Project 4: Computational panbetaCoV immunogen design

Abstract - Project 4 SARS-CoV-2, a member of the genus Betacoronavirus (betaCoV), is the third major zoonotic outbreak of a highly pathogenic betaCoV in the last two decades. We propose to design vaccines to contribute to the global effort to counter the COVID-19 pandemic as swiftly as possible, and then to build on these designs to create panbetaCoV

vaccines that could be used to rapidly contain outbreaks of future coronavirus zoonoses. To these ends, we will design both 1) Spike-targeted antibody vaccines, mindful of SARS-CoV-2 evolution as the pandemic progresses, and 2) conserved-region T-cell vaccine designs, to refocus CD8 T-cell response to regions in the proteome that

cannot escape without a high fitness cost. These efforts toward pandemic vaccines will then be used as a foundation to extend our vaccine design strategies to counter the variability found among BetaCoVs, the highly diverse genus of CoVs that are found in bat populations. Based on our preliminary explorations of BetaCoV

sequence diversity, we expect the design of a trivalent Spike-based vaccine using computational/bioinformatic and structure-based strategies to provide protection against the known range of diversity found in the subgenus Sarbecovirus. This includes both SARS-CoV-1, SARS-CoV-2, and the many related viruses isolated from bats

and pangolins. If successful, these designs will be extended to cover Merbecovirus the subgenus that includes the MERS virus and other related viruses found in wild bats, rodents and cattle. Our Specific Aims are: Aim 1. Track the evolution of the SARS-CoV-2 during the COVID-19 pandemic. Aim 2. Design Spike vaccine antigens

that optimize epitope exposure and betaCoV diversity coverage. Aim 3. Design T cell vaccines utilizing the most conserved regions in betaCoV. Our Spike-based computational vaccine designs will be based on our structural B cell mosaics strategy, and will be informed by Spike glycoprotein structures and molecular dynamic modeling,

and will incorporate alignments of diverse Spike proteins. Using this approach we will design a trivalent set of complementary of proteins that optimally covers the natural diversity found among Sarbecoviruses in the bat reservoir. As we cannot predict with certainty the antigenic profile of viruses that may give rise to future zoonoses,

we propose a two-pronged approach, and will simultaneously explore a conserved-region T-cell strategy that, although it might not block infection, could substantially mitigate disease, reducing both morbidity and transmission. Our T-cell vaccine designs will optimize the coverage of linear epitopes among BetaCoVs with a

trivalent vaccine mix using our computational design strategy called Epigraphs. By focusing on the most conserved regions in the betaCoV proteome, we can more readily cover the broad spectrum of BetaCoVs diversity than in the more diverse Spike.