Development, GMP manufacture, and quality control release of a triple knock out genetically attenuated Plasmodium falciparum sporozoite vaccine

The overarching goal of this project is to develop a highly effective vaccine for prevention of Plasmodium falciparumPfmalaria based on a genetically attenuatedGAtriple gene knockout sporozoiteSPZstage parasite that is asepticpurified and safe for parenteral injectionIn this Phase I applicationwe propose to optimize the manufacturing processes for the vaccineSanariaPfSPZ GAand producelot suitable for clinical testing following Good Manufacturing PracticesGMPsThere is a high likelihood of success based onthe sterilizing immunity induced in humans immunized with attenuated PfSPZst shown insandthe tremendous progress achieved in manufacture and clinical testing of ast generation PfSPZ based vaccinecalled SanariaPfSPZ VaccineIn clinical trials in the U SGermanyMali and TanzaniaPfSPZ Vaccinewhich is attenuated by radiation rather than by discrete gene knockouthas induced andgtsterile protective immunity against controlled human infectionCHMIconductedweeks after immunizationclinical trialsand protection against heterologous CHMI atmonthsMoreoverwe documented sterile protection durable for at leastmonths against intense naturally transmitted Pf malaria in the field in Africaclinical trialsPfSPZ Vaccine is being assessed inclinical trials in the U SGermany and Africawith licensure by the U SFDA anticipated intoyearsImportantlyPfSPZ Vaccine has proven exceptionally safe and well tolerated in all recipientsandgtincluding infantschildren and adultsHowevermanufacture of PfSPZ Vaccine entails operator risksPfSPZ are fully infectious prior to irradiationand the genetic damage is not precisely characterizedFor these reasonswe believe that there would be significant advantagesleading to major savings in cost of goodsCOGsif radiation attenuated parasites were replaced with GA parasitesGA parasites are safer for operatorscannot cause malariathe genetic defect is precisely characterizedand there may be improved in potencyOur colleagues at the Center for Infectious Disease Research demonstrated that eliminating the sappand pgenes leads to complete attenuation at the liver stagesimilar to after radiationThis murine malaria triple knock out elicited excellent protective immunity against SPZ challenge in rodentsand the Pf ppsapSPZ constructPfGAP KOwas safewell tolerated and immunogenic when administered to humans via mosquito biteand did not cause breakthrough blood stage infectionsBased on these encouraging datawe propose expedited development of asepticpurifiedvialedcryopreservedppsapPfSPZThe vaccinePfSPZ GAwill l be manufactured and quality control released in compliance with GMPsSpecific aims are tooptimize production parametersgenerate Master and Working Cell Banksmanufactureclinical lotThis will launch clinical development of the vaccine with the objective of licensing PfSPZ GAfor preventing malaria in travelersfor preventing pregnancy malaria and for mass vaccination programsMVPsaimed at regional malaria elimination PROJECT NARRATIVE Malaria afflicts over two billion peoplekilling overindividuals each year mostly children in AfricaA powerful tool is needed for eliminating Plasmodium falciparum malaria from defined geographical areasThe ideal tool would be a highly effectivelong acting vaccine that prevents infectiondisease and parasite transmissionThis proposal describes the developmentmanufacture and quality control release of a triple knock out genetically attenuated Plasmodium falciparum sporozoite vaccine engineered to completely arrest development in liver stagesas the basis for a next generation whole sporozoite malaria vaccine that is ready for clinical testing