Construction and efficacy testing of novel recombinant vaccine designs for eliciting both broadly neutralizing antibodies and T cells against Lassa virus

PROJECT SUMMARY GeoVaxa clinical stage biotechnology company focusing on vaccine development against infectious diseases and cancerseeks to build on its successful vaccine candidate against Lassa virusLASVto implement a novel immunogen design for eliciting broadly cross reactive neutralizing antibodiesLASV is a member of the Arenaviridae family and is endemic in West Africa where it infectspersons each yearwith approximatelydeathsNo vaccine is currently under clinical development for the prevention of LASV infectionGeoVax created a vaccine against LASVGEO LMusing its proven Modified Vaccinia AnkaraMVAVirus Like ParticleVLPplatformGEO LMincorporates into the MVA genome LASV sequences encoding both a glycoproteinGPCand a matrix proteinZUpon infection of human cellsthe MVA driven expression of these proteins results in the budding from the surface of the infected cells of VLPs that bear natively folded GPC on their surfacePre clinical testing of GEO LMin a lethal mouse model demonstratedprotection after a single dose with strong T cell responses yet meagre antibody responsesin line with other vaccine candidates tested in animalsCapitalizing on recent breakthroughs in the structural characterization of LASV GPCwe propose in this Fast Track Phase I II application to develop and test novel GPC immunogen designs in the context of the MVA VLP systemPhase I will consist of sequence designMVA VLP constructionin vitro testingand efficacy and immunogenicity studies in an established lethal mouse modelIn Phase IIGEO LMand the selected new vaccine candidate will be produced at high titers and tested against all four major lineages of LASV in the established Hartley guinea pig challenge modelBoth vaccines will then be tested for efficacy in non human primates and will be concomitantly evaluated extensively for the magnitude and characteristics of the cellular and humoral immune responsesThe final down selected vaccine candidate will be tested for genetic stability and sterility in preparation for cGMP manufacturing and a Phaseclinical study PROJECT NARRATIVE Approximatelytopersons are infected each year with Lassa virusresulting in severe hemorrhagic fever and roughlydeathsInfection by the virus is preventable by vaccination and this grant proposal assembles a team of scientists who are leveraging recent breakthroughs in virology to engineer an innovative and novel vaccine against the virusThe vaccine will be designedconstructedtested in small and large animal modelsand at the conclusion of these studies will be ready for manufacturing for testing in humans