The Experts below are selected from a list of 192 Experts worldwide ranked by ideXlab platform
Stephen L Hoffman - One of the best experts on this subject based on the ideXlab platform.
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adaptive clinical trials of three pfspz products for development of a whole Sporozoite Vaccine that prevents plasmodium falciparum infection disease and transmission
Malaria Journal, 2012Co-Authors: Stephen L HoffmanAbstract:An ideal, single stage Vaccine useful for elimination of Plasmodium falciparum (Pf) would prevent infection at the pre-erythrocytic stage of the parasite life cycle, thereby preventing all Pf-caused disease and transmission from humans to mosquitoes. The only approach to immunization shown to consistently induce greater than 90% protection against infection and protection sustained for at least 10-28 months has been immunization by mosquito bite with whole Pf Sporozoites (SPZ) of two types. The first type, radiation-attenuated PfSPZ, invade hepatoctyes and expresses new proteins, but cannot replicate. The second type fully develop in hepatocytes, producing tens of thousands of merozoites that invade erythrocytes, but are unable to fully develop within erythrocytes because they are killed by an antimalarial drug. This approach called chemoprophylaxis with Sporozoites (CPS) harnesses the infectious agent’s inherent replicative properties to amplify production of protective immunogens spanning multiple developmental stages, and then eliminates the infectious agent with an anti-infective drug before the onset of disease. Sanaria was founded to develop PfSPZ Vaccines. The first Vaccine developed and tested was the PfSPZ Vaccine. The PfSPZ Vaccine is comprised of aseptic, purified, radiation attenuated, cryopreserved PfSPZ. It was shown to be safe and well-tolerated when administered ID or SC to 80 volunteers in the U.S., but sub-optimally immunogenic. It is now being tested in the U.S. and soon in Tanzania when administered by IV injection, since it induced high levels of PfSPZ-specific CD8+ T cells in the livers of immunized non-human primates when administered IV. A second product, PfSPZ Challenge, is comprised of non-irradiated, fully infectious PfSPZ. PfSPZ Challenge has been shown to infect 100% of volunteers after ID or IM administration by needle and syringe. It has been or will be tested for optimization of adminstration by the ID, IM, and IV routes in 2012 or early 2013 in the Netherlands, UK, Tanzania, U.S., Germany, Spain, and Kenya. A third product, PfSPZ-CVac, is comprised of PfSPZ Challenge administered to volunteers receiving chloroquine chemoprophylaxis. It will be assessed in 2012-2013 in the Netherlands, Mali, Germany and Tanzania. Assessment of these three products in synergistic, interactive and adaptive clinical trials will facilitate progress toward optimizing administration and dosage regimen of all three whole PfSPZ products, as well as those developed in the future from genetically altered parasites, thereby facilitating licensure of one or more PfSPZ-based Vaccines. Progress and plans for development will be discussed.
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plasmodium yoelii infected a stephensi inefficiently transmit malaria compared to intravenous route
PLOS ONE, 2010Co-Authors: Solomon Conteh, Rana Chattopadhyay, Charles T Anderson, Stephen L HoffmanAbstract:It was recently reported that when mosquitoes infected with P. berghei Sporozoites feed on mice, they deposit approximately 100–300 Sporozoites in the dermis. When we inoculate P. yoelii (Py) Sporozoites intravenously (IV) into BALB/c mice, the 50% infectious dose (ID50) is often less than 3 Sporozoites, indicating that essentially all Py Sporozoites in salivary glands are infectious. Thus, it should only take the bite of one infected mosquito to infect 100% of mice. In human subjects, it takes the bite of at least 5 P. falciparum-infected mosquitoes to achieve 100% blood stage infection. Exposure to 1–2 infected mosquitoes only leads to blood stage infection in approximately 50% of subjects. If mosquitoes carrying Py Sporozoites inoculate 100–300 Sporozoites per bite, and 1 to 2 mosquito bites achieve 50% blood stage infection rates, then this would suggest that the majority of Sporozoites inoculated by mosquitoes into the dermis are not responsible for a productive infection, or that a significant number of Sporozoite-infected mosquitoes do not inoculate any Sporozoites. The objective of this study was to determine if this is the case. We therefore studied the infectivity to mice of the bites of 1, 2, 4, or 5–8 Py-infected mosquitoes. The bite of one Py Sporozoite-infected mosquito caused blood stage infection in 41.4% (12/29) of mice, two bites infected 66.7% (22/33), four bites infected 75% (18/24), and five to eight bites infected 100% (21/21). These findings demonstrate that inoculation of Sporozoites by mosquito bite is much less efficient than IV inoculation of Py Sporozoites by needle and syringe. Such data may have implications for determining the best route and dose of administration to humans of our attenuated P. falciparum Sporozoite Vaccine, the scientific basis of which is immunity by bites from irradiated infected mosquitoes, and suggest that the challenge is to develop a method of administration that approximates IV inoculation, not one that mimics mosquito bite.
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development of a metabolically active non replicating Sporozoite Vaccine to prevent plasmodium falciparum malaria
Human Vaccines, 2010Co-Authors: Stephen L Hoffman, Rana Chattopadhyay, Eric R James, Peter F Billingsley, Anusha Gunasekera, Adam Richman, Mark Loyevsky, Tao Li, Sumana Chakravarty, Minglin LiAbstract:Abstract : Immunization of volunteers by the bite of mosquitoes carrying radiation-attenuated Plasmodium falciparum Sporozoites protects greater than 90% of such volunteers against malaria, if adequate numbers of immunizing biting sessions and Sporozoite- infected mosquitoes are used. Nonetheless, until recently It was considered impossible to develop, license and commercialize a live, whole parasite P. falciparum porozoite (PfSPZ) Vaccine . In 2003 Sanaria scientists reappraised the potential impact of a metabolically active , non-replicating PfSPZ Vaccine, and outlined the challenges to producing such a Vaccine. Six years later, significant progress has been made in over coming these challenges. This progress has enabled the manufacture and release of multiple clinical lots of a I generation metabolically active, non -replicating PfSPZ Vaccine, the Sanariar PfSPZ Vaccine , submission of a successful Investigational New Drug application to the US Food and Drug Administration, and initiation of safety, immunogenicity and protective efficacy studies in volunteers in MD, US. Efforts are now focused on how best to achieve submission of a successful Biologics License Application and introduce the Vaccine to the primary target population of African children in the shortest possible period of time. This will require implementation of a systematic, efficient clinical development plan. Short term challenges include optimizing the (I) efficiency and scale up of the manufacturing process and quality control assays, (2) dosage regimen and method of administration, (3) potency of the Vaccine, and (4} logistics of delivering the Vaccine to those who need it most, and finalizing the methods for Vaccine stabilization and attenuation. A medium term goal is to design and build a facility for manufacturing highly potent and stable Vaccine for puvitol Phase 3 studies and commercial launch.
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the effects of radiation on the safety and protective efficacy of an attenuated plasmodium yoelii Sporozoite malaria Vaccine
Vaccine, 2009Co-Authors: Rana Chattopadhyay, Solomon Conteh, Eric R James, Judith E Epstein, Stephen L HoffmanAbstract:We are developing a radiation attenuated Plasmodium falciparum Sporozoite (PfSPZ) malaria Vaccine. An important step was to determine the minimum dose of irradiation required to adequately attenuate each Sporozoite. This was studied in the Plasmodium yoelii rodent model system. Exposure to 100 Gy completely attenuated P. yoelii Sporozoites (PySPZ). Next we demonstrated that immunization of mice intravenously with 3 doses of 750 PySPZ that had received 200 Gy, double the radiation dose required for attenuation, resulted in 100% protection. These results support the contention that a radiation attenuated Sporozoite Vaccine for malaria will be safe and effective at a range of radiation doses.
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rationale and plans for developing a non replicating metabolically active radiation attenuated plasmodium falciparum Sporozoite Vaccine
The Journal of Experimental Biology, 2003Co-Authors: Thomas C Luke, Stephen L HoffmanAbstract:SUMMARY Annually, malaria causes >300 million clinical cases and 1 million deaths, is responsible for the loss of >1% of gross domestic product (GDP) in Africa and is a serious concern for travelers. An effective Vaccine could have a dramatic impact on the disease. For 20 years, scientists have tried to develop modern, recombinant `subunit9 malaria Vaccines. This has been difficult. In fact, there is only one recombinant protein Vaccine on the market for any disease, and no Vaccines based on synthetic peptides, recombinant viruses, recombinant bacteria or DNA plasmids. Most Vaccines are based on attenuated or inactivated whole pathogens or material derived directly from the infectious agent. It is in that context that our recent report summarizing the protection of humans with attenuated Plasmodium falciparum ( Pf ) Sporozoites produced at four different sites over 25 years is important. In studies utilizing live mosquitoes as the Vaccine delivery mechanism, there was complete protection against malaria in 93% of volunteers (13/14) and 94% of challenges (33/35). Sanaria9s goal is to develop and commercialize a non-replicating, metabolically active Pf Sporozoite Vaccine. Three practical questions must be addressed before manufacturing for clinical trials: (1) can one administer the Vaccine by a route that is clinically practical; (2) can one produce adequate quantities of Sporozoites; and (3) can Sporozoites be produced with the physical characteristics that meet the regulatory, potency and safety requirements of regulatory authorities? Once these questions have been answered, Sanaria will demonstrate that the Vaccine protects >90% of human recipients against experimental challenge with Pf Sporozoites, can be produced with an efficiency that makes it economically feasible, and protects >90% of African infants and children from infection, and thus from severe morbidity and mortality. By producing a Vaccine for travelers, Sanaria will provide the infrastructure, regulatory foundation and funds necessary to speed licensure, manufacturing and deployment of the Vaccine for the infants and children who need it most.
Peter F Billingsley - One of the best experts on this subject based on the ideXlab platform.
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the equatoguinean malaria Vaccine initiative from the launching of a clinical research platform to malaria elimination planning in central west africa
American Journal of Tropical Medicine and Hygiene, 2020Co-Authors: Peter F Billingsley, Carl Maas, Ally Olotu, Christopher Schwabe, Guillermo A Garcia, Matilde Riloha Rivas, Dianna Hergott, Claudia DaubenbergerAbstract:Fifteen years of investment in malaria control on Bioko Island, Equatorial Guinea (EG), dramatically reduced malaria-associated morbidity and mortality, but the impact has plateaued. To progress toward elimination, EG is investing in the development of a malaria Vaccine. We assessed the unique public-private partnership that has had such a significant impact on malaria on Bioko Island and now added a major effort on malaria Vaccine development. As part of a $79M commitment, the EG government (75%) and three American energy companies (25%) have invested since 2012 greater than $55M in the Equatoguinean Malaria Vaccine Initiative (EGMVI) to support clinical development of Sanaria® PfSPZ Vaccines. In turn, the Vaccine development program is building human capital and physical capacity. The EGMVI established regulatory and ethical oversight to ensure compliance with the International Conference on Harmonization and Good Clinical Practices for the first importation of investigational product, ethical approval, and conduct of a clinical trial in Equatoguinean history. The Equatoguinean Malaria Vaccine Initiative has completed three Vaccine trials in EG, two Vaccine trials in Tanzania, and a malaria incidence study, and initiated preparations for a 2,100-volunter clinical trial. Personnel are training for advanced degrees abroad and have been trained in Good Clinical Practices and protocol-specific methods. A new facility has established the foundation for a national research institute. Biomedical research and development within this visionary, ambitious public-private partnership is fostering major improvements in EG. The EGMVI plans to use a Plasmodium falciparum Sporozoite Vaccine alongside standard malaria control interventions to eliminate Pf malaria from Bioko, becoming a potential model for elimination campaigns elsewhere.
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attenuated pfspz Vaccine induces strain transcending t cells and durable protection against heterologous controlled human malaria infection
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Kirsten E Lyke, Mary E Enama, Eric R James, Peter F Billingsley, Anusha Gunasekera, Sumana Chakravarty, Andrew S Ishizuka, Adam Dezure, Andrea A Berry, Anita ManojAbstract:A live-attenuated malaria Vaccine, Plasmodium falciparum Sporozoite Vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the Vaccine strain up to 14 mo after final vaccination. No injectable malaria Vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the Vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105 PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35-87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P = 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36-99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all Vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the Vaccine dose and number of immunizations.
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progress with pfspz Vaccine a radiation attenuated plasmodium falciparum Sporozoite Vaccine
Malaria Journal, 2014Co-Authors: Peter F Billingsley, Eric R James, Kim Lee B Sim, Thomas L Richie, Seif Shekalaghe, Sara A Healy, Mahamadou S Sissoko, Benjamin Mordmueller, Julie E Ledgerwood, Barney S GrahamAbstract:Sanaria® PfSPZ Vaccine is composed of aseptic, purified, cryopreserved, attenuated (non-replicating), metabolically active Plasmodium falciparum (Pf ) Sporozoites (SPZ) produced in compliance with good manufacturing practices (GMPs) that meet all regulatory standards. This Vaccine provided full protection against Pf infection in 100% (6/6) volunteers, who received five doses of 1.35 × 105 PfSPZ administered intravenously in a study at the Vaccine Research Center (VRC), NIAID, NIH [1]. Based on these data, the PfSPZ Vaccine Clinical Consortium composed of investigators from USA, Africa, and Europe has developed a four stage clinical development plan (CDP) that maps out a 4-5 year timeline to licensure and a large scale demonstration project to eliminate malaria from an island population in Africa. In 2014, six different clinical trials of PfSPZ Vaccine at seven clinical sites in the United States (Bethesda, Baltimore, Silver Spring), Mali, Tanzania, Equatorial Guinea, and Germany will be underway. These six clinical trials, which include >450 subjects, comprise Stage 1 of the four stage PfSPZ Vaccine CDP. They are designed to 1) assess the reproducibility of the data generated in the VRC study and 2) assess and optimize durability of protection, protection against heterologous strains of Pf, reduction in numbers of doses, immune assays that predict protection, implementation of immunization, and alternative route of administration. We will provide an update of these stage 1 clinical trials and plans for stage 2 studies that will address questions required for progressing to pivotal phase 3 clinical trials in stage 3, and to demonstration projects for focal elimination in small populations.
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protection against malaria by intravenous immunization with a nonreplicating Sporozoite Vaccine
Science, 2013Co-Authors: Robert A Seder, Lee Jah Chang, Mary E Enama, Kathryn L Zephir, Uzma N Sarwar, Ingelise J Gordon, Lasonji A Holman, Eric R James, Peter F Billingsley, Anusha GunasekeraAbstract:Each year, hundreds of millions of people are infected with Plasmodium falciparum , the mosquito-borne parasite that causes malaria. A preventative Vaccine is greatly needed. Seder et al. (p. [1359][1], published online 8 August; see the Perspective by [Good][2] ) now report the results from a phase I clinical trial where subjects were immunized intravenously with a whole, attenuated Sporozoite Vaccine. Three of 9 subjects who received four doses and zero of 6 subjects who received five doses of the Vaccine went on to develop malaria after controlled malaria infection. Both antibody titers and cellular immune responses correlated positively with the dose of Vaccine received, suggesting that both arms of the adaptive immune response may have participated in the observed protection. [1]: /lookup/doi/10.1126/science.1241800 [2]: /lookup/doi/10.1126/science.1244157
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Development of an attenuated Sporozoite Vaccine to prevent and eliminate Plasmodium falciparum malaria
Malaria Journal, 2010Co-Authors: Peter F BillingsleyAbstract:An ideal Vaccine for malaria would target all stages of the parasite life cycle, and thereby prevent infection, severe disease and transmission. However, most malariologists agree that if only one stage is to be targeted, it should be the pre-erythrocytic stage, because induction of highly protective immune responses against this stage will prevent blood stage infection and thus disease and parasite transmission. Our consortium is working to develop such a Vaccine. The first-generation Vaccine is a metabolically active, non-replicating Plasmodium falciparum Sporozoite (PfSPZ) Vaccine that is attenuated by irradiation. The first major challenge was to manufacture adequate quantities of such a Vaccine that met regulatory standards for initial clinical trials, and demonstrate that it was safe, well tolerated and immunogenic in humans. This has been accomplished. The second major challenge is to determine how to administer for the first time in humans an unprecedented, non-replicating and metabolically active (live) whole-organism Vaccine formulation composed of PfSPZ that measure 0.5-1.0 μm x 7-10 μm, to induce > 85% protection. Volunteers immunized by intradermal (ID) or subcutaneous (SC) routes were protected in the first clinical trial. However, the number of protected subjects was low, and despite a dose response immunogenicity was sub-optimal. Animal studies show that intravenous (IV) immunization induces much better immunity and protection than immunization by the SC or ID routes. These data have been used to inform the design of the next clinical trial. Parallel efforts are underway to optimize non-IV administration of PfSPZ, and the efficiency and scale-up of manufacture. We are also determining whether genetic targeting techniques can be used to create a parasite clone that will produce attenuated PfSPZ that are not only more potent, but also as safe as radiation-attenuated PfSPZ. Such PfSPZ could be non-replicating (as are radiation-attenuated PfSPZ), replication deficient, or replication competent, but avirulent. Our goal is to develop, license and deploy a highly effective pre-erythrocytic stage PfSPZ Vaccine that prevents blood stage infection, disease, and transmission. Such a Vaccine could be used at the community level in Pf elimination campaigns, and at the individual level for prevention of Pf malaria in infants, young children, and pregnant women in endemic areas, as well as individuals of all ages who travel to malaria-endemic areas.
Eric R James - One of the best experts on this subject based on the ideXlab platform.
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attenuated pfspz Vaccine induces strain transcending t cells and durable protection against heterologous controlled human malaria infection
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Kirsten E Lyke, Mary E Enama, Eric R James, Peter F Billingsley, Anusha Gunasekera, Sumana Chakravarty, Andrew S Ishizuka, Adam Dezure, Andrea A Berry, Anita ManojAbstract:A live-attenuated malaria Vaccine, Plasmodium falciparum Sporozoite Vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the Vaccine strain up to 14 mo after final vaccination. No injectable malaria Vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the Vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105 PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35-87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P = 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36-99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all Vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the Vaccine dose and number of immunizations.
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progress with pfspz Vaccine a radiation attenuated plasmodium falciparum Sporozoite Vaccine
Malaria Journal, 2014Co-Authors: Peter F Billingsley, Eric R James, Kim Lee B Sim, Thomas L Richie, Seif Shekalaghe, Sara A Healy, Mahamadou S Sissoko, Benjamin Mordmueller, Julie E Ledgerwood, Barney S GrahamAbstract:Sanaria® PfSPZ Vaccine is composed of aseptic, purified, cryopreserved, attenuated (non-replicating), metabolically active Plasmodium falciparum (Pf ) Sporozoites (SPZ) produced in compliance with good manufacturing practices (GMPs) that meet all regulatory standards. This Vaccine provided full protection against Pf infection in 100% (6/6) volunteers, who received five doses of 1.35 × 105 PfSPZ administered intravenously in a study at the Vaccine Research Center (VRC), NIAID, NIH [1]. Based on these data, the PfSPZ Vaccine Clinical Consortium composed of investigators from USA, Africa, and Europe has developed a four stage clinical development plan (CDP) that maps out a 4-5 year timeline to licensure and a large scale demonstration project to eliminate malaria from an island population in Africa. In 2014, six different clinical trials of PfSPZ Vaccine at seven clinical sites in the United States (Bethesda, Baltimore, Silver Spring), Mali, Tanzania, Equatorial Guinea, and Germany will be underway. These six clinical trials, which include >450 subjects, comprise Stage 1 of the four stage PfSPZ Vaccine CDP. They are designed to 1) assess the reproducibility of the data generated in the VRC study and 2) assess and optimize durability of protection, protection against heterologous strains of Pf, reduction in numbers of doses, immune assays that predict protection, implementation of immunization, and alternative route of administration. We will provide an update of these stage 1 clinical trials and plans for stage 2 studies that will address questions required for progressing to pivotal phase 3 clinical trials in stage 3, and to demonstration projects for focal elimination in small populations.
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protection against malaria by intravenous immunization with a nonreplicating Sporozoite Vaccine
Science, 2013Co-Authors: Robert A Seder, Lee Jah Chang, Mary E Enama, Kathryn L Zephir, Uzma N Sarwar, Ingelise J Gordon, Lasonji A Holman, Eric R James, Peter F Billingsley, Anusha GunasekeraAbstract:Each year, hundreds of millions of people are infected with Plasmodium falciparum , the mosquito-borne parasite that causes malaria. A preventative Vaccine is greatly needed. Seder et al. (p. [1359][1], published online 8 August; see the Perspective by [Good][2] ) now report the results from a phase I clinical trial where subjects were immunized intravenously with a whole, attenuated Sporozoite Vaccine. Three of 9 subjects who received four doses and zero of 6 subjects who received five doses of the Vaccine went on to develop malaria after controlled malaria infection. Both antibody titers and cellular immune responses correlated positively with the dose of Vaccine received, suggesting that both arms of the adaptive immune response may have participated in the observed protection. [1]: /lookup/doi/10.1126/science.1241800 [2]: /lookup/doi/10.1126/science.1244157
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development of a metabolically active non replicating Sporozoite Vaccine to prevent plasmodium falciparum malaria
Human Vaccines, 2010Co-Authors: Stephen L Hoffman, Rana Chattopadhyay, Eric R James, Peter F Billingsley, Anusha Gunasekera, Adam Richman, Mark Loyevsky, Tao Li, Sumana Chakravarty, Minglin LiAbstract:Abstract : Immunization of volunteers by the bite of mosquitoes carrying radiation-attenuated Plasmodium falciparum Sporozoites protects greater than 90% of such volunteers against malaria, if adequate numbers of immunizing biting sessions and Sporozoite- infected mosquitoes are used. Nonetheless, until recently It was considered impossible to develop, license and commercialize a live, whole parasite P. falciparum porozoite (PfSPZ) Vaccine . In 2003 Sanaria scientists reappraised the potential impact of a metabolically active , non-replicating PfSPZ Vaccine, and outlined the challenges to producing such a Vaccine. Six years later, significant progress has been made in over coming these challenges. This progress has enabled the manufacture and release of multiple clinical lots of a I generation metabolically active, non -replicating PfSPZ Vaccine, the Sanariar PfSPZ Vaccine , submission of a successful Investigational New Drug application to the US Food and Drug Administration, and initiation of safety, immunogenicity and protective efficacy studies in volunteers in MD, US. Efforts are now focused on how best to achieve submission of a successful Biologics License Application and introduce the Vaccine to the primary target population of African children in the shortest possible period of time. This will require implementation of a systematic, efficient clinical development plan. Short term challenges include optimizing the (I) efficiency and scale up of the manufacturing process and quality control assays, (2) dosage regimen and method of administration, (3) potency of the Vaccine, and (4} logistics of delivering the Vaccine to those who need it most, and finalizing the methods for Vaccine stabilization and attenuation. A medium term goal is to design and build a facility for manufacturing highly potent and stable Vaccine for puvitol Phase 3 studies and commercial launch.
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the effects of radiation on the safety and protective efficacy of an attenuated plasmodium yoelii Sporozoite malaria Vaccine
Vaccine, 2009Co-Authors: Rana Chattopadhyay, Solomon Conteh, Eric R James, Judith E Epstein, Stephen L HoffmanAbstract:We are developing a radiation attenuated Plasmodium falciparum Sporozoite (PfSPZ) malaria Vaccine. An important step was to determine the minimum dose of irradiation required to adequately attenuate each Sporozoite. This was studied in the Plasmodium yoelii rodent model system. Exposure to 100 Gy completely attenuated P. yoelii Sporozoites (PySPZ). Next we demonstrated that immunization of mice intravenously with 3 doses of 750 PySPZ that had received 200 Gy, double the radiation dose required for attenuation, resulted in 100% protection. These results support the contention that a radiation attenuated Sporozoite Vaccine for malaria will be safe and effective at a range of radiation doses.
A.j. Musoke - One of the best experts on this subject based on the ideXlab platform.
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linear peptide specificity of bovine antibody responses to p67 of theileria parva and sequence diversity of Sporozoite neutralizing epitopes implications for a Vaccine
Infection and Immunity, 1999Co-Authors: Vishvanath Nene, E Gobright, Richard P Bishop, S P Morzaria, A.j. MusokeAbstract:A stage-specific surface antigen of Theileria parva, p67, is the basis for the development of an anti-Sporozoite Vaccine for the control of East Coast fever (ECF) in cattle. By Pepscan analysis with a series of overlapping synthetic p67 peptides, the antigen was shown to contain five distinct linear peptide sequences recognized by Sporozoite-neutralizing murine monoclonal antibodies. Three epitopes were located between amino acid positions 105 to 229 and two were located between positions 617 to 639 on p67. Bovine antibodies to a synthetic peptide containing one of these epitopes neutralized Sporozoites, validating this approach for defining immune responses that are likely to contribute to immunity. Comparison of the peptide specificity of antibodies from cattle inoculated with recombinant p67 that were immune or susceptible to ECF did not reveal statistically significant differences between the two groups. In general, antipeptide antibody levels in the susceptible animals were lower than in the immune group and neither group developed high responses to all Sporozoite-neutralizing epitopes. The bovine antibody response to recombinant p67 was restricted to the N- and C-terminal regions of p67, and there was no activity against the central portion between positions 313 and 583. So far, p67 sequence polymorphisms have been identified only in buffalo-derived T. parva parasites, but the consequence of these for Vaccine development remains to be defined. The data indicate that optimizations of the current vaccination protocol against ECF should include boosting of relevant antibody responses to neutralizing epitopes on p67.
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Characterization of an insect cell-derived Theileria parva Sporozoite Vaccine antigen and immunogenicity in cattle.
Infection and immunity, 1995Co-Authors: Vishvanath Nene, Shigeki Inumaru, Declan J. Mckeever, Subhash Morzaria, Michael Shaw, A.j. MusokeAbstract:Previous data showed that six out of a group of nine cattle inoculated with NS1-p67, a recombinant form of a 67-kDa Theileria parva Sporozoite surface protein, were immune to East Coast fever. This bacterially expressed antigen encoded all 709 amino acid residues of p67 fused to the C-terminal end of 87 residues derived from NS1, a structural protein of influenza virus, and a linker DNA sequence. NS1-p67 lacked reactivity with TpM 12, a monoclonal antibody to native p67, and had an estimated molecular mass of 110 kDa, as opposed to the calculated mass of 85,000 Da. We have used the baculovirus expression system in an attempt to express this parasite protein in a native form and thereby increase the protective capacity of the antigen. However, Spodoptera frugiperda SF21AE cells infected with recombinant virus expressed p67 as a 100-kDa molecule. The host cells exhibited a limited capacity to glycosylate this molecule to a 110-kDa form, and p67 was not exported to the surface membrane. TpM 12 did not bind to these recombinant forms but, at time points late during viral infection, reacted with a molecule of about 70 kDa. Since the bulk of insect cell-derived p67 was not expressed in an appropriate form, we tested the immunogenicity of these partially processed recombinant p67 forms in cattle. Two groups of three cattle were inoculated with antigen formulated either with saponin or Freund's adjuvant. As seen previously with NS1-p67, all animals developed high levels of anti-p67 antibodies that neutralized Sporozoite infectivity in vitro, but antigen-specific T-cell proliferative responses were not detected in peripheral blood. Given the caveat of the small number of cattle analyzed, insect cell-derived p67 does not appear to be superior to NS1-p67 as an immunogen, and the latter remains the molecule of choice for the development of Vaccines against East Coast fever.
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characterisation of the gene encoding a candidate Vaccine antigen of theileria parva Sporozoites
Molecular and Biochemical Parasitology, 1992Co-Authors: Vishvanath Nene, K P Iams, E Gobright, A.j. MusokeAbstract:Abstract We have cloned and characterised the gene encoding the 67-kilodalton stage-specific surface antigen, p67, of Theileria parva (Muguga) Sporozoites. The gene which is present in a single copy, is divided into 2 exons by an intron 29 bp long and is transcribed into mRNA of about 2500 nucleotides. The gene is present in all stocks of T.parva and there is a related gene in Theileria annulata. The deduced amino acid sequence of 709 residues predicts that p67 is a membrane protein and that it lacks tandemly repeated sequences. Recombinant p67 has been expressed in Escherichia coli as a fusion protein with Sj-26, a glutathione-S-transferase of Schistosoma japonicum. Antibodies to purified recombinant proteins containing residues 9–316 or 397–709 of p67 bind to p67 in immunoblots and neutralise Sporozoite infectivity in vitro. Recombinant p67 is, therefore, a candidate antigen for development of an anti-Sporozoite Vaccine for East Coast fever in cattle.
Thomas L Richie - One of the best experts on this subject based on the ideXlab platform.
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safety tolerability and immunogenicity of plasmodium falciparum Sporozoite Vaccine administered by direct venous inoculation to infants and young children findings from an age de escalation dose escalation double blind randomized controlled study in
Clinical Infectious Diseases, 2020Co-Authors: Laura C Steinhardt, Thomas L Richie, Julie Gutman, Ryan E Wiegand, D Akach, Mary J Hamel, Reuben Yego, Elizabeth L Nzuu, Allan Dungani, Tooba MurshedkarAbstract:BACKGROUND The whole Plasmodium falciparum Sporozoite (PfSPZ) Vaccine is being evaluated for malaria prevention. The Vaccine is administered intravenously for maximal efficacy. Direct venous inoculation (DVI) with PfSPZ Vaccine has been safe, tolerable, and feasible in adults, but safety data for children and infants are limited. METHODS We conducted an age de-escalation, dose-escalation randomized controlled trial in Siaya County, western Kenya. Children and infants (aged 5-9 years, 13-59 months, and 5-12 months) were enrolled into 13 age-dose cohorts of 12 participants and randomized 2:1 to Vaccine or normal saline placebo in escalating doses: 1.35 × 105, 2.7 × 105, 4.5 × 105, 9.0 × 105, and 1.8 × 106 PfSPZ, with the 2 highest doses given twice, 8 weeks apart. Solicited adverse events (AEs) were monitored for 8 days after vaccination, unsolicited AEs for 29 days, and serious AEs throughout the study. Blood taken prevaccination and 1 week postvaccination was tested for immunoglobulin G antibodies to P. falciparum circumSporozoite protein (PfCSP) using enzyme-linked immunosorbent assay. RESULTS Rates of AEs were similar in Vaccinees and controls for solicited (35.7% vs 41.5%) and unsolicited (83.9% vs 92.5%) AEs, respectively. No related grade 3 AEs, serious AEs, or grade 3 laboratory abnormalities occurred. Most (79.0%) vaccinations were administered by a single DVI. Among those in the 9.0 × 105 and 1.8 × 106 PfSPZ groups, 36 of 45 (80.0%) Vaccinees and 4 of 21 (19.0%) placebo controls developed antibodies to PfCSP (P < .001). CONCLUSIONS PfSPZ Vaccine in doses as high as 1.8 × 106 can be administered to infants and children by DVI, and was safe, well tolerated, and immunogenic. CLINICAL TRIALS REGISTRATION NCT02687373.
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Profiling the Targets of Protective CD8+ T Cell Responses to Infection
Molecular therapy. Methods & clinical development, 2017Co-Authors: Joseph T. Bruder, Martha Sedegah, Ping Chen, Greg Ekberg, Emily C. Smith, Christopher Lazarski, Bennett A. Myers, Jessica Bolton, Eileen Villasante, Thomas L RichieAbstract:T cells are critical effectors of host immunity that target intracellular pathogens, such as the causative agents of HIV, tuberculosis, and malaria. The development of Vaccines that induce effective cell-mediated immunity against such pathogens has proved challenging; for tuberculosis and malaria, many of the antigens targeted by protective T cells are not known. Here, we report a novel approach for screening large numbers of antigens as potential targets of T cells. Malaria provides an excellent model to test this antigen discovery platform because T cells are critical mediators of protection following immunization with live Sporozoite Vaccines and the specific antigen targets are unknown. We generated an adenovirus array by cloning 312 highly expressed pre-erythrocytic Plasmodium yoelii antigens into adenovirus vectors using high-throughput methodologies. The array was screened to identify antigen-specific CD8+ T cells induced by a live Sporozoite Vaccine regimen known to provide high levels of sterile protection mediated by CD8+ T cells. We identified 69 antigens that were targeted by CD8+ T cells induced by this Vaccine regimen. The antigen that recalled the highest frequency of CD8+ T cells, PY02605, induced protective responses in mice, demonstrating proof of principle for this approach in identifying antigens for Vaccine development.
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Protection against malaria at 1 year and immune correlates following PfSPZ vaccination
Nature Medicine, 2016Co-Authors: Andrew S Ishizuka, Lee Jah Chang, Mary E Enama, Ingelise J Gordon, Thomas L Richie, Kirsten E Lyke, Adam Dezure, Andrea A Berry, Floreliz H Mendoza, Uzma N SarwarAbstract:Fifty-five percent of individuals vaccinated with an attenuated Plasmodium falciparum Sporozoite Vaccine remained without parasitemia after controlled human malaria infection one year later; immune correlate analysis in humans and non-human primates suggest a role for liver-resident T cells. An attenuated Plasmodium falciparum (Pf) Sporozoite (SPZ) Vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how Vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10^5 PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21–25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.
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progress with pfspz Vaccine a radiation attenuated plasmodium falciparum Sporozoite Vaccine
Malaria Journal, 2014Co-Authors: Peter F Billingsley, Eric R James, Kim Lee B Sim, Thomas L Richie, Seif Shekalaghe, Sara A Healy, Mahamadou S Sissoko, Benjamin Mordmueller, Julie E Ledgerwood, Barney S GrahamAbstract:Sanaria® PfSPZ Vaccine is composed of aseptic, purified, cryopreserved, attenuated (non-replicating), metabolically active Plasmodium falciparum (Pf ) Sporozoites (SPZ) produced in compliance with good manufacturing practices (GMPs) that meet all regulatory standards. This Vaccine provided full protection against Pf infection in 100% (6/6) volunteers, who received five doses of 1.35 × 105 PfSPZ administered intravenously in a study at the Vaccine Research Center (VRC), NIAID, NIH [1]. Based on these data, the PfSPZ Vaccine Clinical Consortium composed of investigators from USA, Africa, and Europe has developed a four stage clinical development plan (CDP) that maps out a 4-5 year timeline to licensure and a large scale demonstration project to eliminate malaria from an island population in Africa. In 2014, six different clinical trials of PfSPZ Vaccine at seven clinical sites in the United States (Bethesda, Baltimore, Silver Spring), Mali, Tanzania, Equatorial Guinea, and Germany will be underway. These six clinical trials, which include >450 subjects, comprise Stage 1 of the four stage PfSPZ Vaccine CDP. They are designed to 1) assess the reproducibility of the data generated in the VRC study and 2) assess and optimize durability of protection, protection against heterologous strains of Pf, reduction in numbers of doses, immune assays that predict protection, implementation of immunization, and alternative route of administration. We will provide an update of these stage 1 clinical trials and plans for stage 2 studies that will address questions required for progressing to pivotal phase 3 clinical trials in stage 3, and to demonstration projects for focal elimination in small populations.