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Developmental Research Project DP011

Collaborating Institution: University of Iowa, Iowa City, IA

Principal Investigator: Wendy Maury, PhD

Title of the Project: Targeted De-glycosylated Machupo Virus Glycoprotein as a Vaccine Immunogen

Co-investigators:

Expected Product:  Development of a recombinant vaccine against the New World arenavirus Machupo, the cause of Bolivian hemorrhagic fever.

Description: The New World arenavirus, Machupo virus, causes episodic lethal outbreaks of Bolivian hemorrhagic fever due to transmission from its rodent reservoir, Calomys callosus. In addition, there is concern that these viruses will be weaponized, leading to the listing of these viruses on the CDC and NIAID Category A biodefense pathogens lists. No vaccine is available against this virus and, while ribavirin is somewhat efficacious against arenaviruses, additional antivirals are needed. Limited studies with the related New World Clade B arenavirus, Junin, have demonstrated that a recombinant vaccine expressing the viral glycoprotein (GPC) protects against lethal Junin virus challenge in monkeys. However, such a recombinant vaccine is not currently used for protection against Junin virus since a live, attenuated strain of the virus (Candid1) has proved efficacious. The absence of a vaccine for other arenaviruses motivates us to initiate the development of a recombinant vaccine that targets Machupo virus. Here, we propose to develop a Machupo GPC-containing vesicular stomatitis virus (VSV) pseudovirion vaccine. Not only do these studies seek to develop of a Machupo virus GPC pseudovirion vaccine, but this work will also assess if targeted deglycosylation of GPC that exposes conserved residues provides better protection against lethal Machupo virus challenge than heavily glycosylated, wild-type Machupo GPC. Previous vaccine studies with deglycosylated influenza hemagglutinin or Zaire ebolavirus GP provides supporting evidence that protection against homologous challenge may be enhanced by the deglycosylated immunogen. During this one year study, we will solely focus on: 1) determining if a Machupo GPC VSV pseudovirion vaccine is efficacious against lethal Machupo challenge and 2) if targeted GPC deglycosylation provides better efficacy against homologous challenge. However, it is also possible that surface exposure of more conserved GPC residues by deglycosylation will provide not only enhanced efficacy against homologous challenge, but against more distantly related New World arenaviruses. Thus, this approach may yield a potential univalent vaccine against a broad range of New World arenaviruses and may solve one ongoing challenge in the field of biodefense virus vaccinology.