Multivalent emergency vaccine against pandemic influenza

ABSTRACTA safe and effective vaccine providing protection from many subtypes of influenza would considerably improve public health and pandemic preparednessMultiple potentially pandemic viruses continue to circulate and evolve in the environment causing public health concernPreparation of vaccines for each subtype using current technologies is not cost effective and can raise safety and biosecurity concerns if highly pathogenic strains are usedRecombinant virus like particlesVLPsrepresent an intrinsically safe vaccination approachInfluenza VLPs contain viral hemagglutininHAneuraminidaseNAand matrix or gag proteinswhich self assemble into VLPs in cell cultureVLPs morphologically and antigenically resemble influenza virions except they are non infectiousRecombinant VLPs have advantages in safetyefficacyand manufacturing and they circumvent problems like slow virus growthunpredictable yieldsand virus mutations during egg adaptationIn preliminary studieswe described a novel multi subtype VLP design that co localizes multiple HA subtypes within the same VLP particleVLP that contained HA proteins from four distinct avian influenza subtypes HHHand Hproteins induced specific immune responses against all four subtypesThereforemulti subtype VLP design suggests the potential for a broadly protective vaccine that provides specific immunity against multiple influenza viruses of pandemic concernIn this Phase I SBIR applicationwe propose feasibility study of a novel multivalent vaccine containing HA molecules from all seven zoonotic pandemic threat subtypes known to infect humans including these of avian and swine originIn SpAimVLP vaccines will be prepared in the monoand multi subtype formats and optimized for expression of HHHHHHand HantigensVLPs will be expressed using a baculovirus expression system and their structuralantigenicand biochemical characteristics will be evaluatedThe content and the potency of each HA subtype will be measured to determine optimal formulation of VLPsIn SpAimsafetyimmunogenicity and efficacy of the best VLP formulation will be assessed in experimental ferret model in collaboration with the Centers for Disease Control and PreventionCDCFerrets will be vaccinated with the optimized multivalent vaccine from SpAimImmune responses to the expressed avian and swine HA subtypes will be determined including hemagglutination inhibitionHIand virus neutralizationVNtitersIn additionantibodies to NAas well as IFNresponses after VLP immunization will also be determinedVaccine efficacy will be evaluated using challenge with at least two homologous virusesAdditional homologous and heterologous challenge experiments are planned for the follow up Phase II SBIR if approved by the AgencyIf successfulthis high riskhigh reward approach can potentially result in a novel emergency vaccine protecting against multiple potentially pandemic viruses known to infect humans PROJECT NARRATIVEPreparation of vaccines capable of protecting against multiple potentially pandemic influenza viruses is important for public healthThe focus of this Phase I SBIR application is feasibility study of a novelbroadly protective virus like particleVLPvaccine against pandemic influenza viruses of HHHHHHand Hsubtypesall known to cause life threatening human infectionsEvaluation of safetyimmunogenicity and efficacy of vaccine is proposed in ferrets in collaboration with the Centers for Disease Control and PreventionCDCincluding influenza virus challengesThe proposed research of multi subtype VLPs will increase knowledge of multivalent vaccines and contribute to the development of improved influenza vaccines