Augustine Duffy
BioE PhD Proposal Presentation
Time and Date: 12:00pm – 2:00pm, Friday, November 22nd, 2024
Location: EBB 3029
Zoom Link: https://gatech.zoom.us/j/97458840891?pwd=IuFLdOq3Ffthy9n13waz1roTXlMBbv.1
Advisor: Ravi Kane, Ph.D. (School of Chemical and Biomolecular Engineering, Georgia Tech)
Committee Members:
Alberto Moreno, M.D. (Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine)
Anant Paravastu, Ph.D. (School of Chemical and Biomolecular Engineering, Georgia Tech)
Mark Prausnitz, Ph.D. (School of Chemical and Biomolecular Engineering, Georgia Tech)
Shuichi Takayama, Ph.D. (Coulter Department of Biomedical Engineering, Georgia Tech and Emory University)
Computationally Aided Design of Broadly Protective Vaccines Against Coronaviruses and Influenza Viruses
The continuing circulation and immune escape of SARS-CoV-2 and human influenza viruses coupled with the serious risk of zoonotic spillover of related highly pathogenic viruses necessitates the development of broadly protective vaccines for both families of viruses. Current vaccines need to be updated periodically to match circulating strains, and their efficacy against unmatched pandemic strains would likely be minimal. As such, the development of more broadly protective vaccines and a critical understanding of their limits of protection are needed to combat both current and future outbreaks.
Meanwhile, the number and accuracy of computational tools for protein design and other biological applications have greatly increased in recent years, and their use in vaccine development can help accelerate current design efforts. Here, we use antigenic cartography and protein modeling software to design vaccine cocktails and new antigens respectively against coronavirus and influenza virus. We combine these designed antigens with our nanoparticle vaccine scaffolds to enable multivalent display of spike (S) and hemagglutinin (HA) antigens.
In Aim 1, we used antigenic cartography to design cocktails of SARS-CoV-1-like and SARS-CoV-2 spike protein nanoparticle vaccines. We found that a cocktail containing three different spike proteins – from ancestral SARS-CoV-2, from the XBB variant, and from the bat coronavirus SHC014 – was able to protect hamsters from challenges with both SARS-CoV-1-like and SARS-CoV-2-like viruses. In Aim 2, we are using protein design tools to stabilize full prefusion spike proteins and S2 subunit antigens from bat coronaviruses that utilize the same receptors as MERS-CoV and SARS-CoV-2. We have found our designed antigens to be comparably stable to their SARS-CoV-2 equivalents, and our designed bat coronavirus BtKY72 S2 antigens have provided partial protection against SARS-CoV-2 and bat coronavirus challenges in mice. In Aim 3, we are designing novel HA antigens that can elicit a broad stalk-
directed response and will test their ability to protect against a heterosubtypic challenge in mice. In Aim 4, we are designing nanoparticle vaccines targeting the human coronaviruses OC43 and HKU1 and will use antigenic cartography to determine the minimum number of antigens needed to protect against a broad range of variants.