ROCKVILLE, MD, United States
ROCKVILLE, MD, United States

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"These papers report the first steps in the execution of our plans to create room temperature stable, orally self-administered, safe and effective vaccines against shigellosis, typhoid fever, anthrax, enterotoxigenic Escherichia coli, and eventually other causes of diarrheal diseases and agents of bioterrorism," said Dr. B. Kim Lee Sim, President of Protein Potential LLC. "The next step will be to manufacture the vaccines in compliance with current Good Manufacturing Practices and initiate clinical trials to assess the safety, tolerability, immunogenicity, and protective efficacy of these vaccines." Professor Johnny W.  Peterson of the University of Texas Medical Branch Galveston said, "We were extremely pleased to find that immunization with Ty21a-PA-01 protected rabbits against 200 times the 50% lethal dose of anthrax spores. Since this vaccine was stable at room temperature for 20 months and can be administered orally, it holds great promise for community-wide immunization in the face of an anthrax threat." Dr. Richard I. Walker, Director of the Enteric Vaccine Initiative at PATH said, "Shigellosis has emerged as the number one bacterial cause of diarrheal diseases in 1-10 year olds worldwide. An unstable form of Ty21a expressing S. sonnei O antigen was shown to protect volunteers against controlled human infection more than 30 years ago. Protein Potential's engineering of the acid-stabilized Ty21a, which stably expresses S. sonnei O antigen represents a promising step forward in our quest to finally license a vaccine to prevent shigellosis." Protein Potential's research and development efforts for these anthrax and shigellosis vaccines were funded by SBIR and R01 grants from the National Institute of Allergy and Infectious Diseases, NIH. About Protein Potential, LLC: Protein Potential's Research and Development Group focuses on producing intellectual property and recombinant bacteria, recombinant protein, and DNA products. Protein Potential's primary focus is on development of vaccines to protect against enteric diseases including shigellosis, diarrhea caused by ETEC, and typhoid fever and bioterrorism agents using its platform technology of recombinant, acid-stabilized Ty21a.  Protein Potential is also developing subunit vaccines for Plasmodium falciparum and Plasmodium vivax malaria. Protein Potential's Products and Services Group provides pharmaceutical and biotechnology companies, and government and academic institutions with high quality, purified Protein PotentialTM recombinant proteins and DNA plasmids for research and development. Protein Potential also provides process development, documentation, and technological know-how to transition therapeutic, vaccine, and diagnostic proteins and DNA plasmids to large-scale cGMP (Good Manufacturing Practices) manufacture (Protein PotentialTM service packages). This news release contains certain forward-looking statements that involve known and unknown risks and uncertainties, which may cause actual results to differ materially from anticipated results or achievements expressed or implied by the statements made. These forward-looking statements are further qualified by important factors that could cause actual results to differ materially from those in the forward-looking statements. These factors include, without limitation, the Company's ability to raise sufficient funds, the regulatory approval process, results, the Company's patent portfolio, dependence on key personnel and other risks. For further information contact Alexander Hoffman, info@protpot.com, 301-339-0092. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/protein-potential-llc-publishes-on-its-anthrax-and-shigellosis-vaccines-based-on-oral-typhoid-fever-vaccine-platform-300474306.html


Disrupting erythrocyte invasion by Plasmodium falciparum is an attractive approach to combat malaria. P. falciparum EBA-175 (PfEBA-175) engages the host receptor Glycophorin A (GpA) during invasion and is a leading vaccine candidate. Antibodies that recognize PfEBA-175 can prevent parasite growth, although not all antibodies are inhibitory. Here, using x-ray crystallography, small-angle x-ray scattering and functional studies, we report the structural basis and mechanism for inhibition by two PfEBA-175 antibodies. Structures of each antibody in complex with the PfEBA-175 receptor binding domain reveal that the most potent inhibitory antibody, R217, engages critical GpA binding residues and the proposed dimer interface of PfEBA-175. A second weakly inhibitory antibody, R218, binds to an asparagine-rich surface loop. We show that the epitopes identified by structural studies are critical for antibody binding. Together, the structural and mapping studies reveal distinct mechanisms of action, with R217 directly preventing receptor binding while R218 allows for receptor binding. Using a direct receptor binding assay we show R217 directly blocks GpA engagement while R218 does not. Our studies elaborate on the complex interaction between PfEBA-175 and GpA and highlight new approaches to targeting the molecular mechanism of P. falciparum invasion of erythrocytes. The results suggest studies aiming to improve the efficacy of blood-stage vaccines, either by selecting single or combining multiple parasite antigens, should assess the antibody response to defined inhibitory epitopes as well as the response to the whole protein antigen. Finally, this work demonstrates the importance of identifying inhibitory-epitopes and avoiding decoy-epitopes in antibody-based therapies, vaccines and diagnostics. © 2013 Chen et al.


Webb C.J.,Princeton University | Wu Y.,Princeton University | Wu Y.,Protein Potential, Llc | Zakian V.A.,Princeton University
Cold Spring Harbor Perspectives in Biology | Year: 2013

Themoleculareraoftelomere biology began withthe discovery that telomeres usually consist of G-rich simple repeats and end with 30 single-stranded tails. Enormous progress has been made in identifying the mechanisms that maintain and replenish telomeric DNA and the proteins that protect them from degradation, fusions, and checkpoint activation. Although telomeresindifferent organisms (oreveninthe same organismunder different conditions) are maintained by different mechanisms, the disparate processes have the common goals of repairing defects caused by semiconservative replication through G-rich DNA, countering the shortening caused by incomplete replication, and postreplication regeneration of G tails. In addition,standardDNA repair mechanismsmustbesuppressedormodifiedattelomeresto preventtheirbeingrecognizedandprocessedasDNA double-strandbreaks.Here,wediscuss the players and processes that maintain and regenerate telomere structure. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 609.20K | Year: 2015

DESCRIPTION provided by applicant Vaccines are a rational and cost effective means for protecting against infectious diseases in travelers military personnel and in endemic developing country populations Our goal in this proposal is to address several significant vaccine needs the need for an easy to administer needle free and safe oral vaccine vector platform for stable expression and delivery of multiple foreign antigens that generates long term efficacy following a rapid immunization regimen and which can be distributed without the need for refrigeration the lack of a licensed vaccine for prevention of morbidity and mortality due o shigellosis and development of a multivalent oral vaccine that will simultaneously protect against multiple disease agents i e enteric fever plus the major causes of shigellosis To address these challenges we exploit the extensive safety record of the existing live oral attenuated Salmonella Typhi Ty a typhoid vaccine by utilizing it as our lead candidate vector to develop a combination oral vaccine that will simultaneously protect against both typhoid fever with cross protection against some paratyphoid fevers and shigellosis Further we hypothesize that this vaccine can be formulated to be safe stable and highly immunogenic and can be easily administered orally The current proposal is aimed at creating multivalent vaccine strains Ty a expressing S sonnei form O polysaccharide Ty a Ss and Ty a expressing S flexneri a form O polysaccharide Ty a Sf a We will also create acid resistant Ty a Ss and Ty a Sf a by adding Shigella glutamate decarboxylase GAD genes into vaccine candidates and fully characterize each strain genetically and biochemically Immunogenicity and protective efficacy against S Typhi Ty S sonnei G and S flexneri a T in mice of Ty a Ss Ty a Sf a Ty a Ss GAD and Ty a Sf a GAD will be assessed by immunization via intranasal installation of doses followed by mucosal challenge In Phase II we will conduct similar work for S flexneri a and finalize a temperature stable dried product as rapidly dissolvable wafers or tablets conduct all pre clinical IND enabling studies finalize a clinical protocol and submit an IND This Phase I project will provide the foundation for the Phase II to complete construction of a quadrivalent anti shigellosis vaccine that will protect against more than of shigellosis worldwide PUBLIC HEALTH RELEVANCE Our goal is to develop a multivalent oral vaccine that will simultaneously protect against multiple disease agents is easy to administer needle free is a safe oral vaccine vector platform for stable expression and delivery of multiple foreign antigens that generates long term efficacy following a rapid immunization regimen and which can be distributed without the need for refrigeration To address these challenges we exploit the extensive safety record of the existing live oral attenuated Salmonella Typhi Ty a typhoid vaccine by utilizing it as our lead candidate vector to develop a combination oral vaccine that will simultaneously protect against both typhoid fever with cross protection against some paratyphoid fevers and shigellosis We hypothesize that this vaccine can be formulated to be safe stable highly immunogenic and can be easily administered orally


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 297.49K | Year: 2016

Enteric diseases caused by enterotoxigenic E coli ETEC strains Shigella spp and Salmonella Typhi all of which are NIAID Category B priority agents collectively affect andgt million people annually worldwide Currently there is no vaccine against ETEC or shigellosis A typhoid vaccine exists An affordable effective oral multivalent vaccine against all organisms would have enormous public health importance and a substantial commercial market among travelers and military personnel Our long term goal is to create a stable orally administered vaccine against ETEC shigellosis and typhoid To begin the process of achieving this goal we have used the licensed Ty a typhoid vaccine to express the O antigen of Shigella sonnei to produce a vaccine candidate called TyOraSs which is under development The major virulence determinants of ETEC are the colonization factor antigens CFAs or adhesins and two enterotoxins the heat labile LT and heat stable toxin STa An effective ETEC vaccine should induce antibodies that block bacterial attachment and or to neutralize the toxins In animal models antibodies to CFA and toxin are synergistically protective It has been shown by members of our team that a multi epitope fusion antigen MEFA representing separate CFA ETEC adhesins and two toxins can be fused as a single protein designated here as MEFA T to induce cross protective antibodies that blocks adherence of heterogeneous ETEC strains to human colon cancer cells in vitro and neutralizes two toxins in all ETEC strains In this project we will stably express these multiple adhesins and the toxoid form of both toxins stably as a holotoxin structured CFA toxoid fusion cassette antigen in Ty a and assess immunogenicity and protective efficacy of our Ty a ETEC vaccine using the suckling piglet and rabbit challenge models Specifically we will Generate and characterize vaccine strain s of genetically optimized Ty a expressing chromosomally integrated ETEC multi epitope fusion antigen MEFA toxoid LT STa designated Ty a ETEC MEFA T either intra cellularly or in secreted form Demonstrate immunogenicity against ETEC and S Typhi by mucosal immunization of mice and Establish protective efficacy against ETEC in the rabbit colonization model and suckling piglet lethal infection model Our proposal is unique because of our expertise at construction of multivalent ETEC fusion antigens experience with using Ty a as a platform for expressing heterologous antigens and capabilities with animal models to unambiguously assess vaccine protective efficacy A stand alone ETEC typhoid vaccine would have substantial impact however our aim to use success in this project as a foundation for the development of a multivalent vaccine against ETEC typhoid and shigellosis In Phase II we will generate a single triple pathogen vaccine TyOraSs ETEC vaccine or two bivalent vaccines generate a master cell bank of the vaccine candidate strain s for manufacturing in compliance with cGMPs and as a foam dried vaccine product s conduct required pre clinical studies design a clinical protocol and prepare an IND Our goal is to develop a multivalent oral vaccine that will simultaneously protect against multiple disease agents is easy to administer needle free is a safe oral vaccine vector platform for stable expression and delivery of multiple foreign antigens that generates long term efficacy following a rapid immunization regimen and which can be distributed without the need for refrigeration To address these challenges we exploit the extensive safety record of the existing live oral attenuated Salmonella Typhi Ty a typhoid vaccine by utilizing it as our lead candidate vector to develop a combination oral vaccine that will simultaneously protect against both typhoid fever with cross protection against some paratyphoid fevers and enteric fevers We hypothesize that this vaccine can be formulated to be safe stable highly immunogenic and can be easily administered orally


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012

DESCRIPTION (provided by applicant): Malaria caused by Plasmodium falciparum (Pf) results in more than 250 million clinical cases, and nearly one million deaths annually. A vaccine would be the ideal intervention for reducing malaria morbidity and mortality. All clinical manifestations and pathology of malaria are caused by the erythrocytic stage of the parasite life cycle, and thus all sequelae of malaria disease begin when the parasite invades erythrocytes. Blocking parasite invasion of erythrocytes wouldprevent parasite replication and all clinical disease. Pf parasites invade erythrocytes by binding to specific erythrocyte receptors. Thus, blocking parasite invasion of erythrocytes by inducing antibodies that interfere with parasite receptor-ligand interaction during invasion is an important approach to malaria vaccine development. A well-studied Pf ligand is EBA-175 that binds its receptor sialic acids on glycophorin A. Antibodies to EBA-175 can block parasite invasion. Unfortunately there are strains of Pf that invade by alternate pathways not involving sialic acids. Development of vaccines that effectively block invasion must thus induce antibodies against multiple ligands, antibodies that interfere with the sialic acid and alternate pathways of invasion. The reticulocyte binding homolog protein family (PfRH) of proteins has been identified to play a major role in binding and invasion of erythrocytes by alternate pathways excluding sialic acids. We aim to assess if antibodies induced by immunization with the PfRH proteins when combined with antibodies against EBA-175 can effectively block invasion of parasites into erythrocytes. Assessments will be systematically performed using blocking of erythrocyte binding and parasite growth invasion inhibition assays. We will first express recombinant candidate proteins to raise antibodies against these candidates in rabbits. The candidates PfRH 1, 2b, 4 and 5, together with EBA-175 will be assessed. Our immediate goal is to potently interfere with parasite bindingand invasion into erythrocytes using the strategy of a multi-ligand vaccine that induces antibodies that block multiple pathways of invasion. Interfering on multiple fronts with the single crucial step of erythrocyte invasion is at the core of our innovation and approach. We will select the best combination of candidates and propose to develop them in Phase II as a multi-ligand, invasion blocking vaccine. Thus in Phase II we will create producer clones of the selected recombinant candidates and systematically assess them in rhesus monkeys with multiple adjuvant formulations suitable for human use, down select the best adjuvant formulation(s), and produce material under cGMPs in preparation for clinical trials designed to determine the efficacy of this multi-ligand merozoite invasion blocking vaccine. PUBLIC HEALTH RELEVANCE: Malaria causes 400-500 million clinical cases and nearly 1 million deaths annually, and is responsible for gt1% loss of GDP in Africa annually and is a serious concern for travelers and military personnel. Protein Potential's goal is to develop and commercialize a gt90% protective malaria vaccine for primary markets with a potential for gt 1 billion annual revenues; 1) travelers from the developed world, and 2) infants, young children, and adolescent girls in the developing world. Success in this project will significantly decrease the cost of development and reduce time to market for an effective malaria vaccine.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012

DESCRIPTION (provided by applicant): Malaria causes at least 250 million cases and nearly 1 million deaths per year. GSK's malaria vaccine, RTS, S/AS01 is being tested in a Phase 3 clinical trial, and is likely to be licensed for use in children in the developing world, if safe ad effective. This vaccine is based entirely on the repeat region and carboxy terminus of the Plasmodium falciparum (Pf) circumsporozoite protein (CSP). It is administered with an adjuvant AS01, which includes liposomes, monophosphoryl lipid A, and a purified plant extract, QS21, but was initially developed with an oil in water-based adjuvant. Downselection of adjuvants for clinical trials was done through a series of iterative studies in mice and non-human primates (NHPs). In its final formulation this vacccine protects 50% of volunteers against experimental challenge with Pf for 2 weeks after last dose, and 22% of volunteers for 6 months. Protection is thought to be primarily mediated by antibodies against the repeat region of PfCSPand possibly CD4+ T cell responses against the C' terminus of the PfCSP. The vaccine does not induce meaningful CD8+ T cell responses. However, many malariologists believe that long- term protection will be dependent on induction of Pf-specific CD8+ T cellimmunity, as has been obseved in mice and NHPs immunized with irradiated sporozoites. RTS, S/AS01 is not being considered for non-immune travelers and military personnel, because its protective efficacy is too low. A vaccine for this population needs to provide gt80% protective immunity for at least 6 months to have a substantial market. We hypothesize that by adding highly functional, protective CD8+ T cell responses to antibody responses against the PfCSP, such protective immunity can be achieved. Recombinant adenovirus (Ad) expressing proteins like the PfCSP is currently a popular method for inducing CD8+ T cell responses in humans. However, despite the induction of antigen-specific CD8+ T cell responses of very high magnitude such Ad-based vaccines havenot been highly protective in humans, especially against malaria. Recently, it was shown in mice that recombinant attenuated Listeria monocytogenes (Lm) induced much higher quality (functional) CD8+ T cell responses than did recombinant Ad5. We will use aheterologous prime-boost regimen combining an adjuvanted recombinant PfCSP protein (rPfCSP) and Lm expressing PfCSP (Lm-PfCSP). The goal of this strategy is to induce PfCSP- specific protective antibodies and protective CD8+ and CD4+ T cell responses thatprovide gt80% protection that is sustained for at least 6 months. In Phase I we will identify combinations of rPfCSP, adjuvant and Lm- PfCSP that induce high level antibodies, and CD8+ and CD4+ T cell responses in mice. In Phase II we will take the approach used by GSK, and use immunogenicity in NHPs to downselect combinations for clinical trials of a vaccine that is intended to have efficacy adequate to prevent gt80% of vaccinees from developing Pf parasitemia; a vaccine suitable for the potential multi-billion dollar non-immune traveler, business, and military markets, and for eliminating Pf in geographically focused campaigns in the developing world. PUBLIC HEALTH RELEVANCE: Malaria causes 400-500 million clinical cases and gt1 million deaths annually, is responsible for gt1% loss of GDP in Africa annually and is a serious concern for travelers and military personnel. Protein Potential's goal is to develop and commercialize a gt90% protective malaria vaccine for primary markets with a potentialfor gt 1 billion annual revenues; 1) travelers from the developed world, and 2) all populations in the developing world. Success in this project will significantly decrease the cost of development and time to market for this malaria vaccine.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012

DESCRIPTION (provided by applicant): We believe that eradication of malaria is achievable but not without a potent vaccine that interrupt malaria transmission (VIMT) transmission blocking vaccine. A logical and promising strategy is to combine target antigens from multiple stages to potently prevent transmission. To prevent transmission a vaccine should target the pre-erythrocytic (sporozoite and liver stages) and the sexual-mosquito stages of the life cycle. An ideal malaria vaccine would prevent infection, disease, and transmission by targeting at a minimum the pre- erythrocytic (sporozoites and liver stages) and optimally other stages of the parasite life cycle also. Pre- erythrocytic stage vaccine development is based on the observation that immunizationvia bites of irradiated mosquitoes infected with Plasmodium falciparum (Pf) sporozoites (SPZ) provides high-level protection. The circumsporozoite protein (CSP) was discovered by immunizing mice with irradiated SPZ. A higher percent of volunteers immunized with radiation attenuated PfSPZ have T cells that recognize Pf cell-traversal protein for ookinetes and sporozoites (PfCelTOS) than PfCSP, and immunization of mice with PfCelTOS protects against challenge with rodent malaria SPZ at the pre-erythrocytic stage. We have discovered that antibodies induced in mice by immunizing with recombinant (r) PfCelTOS with adjuvant inhibited Pf development to oocysts in mosquitoes in vivo and PfSPZ invasion and development in hepatocytes in vitro. When mice were immunized with rPfCelTOS alone, rPfCSP alone, or both, mice immunized with both proteins had higher Abs against PfSPZ and activity in blocking SPZ invasion and development in hepatocytes (86%) than did mice immunized with either protein individually. The observations that antibodies against rPfCelTOS, had biological activity against parasite mosquito (ookinete) and pre-erythrocytic (SPZ) stages, and were additive or synergistic with anti-PfCSP antibodies against SPZ are unique, and argue for further development ofthis protein. To further enhance VIMT effects, we will assess Pf von Willebrand factor A domain-related protein (PfWARP), a highly conserved, soluble ookinete specific protein that we have shown previously to potently inhibit development of oocysts in themosquito midgut. Our aim in this study is to develop a combined multiple stage vaccine to potently prevent transmission by inhibition of oocyst development. PfCelTOS and PfCSP are also expressed in hemocoel stage sporozoites and thus our strategy would also target the conversion of oocysts to infectious sporozoites in the salivary glands. We will study the three proteins as immunogens alone and in combination, aiming to induce 100% transmission blocking activity. We believe that eradication of malaria is achievable but not without a potent transmission blocking vaccine, and that these 3 proteins can achieve this goal. Such a vaccine would be used in infants, young children, adolescent females (prevent malaria in pregnancy) and malaria elimination campaigns as a public health measure; an enormous global health market. PUBLIC HEALTH RELEVANCE: Malaria causes 400-500 million clinical cases and gt1 million deaths annually, is responsible for gt1% loss of GDP in Africa annually and is a serious concern for travelers and military personnel. We believe that eradication of malaria is achievable but not without a potent transmission blocking vaccine. A logical and promising strategy is to combine multiple stage targets to potently prevent transmission. Such avaccine would have huge public-sector markets. In public sector markets it would be used in infants, young children, adolescent females (prevent malaria in pregnancy) and malaria elimination campaigns as a public health measure.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.99K | Year: 2010

DESCRIPTION (provided by applicant): Vaccines are a proven and effective approach for assuring widespread protection of large populations prior to or immediately following a bioterrorism attack. Our goal is to address two significant problems currently raised by bioterrorism threats: 1) the need for an easy method of mass vaccination and 2) the shortcomings of the current anthrax vaccine (NIAID category A agent) which requires needles and health professionals for administration, an extended vaccination schedule for protection (6 doses over 18 months) and the concern over adverse effects. To address this challenge, we have exploited the extensive safety record of the existing live, oral Salmonella Typhi Ty21a vaccine by utilizing it as a vector to develop a live oral vaccine carrier stably expressing rPA. We hypothesize that Ty21a is a suitable vaccine carrier for the stable expression of the rPA gene harbored on a low copy number plasmid. Further, we hypothesize that this vaccine can be formulated so that it will be safe, stable, and highly immunogenic and can be easily administered orally. The current proposal is aimed at completing the necessary final development steps (e.g. removal of antibiotic resistance gene from vector plasmid) and full characterization (genetic and microbiological) of the candidate prior to constructing a genetic seed bank and small-scale (5-10 liter) manufacture and lyophilization. Finally, the candidate will be studied for genetic stability, safety, immunogenicity and efficacy in a mouse model of anthrax disease. Successful completion of this Phase I SBIR will provide the foundation for development of an oral anthrax vaccine in a Phase II proposal, and for a platform technology for oral vaccines against multiple other infectious agents. PUBLIC HEALTH RELEVANCE: Anthrax bacteria produce spores that can be processed to become easily airborne. Vaccines are a proven and effective approach for assuring widespread protection of large populations prior to or immediately following a bioterrorism attack. Our goal is to address two significant problems currently raised by bioterrorism threats: 1) the need for an easy method of mass vaccination and 2) the shortcomings of the current anthrax vaccine (NIAID category A agent) which requires needles and health professionals for administration, an extended vaccination schedule for protection (6 doses over 18 months) and the concern over adverse effects. Further, we hypothesize that this vaccine can be formulated so that it will be safe, stable, and highly immunogenic and ultimately can be easily administered orally.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.89M | Year: 2010

DESCRIPTION (provided by applicant): Plasmodium vivax recombinant CS protein vaccine Plasmodium vivax (Pv) is responsible for hundreds of millions of malaria cases annually, as many cases of malaria in travelers as P. falciparum (Pf), and a substantial economic burden. Severe malaria with mortality due to Pv has recently been reported from Oceania, south Asia, and South America. During the last decade, drug resistant Pv has emerged. There is a huge potential market for a Pv vaccine in travelers and military from the developed world, and among populations in countries with endemic Pv. Pv vaccine research has been neglected. The fact that Pf and Pv co-exist in most malaria endemic areas worldwide presents technical and ethical constraints for deployment of a vaccine effective only against Pf. Malaria cannot be eradicated without eliminating Pv. The only subunit malaria vaccines that have been reproducibly shown to prevent Pf malaria in humans are based on the Pf circumsporozoite protein (PfCSP). These protective vaccines elicit antibodies against the central repeat region of the molecule, which is conserved in all isolates of Pf, and against T cell epitopes in the C-terminal flanking region. It has not been possible to produce successfully a PfCSP recombinant (rec) protein vaccine that includes the N-terminal flanking region. Development of a PvCSP rec protein vaccine has been complicated by the fact that there are 2 major alleles of the PvCSP (210 and 247) based on variation in sequence of the central repeats. In Phase I we constructed PvCSP rec proteins that combined 3 copies of PvCSP 210 repeats and 3 copies of PvCSP 247 repeats with N-terminus (Protein 1), C- terminus (Protein 2) or N- and C-termini (Protein 3) of the PvCSP. All were expressed at levels adequate for GMP production. Protein 2 aggregated making purification and characterization difficult. All induced in mice antibodies that recognized PvCSP and Pv sporozoites expressing PvCSP 210 or 247, and inhibited Pv sporozoite invasion and development in human hepatocytes. Protein 2 did not induce antibodies against the Pv247 repeats, and could not be evaluated in T cell studies. Protein 3 induced better immune responses than Protein 1, and since Protein 3 includes essentially the full-length protein with all B and T cell epitopes, we have selected Protein 3 for Phase II. In Phase II we will: 1) Optimize protein 3 expression and generate a master clone and master cell bank, 2) Define specifications for fermentation procedure at scale under cGMPs, 3) Formulate candidate protein with 4 different adjuvants, 4) Down select optimal protein/adjuvant/formulation by comparative immunogenicity in mice and monkeys, 5) Define specifications for process, generate technical transfer records and documentation for cGMP manufacture, 6) Manufacture vaccine, conduct release assays, release bulk drug substance and conduct stability studies. By end of Phase II PvCSP Protein 3 vaccine/adjuvant will be available for pre-clinical toxicology studies and Phase 1/2a clinical trials. PUBLIC HEALTH RELEVANCE: Plasmodium vivax (Pv) is responsible for hundreds of millions of malaria cases annually, as many cases of malaria in travelers as P. falciparum (Pf), and a substantial economic burden. Severe malaria with mortality due to Pv has recently been reported from Oceania, south Asia, and South America. During the last decade, drug resistant Pv has emerged. There is a huge potential market for a Pv vaccine in travelers and military from the developed world, and among populations in countries with endemic Pv. This project will develop and manufacture such a vaccine.

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