Grant: Project Grant - PA: Pandemic Preparedness and Health Emergencies Research

Globally, as of August 2022, there have been an estimated 600 million cases of COVID-19 worldwide, and over 6.4 million deaths. Novel variants of SARS-CoV-2 virus continue to emerge and escape immunity by either previous infection or vaccination, resulting in repeated infection with potentially serious consequences. In this research program, we will develop rationally designed therapeutics that are robust to mutation of the virus, in preparation for future pandemic waves. We propose to develop both an antibody and a vaccine immunogen that exploit unconventional strategies in order to remain effective in spite of the rapid mutation of the virus. The vaccine candidate is designed to elicit a patient's antibodies to target a portion of the viral protein that is conserved and unlikely to mutate without altering essential functions that would themselves hinder the virus. The antibody is designed to remain effective in blocking the virus from entering cells so long as the virus uses the same cell recognition protein on its entry pathway. Since we know the virus will continue to mutate, it is critical to know how it may mutate to evade existing therapeutics or immunogenic response. We will investigate this question using a "chimeric" version of the virus which looks like SARS-CoV-2 on the outside, but is relatively harmless on the inside (a "sheep in wolf's clothing"). We can induce escape mutations in this chimeric virus by applying selection pressures using either convalescent or vaccinated patient sera, or existing recombinant antibody therapeutics. These escape mutants may share common features with variants of concern in the future. This powerful development platform will provide a strategy for generating pre-emptive therapeutics that can be pivoted to future outbreaks of other novel viruses.