Development of a whole parasite Plasmodium falciparum sexual and mosquito stages Vaccine to Interrupt Malaria Transmission

开发一种完整的寄生虫恶性疟原虫性阶段和蚊子阶段疫苗以阻断疟疾传播

• 批准号: 8906017
• 负责人: Peter F. Billingsley
• 金额: $ 30.08万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-18 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8906017
• 关键词: 5 year old; Adjuvant; Affect; Antibodies; Antibody Response; Antigens; Attention; Attenuated; Biological Assay; Bite; Cells; Cessation of life; Child; Clinical Trials; Combined Vaccines; Complement; Culicidae; Cyclic GMP; Development; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; Erythrocytes; Germ Cells; Harvest; Human; Immune response; Immunization; Immunofluorescence Immunologic; In Vitro; Individual; Infection; Infection prevention; Injection of therapeutic agent; Investigational New Drug Application; Lead; Malaria; Malaria Vaccines; Measures; Membrane; Methods; Mus; Outcome; Parasites; Parasitic Diseases; Phase; Phase I Clinical Trials; Plasmodium falciparum; Preparation; Prevention approach; Production; Proteins; Protocols documentation; Quality Control; Radiation; Recombinant Vaccines; Regimen; Relative (related person); Research Design; Resistance; Serum; Sporozoite vaccine; Staging; Testing; Time; Vaccine Research; Vaccines; Venous; base; clinical toxicology; controlled release; dosage; experience; feeding; improved; in vivo; malaria transmission; manufacturing scale-up; pre-clinical; prevent; programs; public health relevance; response; success; tool; transmission process; vaccine candidate; vector mosquito; volunteer; zygote

 DESCRIPTION (provided by applicant): This proposal will demonstrate proof of concept for a whole parasite (WP) vaccine directed against Plasmodium falciparum (Pf) sexual and mosquito stages (SMS) that will be used alone or in combination with PfSPZ Vaccine for interrupting malaria transmission (VIMT) from the human host to the mosquito vector. Such a PfSMS-WP-VIMT will be an ideal complement to the PfSPZ Vaccine, which has shown complete protection against parasite infection in recent clinical trials. If the PfSPZ Vaccine prevents infection and transmission in 90% of recipients and PfSMS-WP-VIMT prevents transmission in 90% of recipients, the combination will prevent transmission in at least 99% of recipients. The PfSMS-WP-VIMT offers major advantages to a subunit PfSMS vaccine based on one or a few antigens. This vaccine approach will increase the chance that more individuals will have protective immune responses and reduce the possibility of the parasites being able to select for evasion of immune responses by dramatically increasing the number of immunogens against which protective antibodies are induced. When used in combination with PfSPZ Vaccine, PfSMS-WP-VIMT will prevent transmission of parasites that may be selected for resistance to PfSPZ Vaccine. Sanaria uniquely produces Pf gametocytes (sexual stages) under GMP conditions and now consistently produces a mixture of gametes, zygotes and ookinetes, enriched for ookinetes, in vitro. We partially purified these parasites, immunized mice with the preparation in adjuvant, and showed that the sera from the immunized mice completely (100%) inhibited transmission of parasites to mosquitoes. We will exploit Sanaria's unique expertise in GMP-compliant gametocyte production and in vitro PfSPZ production, as well as extensive experience in parasite purification and in vivo transmission blocking feeding assays to develop, produce and test PfSMS-WP- VIMT. We will produce cultures of PfSMS from three time points (30-60 min, 8 h and 30 h) to ensure that all PfSMS stages are present. We will purify PfSMS in these cultures away from RBCs to obtain purified vaccine preparations. Proof of concept will be demonstrated by immunizing mice with the PfSMS-WP preparations in combination with adjuvants, then testing for antibody responses against cultured parasites and known PfSMS antigens, and for transmission blocking activity in an in vivo standard membrane feeding assay. The lead candidates will be further tested in mice for interactions with the PfSPZ Vaccine after co-administration by direct venous inoculation (DVI). In Phase II we will finalize methods for scaled-up manufacturing in compliance with cGMPs and quality control (QC) release and stability assays, manufacture in compliance with cGMPs, conduct QC release assays, initiate QC stability studies, conduct pre-clinical toxicology studies, design a clinical trial, and prepare al information for an Investigational New Drug application (IND).

 描述（由适用提供）：该提案将展示针对针对恶性疟原虫（PF）性和蚊子阶段（SMS）的整个寄生虫（WP）疫苗的概念证明，该疫苗将单独使用，或与PFSPZ疫苗合并，与PFSPZ疫苗合并，用于中断来自人类的Mosquito to Mosquito Vector的Mosquito Vector。这样的PFSMS-WP-VIMT将是PFSPZ疫苗的理想完成，该疫苗在最近的临床试验中显示了针对寄生虫感染的完全保护。如果PFSPZ疫苗阻止90％的受体和PFSMS-WP-VIMT的感染和传播可防止90％的受体的传播，则该组合将防止至少99％的受体传播。 PFSMS-WP-VIMT基于一种或几种抗原为亚基PFSMS疫苗提供了主要优势。这种疫苗方法将增加更多个体可以保护免疫复杂的机会，并减少寄生虫能够通过大大增加诱导受保护抗体的免疫原子数量来选择免疫复杂的进化。当与PFSPZ疫苗结合使用时，PFSMS-WP-VIMT将防止寄生虫传播，这些寄生虫可以选择以抗PFSPZ疫苗。 Sanaria独特地在GMP条件下产生PF配子细胞（性阶段），现在始终产生gamestes，zygotes和kiginetes的混合物，并在体外富含烟囱。我们部分纯化了这些寄生虫，通过调整制剂进行免疫化小鼠，并表明来自免疫小鼠的血清完全（100％）抑制了寄生虫向蚊子的传播。我们将探索Sanaria在GMP兼容的配子体生产和体外PFSPZ生产方面的独特专业知识，以及在寄生虫纯化和体内传输阻断喂养主张方面的丰富经验，以开发，生产和测试PFSMS-WP- VIMT。我们将在三个时间点（30-60分钟，8小时和30小时）中生产PFSM的培养物，以确保存在所有PFSMS阶段。我们将净化这些培养物中的PFSM，以获得纯化的疫苗制剂。概念证明将通过与调节器结合使用PFSMS-WP制剂进行免疫小鼠，然后测试针对培养的寄生虫和已知PFSMS抗原的抗体反应，以及在体内标准膜喂养测定中的传输阻断活性。通过直接静脉接种（DVI）共同给药后，将在小鼠中进一步测试铅候选者与PFSPZ疫苗的相互作用。在第二阶段，我们将按照CGMP和质量控制（QC）释放和稳定评估来最终确定制造的方法，符合CGMP，进行QC释放测定，开始QC稳定性研究，进行QC稳定性研究，进行临床前毒理学研究，设计临床试验，并为研究新的药物应用程序准备信息（IND）。