines. In Aim 1, we will establish automated computational pipelines that identify sets of novel prefusion-stabilizing mutations in the spike proteins of various sarbecovirus, merbecovirus, and embecovirus strains we will use in our broadly protective vaccines. Our recent work has also demonstrated the utility of using deep mutational scanning data to guide the identification of stabilizing mutations in isolated SARS-CoV-2 receptor-binding domains (RBD). The computational pipelines we develop will extend this method to the design of additional stabilized RBD antigens across all four known clades of sarbecoviruses for use in pan-sarbecovirus vaccines. In Aim 2, we will computationally design novel self-assembling protein nanoparticle scaffolds that present prefusion spike trimers in arrays specifically designed to allow unconstrained B cell receptor/antibody access to broadly conserved epitopes. We hypothesize that these scaffolds will elicit antibody responses with superior protective breadth, particularly when used as the basis for mosaic nanoparticle immunogens. We will experimentally validate several novel nanoparticles and prototype their functional performance as monovalent nanoparticle immunogens in immunization and challenge studies in mice to identify the scaffolds that best focus the humoral immune response on conserved epitopes. In Aim 3 we will build on our recent work demonstrating the elicitation of broadly protective immune responses against influenza by generating multivalent nanoparticle vaccines displaying multiple coronavirus RBDs or prefusion spikes. We will take a hierarchical, phylogeny-driven approach. We will focus at first on developing a pan-sarbecovirus vaccine, which will display multiple RBD or prefusion spike antigens. We will then generate broadly protective merbecovirus and embecovirus vaccines displaying multiple prefusion spikes. Finally, we will define the optimal composition of a pan-betacoronavirus nanoparticle vaccine. We will work closely with the other groups in our Program to identify lead pan-sarbecovirus and pan-betacoronavirus vaccine candidates for further preclinical and clinical development at the end of Years 2 and 5 of our Program, respectively.