PROJECT SUMMARY – OVERALL: Structure-based design of broadly protective coronavirus vaccines
We propose a highly synergistic research Program focused on developing two broadly protective coronavirus
vaccine candidates: a pan-sarbecovirus vaccine at the end of Year 2, and a pan-betacoronavirus at the end of
Year 5. Our Program brings together six research groups with complementary and synergistic expertise in
structure-based vaccine design, coronavirus structural biology and immunity, the immunology of vaccines,
animal model development, and viral evolution. This team emerged in response to the SARS-CoV-2 pandemic
to rapidly develop an ultrapotent protein nanoparticle vaccine that is currently in Phase I/II clinical trials, with
funding secured for Phase III. Our Program comprises three Scientific Projects supported by four Scientific Cores
and an Administrative Core. This structure will allow maximal synergy between our groups in pursuit of the three
central outputs of our Program: Tools, Antibodies, and Vaccines. Tools: we will develop reverse genetic platforms
for producing panels of wild-type and indicator viruses and new animal models of human coronavirus disease
that can be used to assess neutralizing and protective breadth. We will also develop platforms for deep
mutational scanning of spike proteins spanning the betacoronavirus phylogeny to inform antigen design and
model development and assess the breadth and mutational resistance of vaccine-elicited antibodies. Antibodies:
our Program will identify conserved epitopes in betacoronavirus spike proteins targeted by cross-reactive
antibodies, and characterize the structural basis for broad neutralization and protection at high resolution. This
information will be used to iteratively inform structure-based antigen and vaccine design and will generate
antibody therapeutics that could blunt the effects of future zoonotic spillovers. Vaccines: we recently showed that
co-displaying multiple hemagglutinin antigens on the same self-assembling protein nanoparticle, an approach
termed mosaic nanoparticle display, induced broadly protective humoral immunity against influenza. We will
combine this approach with cutting-edge computational methods for stabilizing glycoprotein antigens and
designing nanoparticle scaffolds tailored to display coronavirus spikes in optimal geometries. We expect the
resultant nanoparticle vaccine candidates to elicit potent and broadly protective antibody responses against
conserved epitopes in betacoronavirus spikes. We will mechanistically and functionally evaluate the performance
of these vaccine candidates formulated with clinically relevant adjuvants in relevant animal models, including
nonhuman primates. To facilitate successful transfer to industry partners, we will prepare technology transfer
packages for the two lead vaccine candidates that will be produced by our Program: a pan-sarbecovirus vaccine
at the end of Year 2, and a pan-betacoronavirus vaccine at the end of Year 5.