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ROCKVILLE, MD, United States

Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 613.41K | Year: 2015

DESCRIPTION provided by applicant This proposal will demonstrate proof of concept for a whole parasite WP vaccine directed against Plasmodium falciparum Pf sexual and mosquito stages SMS that will be used alone or in combination with PfSPZ Vaccine for interrupting malaria transmission VIMT from the human host to the mosquito vector Such a PfSMS WP VIMT will be an ideal complement to the PfSPZ Vaccine which has shown complete protection against parasite infection in recent clinical trials If the PfSPZ Vaccine prevents infection and transmission in of recipients and PfSMS WP VIMT prevents transmission in of recipients the combination will prevent transmission in at least of recipients The PfSMS WP VIMT offers major advantages to a subunit PfSMS vaccine based on one or a few antigens This vaccine approach will increase the chance that more individuals will have protective immune responses and reduce the possibility of the parasites being able to select for evasion of immune responses by dramatically increasing the number of immunogens against which protective antibodies are induced When used in combination with PfSPZ Vaccine PfSMS WP VIMT will prevent transmission of parasites that may be selected for resistance to PfSPZ Vaccine Sanaria uniquely produces Pf gametocytes sexual stages under GMP conditions and now consistently produces a mixture of gametes zygotes and ookinetes enriched for ookinetes in vitro We partially purified these parasites immunized mice with the preparation in adjuvant and showed that the sera from the immunized mice completely inhibited transmission of parasites to mosquitoes We will exploit Sanariaandapos s unique expertise in GMP compliant gametocyte production and in vitro PfSPZ production as well as extensive experience in parasite purification and in vivo transmission blocking feeding assays to develop produce and test PfSMS WP VIMT We will produce cultures of PfSMS from three time points min h and h to ensure that all PfSMS stages are present We will purify PfSMS in these cultures away from RBCs to obtain purified vaccine preparations Proof of concept will be demonstrated by immunizing mice with the PfSMS WP preparations in combination with adjuvants then testing for antibody responses against cultured parasites and known PfSMS antigens and for transmission blocking activity in an in vivo standard membrane feeding assay The lead candidates will be further tested in mice for interactions with the PfSPZ Vaccine after co administration by direct venous inoculation DVI In Phase II we will finalize methods for scaled up manufacturing in compliance with cGMPs and quality control QC release and stability assays manufacture in compliance with cGMPs conduct QC release assays initiate QC stability studies conduct pre clinical toxicology studies design a clinical trial and prepare al information for an Investigational New Drug application IND PUBLIC HEALTH RELEVANCE Malaria remains the most important parasitic disease affecting mankind There are over deaths per year due to malaria most of these deaths are in children under years old Over million infections occur each year worldwide Success in this project will be a major step towards developing a whole parasite vaccine that will prevent transmission of malaria from human hosts to mosquitoes which if used in combination with Sanariaandapos s highly protective PfSPZ Vaccine will be the ideal tool for malaria elimination


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.00M | Year: 2015

DESCRIPTION provided by applicant Sanariaandapos s platform technology is production of aseptic purified cryopreserved Plasmodium falciparum Pf sporozoites SPZ This technology has produced three products administered by needle and syringe all of which are in clinical trials PfSPZ Vaccine radiation attenuated PfSPZ PfSPZ Challenge infectious PfSPZ for controlled human malaria infection CHMI and PfSPZ CVac PfSPZ Challenge given with antimalarial drugs as a vaccine PfSPZ Vaccine protected volunteers against CHMI in a clinical trial at the NIH The reproducibility of the NIH findings durability of protection protection against heterologous Pf parasites and reduced numbers of doses with altered vaccine regimens are being assessed in clinical trials at sites in the U S Europe and Africa By March our Malian collaborators had injected andgt volunteers twice at a week interval by direct venous inoculation DVI the injections have gone perfectly and been extremely well tolerated clinical trials of PfSPZ Challenge have been conducted in countries infection was achieved in five of the trials A trial of the PfSPZ CVac approach begins in Germany in May There is tremendous international support for our whole PfSPZ approach for malaria vaccines and products for CHMI Sanariaandapos s products rely on production of PfSPZ in aseptic mosquitoes Our Phase I SBIR project proposed developing a method for producing PfSPZ in culture in vitro that would eliminate the need for mosquitoes We estimated this would reduce cost of producing vaccine by The Phase I SBIR was successful We developed methods for producing Pf oocysts in vitro with an efficiency times greater than when we produce oocysts in mosquitoes We repeatedly produced PfSPZ in vitro that invaded and developed to mature day liver stage schizonts expressing Pf merozoite surface protein with the same efficiency as PfSPZ freshly dissected from mosquitoes This is a andquot firstandquot in the history of malaria research Although we will significantly improve efficiency and quality of in vitro production of PfSPZ in Phase II we could now actually manufacture enough PfSPZ in vitro to support a CHMI clinical trial of PfSPZ Challenge in vitro In this Phase II projet we will optimize methods for manufacture of clinical grade PfSPZ in vitro We will use D cell culture technologies to fully optimize methods for production of PfSPZ in vitro and then demonstrate these PfSPZ can reproducibly invade and develop in human hepatocytes in vitro and in vivo and complete the Pf life cycle This will be done in vivo using human liver chimeric mice transfused with human blood We will establish a method for purifying PfSPZ and an assay for quantifying purity Our manufacturing quality and regulatory teams will ensure all reagents and processes are compliant with cGMPs and adequate for manufacturing conduct engineering runs and submit a pre IND package to FDA for a CHMI clinical trial of PfSPZ Challenge in vitro to demonstrate infectivity to humans thereby establishing a rationale for moving from mosquito to in vitro produced PfSPZ for our vaccines PUBLIC HEALTH RELEVANCE A highly effective malaria vaccine would have an enormous public health benefit Sanariaandapos s attenuated malaria sporozoite vaccine PfSPZ Vaccine has been found to be highly effective in clinical trials Currently the PfSPZ Vaccine is manufactured using aseptic mosquitoes This project aims to establish methods for the manufacture of PfSPZ Vaccine in vitro thereby eliminating the need for mosquitoes at any stage in the manufacturing process and thereby reducing cost of goods by approximately


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.00M | Year: 2015

DESCRIPTION provided by applicant We build on the successful work in Phase II SBIR R AI in which a genetically attenuated Plasmodium falciparum Pf parasite GAP was produced and shown to generate aseptic Pf sporozoites SPZ that invade hepatocytes but do not replicate We will use this genetically attenuated double mutant parasite deficient in the genes encoding SLARP and B Pf slarp b GAP to manufacture characterize and release a corresponding PfSPZ Vaccine PfSPZ slarp b Vaccine also known as PfSPZ GA Vaccine in compliance with current Good Manufacturing Practices cGMPs conduct pre clinical Investigational New Drug application IND enabling studies develop a protocol for a phase clinical trial and submit an IND to the FDA The work is based on a wealth of literature describing the robust protective immunity that can be induced in humans immunized with PfSPZ that invade hepatocytes but arrest during liver stage development Sanariaandapos s PfSPZ Vaccine consisting of radiation attenuated aseptic purified cryopreserved PfSPZ protected of volunteers who received the highest dose of PfSPZ administered in the recent phase clinical trial The PfSPZ Vaccine is now being further assessed in clinical trials in the U S and Mali with additional trials pending soon in Tanzania Germany and Equatorial Guinea and is on an accelerated development program leading to licensure in years for elimination campaigns in Africa and prevention of malaria in travelers However there would be manufacturing advantages and potential potency and regulatory advantages leading to significant cost of goods COG savings if the radiation attenuated parasites were replaced with GAPs We have demonstrated that eliminating the slarp and b genes leads to attenuation similar to radiation and that in rodent malarias slarp b SPZs elicit excellent protective immunity against SPZ challenge and do not lead to blood stage infection All prior Pf GAPs showed leaky attenuation and breakthrough liver stage development in vivo or in vitro To overcome this critical problem our previous Phase II SBIR involved Pf strain engineering phenotypic characterization and proof of concept production of PfSPZ bearing knockout KO lesions in two attenuating genes double KO strains that would express a tight attenuated phenotype with no breakthroughs and yet possess robust characteristics suited for our manufacturing process A number of knock out parasites were produced and assessed but only the slarp and b deficient clone of Pf met all of our requirements for moving forward in development PfSPZ produced from the slarp and b deficient clone of Pf were completely attenuated at the early liver stage with no breakthroughs A Master Cell Bank of this clone was made and an engineering production run was performed to demonstrate that the Pf slarp b GAP was suitable for producing aseptic purified cryopreserved PfSPZ This was successfully accomplished We now propose to initiate full pre clinical development and IND submission in preparation for a phase clinical trial of PfSPZ slarp b Vaccine PUBLIC HEALTH RELEVANCE Malaria afflicts hundreds of millions of people killing over individuals each year A powerful tool is needed for eliminating Plasmodium falciparum malaria from defined geographical areas Ideally this would be a highly effective long acting vaccine that prevents disease and parasite transmission This proposal describes a project to manufacture a genetically attenuated form of P falciparum engineered to completely arrest development in liver stages as the basis for a next generation whole sporozoite malaria vaccine that is ready for clinical testing


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2016

DESCRIPTION provided by applicant Plasmodium vivax Pv the second most important human malaria parasite causes more than million cases annually including severe fatal disease Prevention and control are challenged by emerging drug resistance and relapses from dormant liver stage parasites called hypnozoites The only therapy against relapse primaquine causes life threatening acute hemolytic anemia in patients with G PD deficiency the most prevalent human genetic disorder affecting of people in malaria endemic nations This barrier to treatment results in repeated Pv attacks aggravating the problem of control The demonstration of high level long lasting at least months protective efficacy of Sanariaandapos s sporozoite SPZ based vaccines against Pf malaria is a significant milestone and indicates that such vaccines will constitute a viable approach to containing and eliminating Pf We believe that the same vaccine approach could work for Pv In the development of the Pf vaccines controlled human malaria infection CHMI has been an engine of progress accelerating the testing of vaccine candidates Pf CHMI has recently been revolutionized by the development of Sanariaandapos s PfSPZ Challenge aseptic purified cryopreserved fully infectious PfSPZ derived from in vitro cultures of Pf gametocytes enabling the successful infection of volunteers by intradermal intramuscular and intravenous injection in countries in Africa and countries in Europe that had never conducted CHMI before In contrast development of Pv SPZ based products has suffered from lack of available technology to culture Pv parasites in vitro such that generating infected mosquitoes for CHMI required membrane feeding on fresh Pv infected blood from Pv patients We have now overcome this major limitation by using Pv gametocyte infected Saimiri boliviensis non human primates NHPs to produce PvSPZ In fact we are the only laboratory with an inventory of vialed PvSPZ made from NHP infected blood having produced as much as million PvSPZ vialed in day from mosquitoes These cryopreserved PvSPZ are infectious to hepatocyte cell lines in vitro in traditional monolayer formats over days and in micro patterned co cultured primary human hepatocytes over days and infectious to NHPs in vivo We now propose to produce aseptic purified cryopreserved infectious PvSPZ PvSPZ Challenge by using a specific germ free colony of the permissive S boliviensis as the source for Pv infected blood This novel pipeline will generate cGMP compliant controlled batches of PvSPZ including a wide variety of primary and clonal Pv lines isolated from humans This innovation by Sanaria will offer a consistent quality controlled stock of cryopreserved PvSPZ to promote well controlled reproducible in vitro and in vivo studies in Pv including CHMI This enabling technology will support the development and testing of anti Pv drugs and vaccines in CHMIs world wide just as PfSPZ Challenge has done for Pf CHMIs It will also form the basis of a powerful vaccine approach to preventing Pv malaria when administered with anti malarial chemoprophylaxis the PvSPZ chemoprophylaxis vaccine PvSPZ CVac PUBLIC HEALTH RELEVANCE We propose development of the capacity to manufacture aseptic purified vialed cryopreserved Plasmodium vivax sporozoites PvSPZ that meet regulatory standards and can be used initially to infect human subjects in controlled human malaria infections CHMI to assess the efficacy of anti Pv drugs and vaccines and subsequently as a PvSPZ based vaccine This product will be called Sanaria r PvSPZ Challenge and similar to PfSPZ Challenge will provide the larger malaria community with a tool to assess drugs and vaccines against vivax malaria with a safer quality controlled reagent that exhibits minimal lot to lot variability in potency and is logistically more feasible to administer barring any geographical limitations compared to traditional CHMI using mosquito bites


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.00M | Year: 2016

DESCRIPTION provided by applicant The world needs a highly effective malaria vaccine Sanaria r PfSPZ Vaccine composed of aseptic purified cryopreserved radiation attenuated PfSPZ protected of volunteers in an NIH clinical trial The vaccine has been administered by direct venous inoculation DVI to subjects in Mali Tanzania Equatorial Guinea EG and USA Safety tolerability high grade protection heterologous protection after Controlled Human Malaria Infection durable protection in the field efficacy with doses and safety at x the protective dose have been established Sanaria has met with the World Health Organization to plan for pre qualification and establishment of a Technical Advisory Group for PfSPZ Vaccine administered by DVI In the vaccine will be assessed by DVI in Tanzania Kenya infants Mali Burkina Faso EG Germany and USA The first licensure submission in USA is planned for late Reduction in the number of PfSPZ regimen number of doses and or time to complete an immunization regimen and prolongation of efficacy will reduce costs and improve implementation Being able to immunize by cutaneous or intramuscular routes will increase capacity to immunize young infants and facilitate immunization by less experienced personnel To these ends we have studied adjuvants that augment prolong immune responses Traditional and experimental adjuvants including multiple toll like receptor ligands do not work likely because the vaccine is composed of live attenuated organisms and no licensed adjuvants are known to enhance the CD T cell mediated immunity which appears to underlie protective efficacy against PfSPZ Vaccine A novel glycolipid DW which binds CD d and stimulates iNKT cells has strong adjuvant effects in mice immunized with irradiated P yoelii sporozoites irrPySPZ and enabled reduction to one dose when irrPySPZ were administered by DVI protection and from to doses when administered intradermally protection Protection lasted for at least weeks Four DVI doses during a week of x purified cryopreserved irrPySPZ with and without DW protected and of mice respectively p raising the possibility of an accelerated immunization regimen that would be ideal for travelers and mass administration campaigns In non human primates NHPs DW with PfSPZ Vaccine was well tolerated greatly enhancing the magnitude of splenic CD and CD T cell responses months post vaccination These findings support development of DW for use with PfSPZ Vaccine administered both by intravascular and traditional routes to allow for reduced cost of goods rapid immunization and increased durability of protection In this project we will assess DW with rodent human and simian SPZ in mice and NHPs and manufacture DW in compliance with cGMPs Accomplishing the Specific Aims of this proposal will provide the foundation for the first phase clinical trial of PfSPZ Vaccine administered with DW and eventual use of this combination for rapid and cost effective immunization of travelers military and for mass malaria elimination campaigns PUBLIC HEALTH RELEVANCE In our screens to identify an adjuvant that can promote dose sparing and prolong duration of protection with an attenuated malaria vaccine a novel glycolipid DW that binds CD d and stimulates iNKT cells was the only agent over several TLR ligands tested to demonstrate significant enhancement in a mouse malaria model We propose further pre clinical characterization of adjuvant activity in mice and primates to support its inclusion with Sanariaandapos s radiation attenuated PfSPZ Vaccine in order to significantly enhance vaccine potency efficacy and feasibility of use

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