Developing broad-spectrum pan-sarbecovirus countermeasures

Abstract

Two sarbecoviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, have crossed species barriers and spilled over to humans. The latter of the two resulted in a pandemic exerting an unprecedented toll on global healthcare capacity, claiming millions of lives while simultaneously inflicting collateral damage to the world economy. Pandemic experience has deepened our understanding of sarbecoviruses and shaped our frameworks for developing therapeutics and vaccines against them. Sarbecovirus spike glycoprotein is the key molecular machinery for viral entry and fusion into the host cell, making it the principal target when developing countermeasures against sarbecoviruses. The primary goal of therapeutics and vaccines is to directly neutralize the virus and/or to confer protection by eliciting immune responses. In the following chapters of this dissertation, I detail our efforts to develop pan-sarbecovirus countermeasures with a broad spectrum. First, I will describe a de novo designed miniprotein against the SARS-CoV-2 receptor binding domain that retained its inhibitory functions across multiple SARS-CoV-2 variants. Then, I will delineate the potential of receptor tropism and zoonotic spillover of a clade 3 sarbecovirus and what countermeasures might be applicable, propelling us to prepare better for a pandemic should there be another one from sarbecoviruses. In the final sections of the dissertation, I will focus on the development and assessment of broad-spectrum pan-sarbecovirus vaccines focusing on the highly conserved prefusion-stabilized fusion machinery of sarbecoviruses. Our focus on prefusion-stabilized sarbecovirus fusion machinery vaccines provides a roadmap for the development of next-generation pan-sarbecovirus vaccines. Our work, collectively, highlights the importance of sarbecovirus countermeasures and provides a foundation for developing broadly applicable therapeutics and vaccines.