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Patent
Sanaria, Inc. | Date: 2017-03-08

The application is directed to in vitro-reared Plasmodium sporozoites of human host range wherein sporogony from gametocyte stage to sporozoite stage is external to mosquitoes, and methods of producing the same. Provided herein are in vitro-reared infectious Plasmodium sporozoites (SPZ) of human host range, particularly P. falciparum, P. vivax, P. ovale, P. malarlae, and P. knowlesi, wherein sporogony from gametocyte stage to sporozoite stage is external to mosquitoes, and methods of producing the same.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 989.30K | Year: 2016

ABSTRACT Sanaria s Plasmodium falciparum Pf sporozoite SPZ vaccines development program is receiving global support Trials of PfSPZ Vaccine radiation attenuated PfSPZ or PfSPZ CVac PfSPZ Chemoprophylaxis Vaccine administered by direct venous inoculation DVI including adults to infants were initiated in December Tanzania U S or will be initiated in early in Mali Kenya infants Ghana Equatorial Guinea Germany and additional U S sites These trials will assess or dose regimens as protective efficacy at weeks after last dose has been established with a dose regimen Protective efficacy has been shown to be durable against controlled malaria infection CHMI for at least a year and against intense natural transmission in Mali of heterogeneous strains of Pf for at least months PfSPZ Vaccine and PfSPZ CVac are comprised of PfSPZ of the NF strain of Pf Short term protection weeks by PfSPZ Vaccine against a heterologous different from the vaccine strain CHMI with Pf G parasites was but despite a significant delay in onset of parasitemia month sterile protective efficacy was only Sanaria is taking two approaches to improving protective efficacy against heterologous heterogeneous strains The st is to increase the dose of PfSPZ NF per immunization based on the hypothesis that this will broaden and strengthen the protective immune responses against shared dominant and sub dominant epitopes All of the trials described above utilize this approach The nd and potentially more efficient approach will be to combine PfSPZ from different strains of Pf in the same vaccine Our analysis of genomic sequence data predicted proteomes and predicted T cell epitopes indicates that using two strains of Pf should be sufficient This project fills an important gap We have funding from VRC NIAID NIH to conduct a clinical trial of a multivalent PfSPZ vaccine but require the funds to manufacture characterize and release the multi valent vaccine and to navigate the regulatory clinical affairs pathways required to initiate the trial In this Phase IIB SBIR project we propose to Manufacture and QC release chloroquine sensitive PfSPZ Challenge of a W African Pf clone NF that can be used for CHMI studies and as a component of a multi strain PfSPZ CVac Manufacture and release PfSPZ Vaccine based on the Brazilian Pf clone G and PfSPZ Vaccine NF for a two strain clone PfSPZ Vaccine combination Manufacture and release PfSPZ Challenge G and PfSPZ Challenge NF for a two strain combination PfSPZ CVac and Conduct an end of phase meeting with FDA to propose and finalize a plan for using phase CHMI trials with PfSPZ Challenge NF G NF C and NF to replace phase field trials to establish protective efficacy of the vaccines Success will reduce the time to licensure of a PfSPZ vaccine for travelers military by at least a year and save andgt $ M It will also facilitate more rapid development of all pre erythrocytic stage vaccines intended to provide the high level andgt protection required for a vaccine for travelers military and elimination campaigns PROJECT NARRATIVE Since inception this SBIR has been focused on providing the foundation for moving to a multivalent approach to vaccination if needed a multi strain clone approach to controlled human malaria infection with Sanaria s Plasmodium falciparum Pf sporozoite SPZ based products In this new project we will develop an optimized strain clone vaccine and multi strain clone controlled human malaria infection system and an optimized approach for a travelers military vaccine for pivotal phase trials that takes advantage of these key parasites and thereby significantly reduces the time and cost to achieve vaccine licensure and commercial launch


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


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


Patent
Sanaria, Inc. | Date: 2016-01-21

Disclosed are substantially purified Plasmodium sporozoites and preparations of Plasmodium sporozoites substantially separated from attendant non-sporozoite material, where the preparations of Plasmodium sporozoites have increasing levels of purity. Vaccines and pharmaceutical compositions comprising purified Plasmodium sporozoites are likewise provided. Methods of purifying preparations of Plasmodium sporozoites are also provided.


Patent
Sanaria, Inc. | Date: 2016-04-11

The application is directed to in vitro-reared Plasmodium sporozoites of human host range wherein sporogony from gametocyte stage to sporozoite stage is external to mosquitoes, and methods of producing the same. Provided herein are in vitro-reared infectious Plasmodium sporozoites (SPZ) of human host range, particularly P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi, wherein sporogony from gametocyte stage to sporozoite stage is external to mosquitoes, and methods of producing the same.


Patent
Sanaria, Inc. and Rockefeller University | Date: 2016-02-18

Disclosed herein are pharmaceutical compositions comprising Plasmodium sporozoite-stage parasites and compatible glycolipid adjuvants useful in vaccines for preventing or reducing the risk of malaria. In particular, human host range Plasmodium and analogues of -galactosylceramide (-GalCer), a ligand for natural killer T (NKT) cells, are combined in pharmaceutical compositions, which are useful as vaccines against malaria. Methods of use are also provided.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 991.53K | Year: 2016

ABSTRACT Sanaria s Plasmodium falciparum Pf sporozoite SPZ vaccines development program is receiving overwhelming global support Eleven trials of Sanaria s two primary PfSPZ vaccines which include subjects were initiated in late Tanzania U S or will start in early Kenya Ghana Equatorial Guinea EG Burkina Faso Germany and the U S These trials will assess to dose regimens based on a trial in Germany showing protective efficacy against controlled human malaria infection CHMI weeks after the last dose of a dose week regimen Protective efficacy is durable against CHMI for at least a year and against intense natural transmission in Mali for at least months This success has led to the development in collaboration with the International PfSPZ Consortium of a stage clinical development plan The completed trials stage and above mentioned new trials stage are intended to optimize immunization regimens in preparation for pivotal phase clinical trials stage to support a Biologics License Application BLA to the FDA and commercialization launch Stage post licensure includes a mass vaccine administration MVA campaign to halt transmission of Pf and eliminate the parasite from the andgt population of Bioko Island EG Through SBIR grants and U S military contracts Sanaria is scaling up manufacturing and improving its vaccine manufacturing facility to meet phase and launch compliance However there are critically important unfunded components of our quality assurance QA quality control QC manufacturing regulatory and clinical quality and data management programs which must be upgraded and finalized This CRPP project will address several of these key components The overarching goal is to augment Sanaria s current efforts to achieve commercialization readiness and optimize chances of a successful phase program BLA product launch and post launch phase testing and maintenance We will Establish and implement a QA and QC program that meets harmonized regulatory standards with appropriate organizational and systems infrastructure Formally assess manufacturing processes including Failure Modes and Effects Analysis FMEA risk assessment and validation of the aseptic manufacturing processes Transition to regulatory submissions in electronic common technical document eCTD format establish a platform for hosted regulatory document management develop a strategic framework for FDA submissions and interactions and develop and implement plans for BLA submission and regulatory SOP completion and Develop phase compliant clinical quality systems including clinical SOPs establish a CDISC compliant clinical data management platform import data from clinical trials generate Clinical Study Reports CSRs for all clinical trials lacking CSRs and conduct a quality review audit of trial master files Funding of this proposal will significantly shorten the time until product licensure and launch which will lead to sales and income at least a year earlier than otherwise possible and will save many lives PUBLIC HEALTH RELEVANCE Project Narrative Malaria afflicts over two billion people killing over individuals each year mostly children in Africa A powerful tool is needed for eliminating Plasmodium falciparum malaria from defined geographical areas The ideal tool would be a highly effective long acting vaccine that prevents infection disease and parasite transmission the Sanaria PfSPZ Vaccine is the leading candidate that fits these characteristics This proposal will accelerate to market Sanaria s PfSPZ Vaccine by providing support for Quality Assurance Quality Control Manufacturing compliance regulatory and clinical QA and reporting This support will allow the submission of BLAs for the vaccine and post licensure management

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