Structure-guided design of durable pan-lyssavirus vaccines and anti-viral antibody therapies

Untreated rabies infections are nearly 100% lethal and kill over 50,000 people every year, disproportionately affecting children. While lifesaving, current rabies vaccines and post-exposure therapies can be prohibitively expensive and do not elicit long-lasting protection, with some individuals needing revaccination as frequently as every 6 months. Modern techniques, such as rational vaccine design and monoclonal antiviral antibody cocktails have excellent potential to develop more affordable post-exposure therapies and longer lasting vaccines. However, these techniques require high-resolution structural information about how antibodies bind to rabies glycoprotein (RABV-G) to neutralize infection and how RABV-G interacts with cellular receptors to facilitate infection. To address the knowledge gap in rabies protein structures, I will use the resources available in the Advanced Biological Imaging and Cell Analysis (ABICA) research core to determine multiple high-resolution cryo-electron microscopy (cryo-EM) structures of RABV-G in complex with receptors and neutralizing antibodies. These structures will allow identification of the specific protein-protein binding interactions between RABV-G, antibodies, and cellular receptor(s) and will serve as a road map to inform future rational design of improved rabies vaccines and antiviral therapeutics. I will express and purify anti-rabies monoclonal antibodies from sequencing (NCBI) and patent databases, determine the strength and mechanism of antibody neutralization, solve high-resolution RABV- G/antibody structures, and then correlate strength and mechanism of neutralization to specific protein-protein contacts in the structures. I will also cleave N- and O-linked glycans from the cell surface and quantify the changes in rabies pseudovirus cell binding to determine if glycans act as attachment factors during infection, identify nicotinic acetylcholine receptor (nAChR) isoforms with high affinity for RABV-G with bio-layer interferometry, and solve high-resolution cryo-EM structures of high binding affinity nAChR/RABV-G complexes. This work will result in at least three manuscripts, establishing me as an independent researcher in the fields of rabies virology and cryo-electron microscopy, and will serve as key preliminary data in my first R01 grant application. The Cell and Molecular Pathogenesis (CAMP) Core will further support my development as an independent researcher by providing me with access to key equipment and technical expertise through the ABICA research core. My internal and external mentors will help me develop and revise my R21 and R01 grants, advise me on personnel and logistics as I set up my laboratory, and provide me with feedback on my research as I write my first independent manuscripts. CAMP’s available support and workshops on translational science will also help me progress my long-term research goal of developing an improved rabies vaccine and antiviral therapeutics by connecting me with the resources to submit patents, conduct clinical trials, and find industry partners to develop, produce, and market these products. Project Number: 1P20GM162003-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Heather Callaway | Institution: MONTANA STATE UNIVERSITY - BOZEMAN, BOZEMAN, MT | Award Amount: $213,562 | Activity Code: P20 | Study Section: Special Emphasis Panel[ZRG1 MBBC-Q (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11268444