Development and Characterization of a Broadly Protective Lyssavirus Vaccine

Christine Rettew Fisher, Thomas Jefferson University

Abstract

Lyssaviruses are rabies-related viruses which are spread predominantly by bats and cause severe disease in mammals. Vaccines and biologics that protect against rabies disease are safe, effective, and well-established, but they are based exclusively on rabies virus (RABV) and offer limited to no protection against other lyssaviruses. This thesis focuses on the design and characterization of a lyssavirus vaccine featuring a chimeric glycoprotein (G). Structural modeling enabled the design of the chimeric G, which incorporates parts of two divergent lyssaviruses: RABV and Mokola virus (MOKV). The vaccine was characterized in vitro for growth, purity, and expected antigenicity. The vaccine was also tested in vivo for its ability to stimulate robust neutralizing antibody titers in a murine model and protect against viral challenge. The chimeric G was functional, enabling viral growth, and conferred expanded antigenicity to the vaccine compared to its component viruses: biologics generated against RABV G and MOKV G both bound to the chimeric G whereas they did not cross-react with the other wildtype G. The vaccine also stimulated seroconversion in mice, as determined by enzyme-linked immunosorbent assays and based virus neutralization assays, and protected mice from disease after intranasal challenge. Finally, administration of an immune adjuvant along with either the chimeric G vaccine or a classical RABV vaccine induced a higher magnitude of antibodies in mice and broadened the cross-neutralization against additional lyssaviruses not included in the design of the vaccine. Altogether, this work demonstrates the utility of structural modeling in rational vaccine design and lays the foundation for further development of a multivalent lyssavirus vaccine.

Subject Area

Immunology|Microbiology|Virology

Recommended Citation

Fisher, Christine Rettew, "Development and Characterization of a Broadly Protective Lyssavirus Vaccine" (2020). ETD Collection for Thomas Jefferson University. AAI28092857.
https://jdc.jefferson.edu/dissertations/AAI28092857

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