Unraveling the Evolution of COVID-19: The Impact of Variant Mutations and ORF8 on Virus Replication and Pathogenesis to Enhance Pandemic Preparedness

The response to the COVID-19 pandemic stands as a testament to scientific achievement. In less than a year, society transitioned from vulnerability to the SARS-CoV-2 virus to vaccine-driven protection. Coupled with mass immunization initiatives, these vaccines allowed the world to tentatively reopen. Yet, the pandemic is not over and continued waves of SARS-CoV-2 infections through world human population could pressure the emergence of new and potentially dangerous viruses. Global surveillance systems proficiently identify viruses with genetic changes, but the key challenge is distinguishing important genome alterations from benign ones. While informative methods can predict potentially important mutations based on sequence data only, linkage with empirical data are required to confirm and improve predictions. While there is some empirical data regarding how specific spike mutations affect infections the contributions of mutations in outside of spike, in other structural genes, within the non-structural genes, and accessory genes remain poorly characterized. To bridge this knowledge gap, this proposal embarks on a comprehensive exploration focusing on the Delta and Omicron variants and some of their non-spike mutations. By using reverse genetics and recombinant SARS-CoV-2 viruses this study will scrutinize the impacts of specific mutations, mutant genes, and accessory genes on virus growth, immune evasion, and disease progression. By unravelling the intricacies at play, this project aims to identify pivotal mutations. Such insights hold profound implications, guiding dangerous variant predictions, public health strategies, vaccine design, and treatment approaches. The pursuit of understanding within this initiative is not only a means to navigate the present pandemic but also creates the foundation for future pandemic preparedness.