Mcguire, Andrew TMalhi, Harman2023-01-212023-01-212023-01-212022Malhi_washington_0250E_24931.pdfhttp://hdl.handle.net/1773/49676Thesis (Ph.D.)--University of Washington, 2022Epstein-Barr virus (EBV) is a cancer-associated pathogen responsible for 165,000 deaths per year. EBV is also the etiological agent of infectious mononucleosis and is associated with multiple sclerosis and rheumatoid arthritis. Thus, an EBV vaccine could alleviate significant morbidity and mortality. EBV is orally transmitted and has tropism for both epithelial cells and B cells. Therefore, a vaccine would need to prevent infection of both cell types in the oral cavity. I describe how the passive transfer of AMMO1, a dual-tropic neutralizing monoclonal antibody targeting the viral gH/gL glycoprotein complex, prevents experimental EBV infection in humanized mice and rhesus macaques, suggesting that gH/gL is an attractive vaccine candidate. Spurred by these findings, we produced and evaluated the immunogenicity of several nanoparticle immunogens displaying gH/gL with distinct valencies and geometries. After one or two immunizations, all nanoparticles elicited superior binding and neutralizing titers relative to monomeric gH/gL. Antibodies elicited by a computationally designed self-assembling nanoparticle that displays 60 copies of the gH/gL protein conferred protection against a lethal dose of EBV in a humanized mouse challenge model, whereas antibodies elicited by monomeric gH/gL did not. Taken together, these data motivate further development of nanoparticle vaccine candidates for EBV which target the gH/gL glycoprotein.application/pdfen-USCC BY-NC-NDEpstein-Barr VirusNanopartcleVaccineVirologyImmunologyVirologyMedicineMolecular medicine and mechanisms of diseaseThesis