Remodeled glycoprotein for broad protection against ebolaviruses

Project summary TheEbola virus diseaseEVDoutbreak in West Africacaused by the Zaire Ebola virusEBOVresulted in overcases anddeathsThis has been a sobering reminder of the growing threat of the filoviruses for global public healthDriven by the unprecedented dimension of this outbreakmost of the efforts to develop vaccines against the different species of ebolaviruses has been focused on EBOVHoweverother ebolavirus species such as Sudan virusSUDVand Bundibugyo virusBDBVhave also caused sizable outbreaks in the pastyears and the species causing future EVD outbreaks cannot be predictedThe vaccines currently in developmentincluding adenovirus based vaccines and VSV ZEBOV that was successfully tested in a Phase III clinical trial in Africaare specific to EBOV and do not provide cross protection against SUDV or BDBVA major obstacle for elicitation of broadly neutralizing responses is the fact that most conserved regions of the ebolavirus glycoproteinGPincluding the receptor binding siteRBSare largely concealed on the viral surfaceUsing a special immunogen cocktail we have recently isolated several broadly neutralizing monoclonal antibodiesbNAbscharacterized their epitopes in collaboration with Integral Molecularand for the first timeidentified a cocktail of two antibodies that simultaneously protects against EBOVSUDVand BDBVThis body of knowledge can now be exploited to develop a single vaccine that protects against all ebolavirusesOur proposal is based on two key and novel observationsiWe have identified several residues in the base of the EBOV GP trimer thatwhen mutatedincrease the exposure of broadly neutralizing epitopes on the apical face of GPincluding the RBS that is otherwise largely concealedWe have also demonstrated that immunization with such mutants broadens the antibody response towards SUDV and BDBViiWe have demonstrated that a proteolytically remodeled form of GP representing the post entry form of GP in the host endosomes binds to the most potent bNAbs with very high affinitysuggesting that thiscleaved GPGPCLcan be a candidate panebolavirus vaccineBuilding upon these observationsthis Phase I project is designed in three specific AimsIn Aimusing the information gained from our extensive alanine scanning mutagenesis studiesa variety of mutants will be generated on the backbone of VSV EBOV GP pseudotype virusand their ability to elicit broadly neutralizing responses will be evaluatedAimfocuses on generation and functional testing of immunogens based on GPCLAdditional specific mutations identified in Aimwill be incorporated into GPCL immunogen and evaluated in immunogenicity studiesIn Aimthe best candidates identified in Aimsandwill be tested in proof of concept efficacy studies in murine challenge models of EBOV and SUDVUpon successful proof of conceptwe anticipate a phase II to demonstrate efficacy of the vaccine against EBOVSUDVand BDBV in non humane primate models of infection as well as initiation of IND enabling studies TheEbola virus disease outbreak in West Africacaused by the Zaire Ebola virusresulted in overcases anddeathsWhile several vaccines have been tested against the Zaire strain of Ebola which caused theoutbreakthese vaccines do not protect against other ebolaviruses like Sudan and Bundibugyo viruses that also have cause deadly outbreaksThe goal of this proposal is to generate novel vaccine candidates that protect against all ebolaviruses