Improving HSV-2 vaccine efficacy by focusing antibody epitope coverage.

A vaccine for prevention of genital herpes is a high public health priorityWe are evaluating a trivalent subunit antigen vaccine that contains herpes simplex virus typeHSVglycoproteins CDand EgCgDgEGlycoprotein D is involved in virus entry and cell to cell spreadwhile gCand gEare immune evasin molecules that inhibit complement and antibodyWe used the Carterra high throughput biosensor technology to evaluate whether immunization with gDsubunit antigen in guinea pigs produced antibodies to each of seven crucial gDepitopes involved in virus attachment to cellsactivation of downstream entry molecules glycoproteins H and LgHgLor cell to cell spreadUnexpectedlywe found that gDimmunized guinea pigs produced antibodies that blocked on average only four of seven crucial epitopesSome animals blockedepitopeswhile others blocked six or sevenThe more epitopes blockedthe better was the protection against intravaginal HSVchallengeWe compared the epitope specific results in guinea pigs with our earlier studies of subjects enrolled in the GlaxoSmithKline gDHerpevac Trial for WomenHumans responded to even fewer epitopes than guinea pigsSome epitopes were weak immunogens in humans and guinea pigsincluding one that mediates receptor attachment and another involved in cell to cell spreadOur goal in this Phasestudy is to improve the immunogenicity of weakly immunogenic epitopesWe will use EpiSweep computer based structural technology to stealth or de immunize epitopes that are highly immunogenic in an effort to enhance the immunogenicity of weakly immunogenic epitopesWe will focus initially on stealthing a gDepitope that interacts with gHgLduring entryThis epitope is highly immunogenic in guinea pigs and humansWe will combine a computer based approach with our knowledge of gDstructure to develop gDconstructs with altered amino acid sequencesWe will prepare these constructs as subunit antigens in baculovirus and use the Carterra biosensor platform and our large panel of gDmonoclonal antibodies to determine whether we have stealthed the epitope as intendedWe will then immunize guinea pigs with the modified antigens and use the Carterra platform to determine whether antibodies are produced to the previously weakly immunogenic epitopesIf the stealthing process results in an unintended loss of immunogenicity of the strong epitopewe will boost with unmodified gDsubunit antigen to stimulate a responseOur focus in this Phasestudy is to improve the immunogenicity of gDOur longer term goal is to use this technology to improve epitope responses to gCand gEantigens in the vaccine Genital herpes disease caused by herpes simplex virus typeis a major global health problemA vaccine for prevention of genital herpes is urgently neededOur approach to vaccine development is to use computer based prediction software to modify vaccine antigens to improve immunogenicityWe will use Carterra high throughput biosensor technology to assess whether the modifications are effective at improving immunogenicityResults from this pre clinical study will help design improved vaccine antigens for future human trials