Grant: Project Gr. PA: Res. on Prevention/Response to Covid-19/Similar Future Pandemics

Globally, as of August 2023, there have been an estimated 769 million cases of COVID-19 worldwide, and over 6.95 million deaths. COVID-19 provides a sobering case study of the consequences of insufficient pandemic preparedness. Novel variants of SARS-CoV-2 virus now continue to emerge and escape immunity by either previous infection or vaccination, resulting in repeated infection with potentially serious consequences. All historical precedents indicate that future outbreaks will continue to occur. In this research program, we will pursue a preventative program against future pandemics, by developing rationally designed therapeutics that are robust to viral mutation, and thus effective in preparation for future pandemics. We will develop antibody and vaccine immunogen therapeutics that exploit unconventional strategies to remain effective in spite of the rapid mutation of the virus. We design antibodies that will remain effective in blocking the virus from entering cells so long as the virus uses the same cell receptor on its entry pathway. The vaccine immunogen candidates we design will target a portion of the virus that is conserved and unlikely to mutate because it is functionally necessary. We will test the efficacy of these therapeutics against live SARS-CoV-2 virus infection in mice, where these therapeutics are expected to provide sustained protection against all strains of SARS-CoV-2. We have also developed a safe "pseudovirus" platform where the spike protein of the virus can mutate. In our proposed experiments, our therapeutics are again expected to remain effective as the pseudovirus mutates, while conventional therapeutics will be expected to gradually lose efficacy. The above powerful development platform provides a strategy for generating pre-emptive therapeutics that can be pivoted to future outbreaks of other novel viruses. Extending our SARS-CoV-2 studies, we will apply it to other related viruses with pandemic potential.