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(由申请人提供)：这项提案将展示针对恶性疟原虫(PF)性阶段和蚊子阶段(SMS)的完整寄生虫(WP)疫苗的概念证明，该疫苗将单独使用或与PfSPZ疫苗结合使用，以阻断疟疾从人类宿主向蚊子媒介的传播(VIMT)。这种PfSMS-WP-VIMT将是PfSPZ疫苗的理想补充，在最近的临床试验中，PfSPZ疫苗已显示出对寄生虫感染的完全保护。如果PfSPZ疫苗在90%的接受者中防止了感染和传播，而PfSMS-WP-VIMT在90%的接受者中防止了传播，那么这两种疫苗的组合将防止至少99%的接受者传播。与基于一个或几个抗原的亚单位PfSMS疫苗相比，PfSMS-WP-VIMT具有重大优势。这种疫苗方法将增加更多个体产生保护性免疫反应的机会，并通过大幅增加诱导保护性抗体的免疫原数量，降低寄生虫能够选择逃避免疫反应的可能性。当与PfSPZ疫苗联合使用时，PfSMS-WP-VIMT将防止对PfSPZ疫苗产生抗药性的寄生虫的传播。Sanaria在GMP条件下独特地产生Pf配子体(有性期)，现在在体外持续产生配子、受精卵和动子的混合物，丰富了动子。我们对这些寄生虫进行了部分纯化，并用制备的佐剂免疫小鼠，结果表明，免疫小鼠的血清完全(100%)抑制了寄生虫向蚊子的传播。我们将利用Sanaria在符合GMP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播阻断喂养试验方面的丰富经验，开发、生产和测试PfSMS-WP-VIMT。我们将从三个时间点(30-60分钟，8小时和30小时)进行PfSM培养，以确保PfSM的所有阶段都存在。我们将在这些远离红细胞的培养物中纯化PfsM，以获得纯化的疫苗制剂。概念验证将通过用PfSMS-WP制剂结合佐剂免疫小鼠，然后测试对培养的寄生虫和已知的PfSMS抗原的抗体反应，以及体内标准膜喂养试验中的传播阻断活性来证明。在通过直接静脉接种(DVI)共同接种PfSPZ疫苗后，将在小鼠身上进一步测试候选铅与PfSPZ疫苗的相互作用。在第二阶段，我们将最终确定符合cGMPs和质量控制(QC)释放和稳定性分析的规模化生产方法，按照cGMPs生产，进行QC释放分析，启动QC稳定性研究，进行临床前毒理学研究，设计临床试验，并为研究性新药申请(IND)准备信息。