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）：该提案将证明针对恶性疟原虫（Pf）性阶段和蚊子阶段（SMS）的全寄生虫（WP）疫苗的概念验证，该疫苗将单独使用或与 PfSPZ 疫苗联合使用以阻断疟疾这种 PfSMS-WP-VIMT 将是 PfSPZ 疫苗的理想补充，该疫苗已显示出对蚊子媒介的全面保护。在最近的临床试验中，如果 PfSPZ 疫苗可以预防 90% 的接受者的感染和传播，而 PfSMS-WP-VIMT 可以预防 90% 的接受者的传播，那么该组合将可以预防至少 99% 的接受者的传播。 WP-VIMT 为基于一种或几种抗原的亚单位 PfSMS 疫苗提供了主要优势，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，并降低发生保护性免疫反应的可能性。当与 PfSPZ 疫苗联合使用时，寄生虫能够通过显着增加诱导保护性抗体的免疫原数量来选择逃避免疫反应，PfSMS-WP-VIMT 将阻止可能被选择抵抗的寄生虫的传播。 PfSPZ 疫苗在 GMP 条件下独特地产生 Pf 配子细胞（性阶段），现在持续产生配子、合子和动合子的混合物，富含我们在体外部分纯化了这些寄生虫，用佐剂制剂对小鼠进行了免疫，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 GMP 合规方面的独特专业知识。我们拥有配子体生产和体外 PfSPZ 生产，以及在寄生虫纯化和体内传播阻断喂养测定方面的丰富经验，以开发、生产和测试 PfSMS-WP-VIMT。将在三个时间点（30-60 分钟、8 小时和 30 小时）产生 PfSMS 培养物，以确保所有 PfSMS 阶段都存在。我们将从这些培养物中纯化 PfSMS，使其远离红细胞，以获得纯化的疫苗制剂。通过使用 PfSMS-WP 制剂与佐剂结合免疫小鼠，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传播阻断活性来证明在体内标准膜试验饲喂试验中，将在小鼠中进一步测试通过直接静脉接种 (DVI) 共同给药后的主要候选药物与 PfSPZ 疫苗的相互作用。符合 cGMP 和质量控制 (QC) 释放和稳定性，按照 cG 测定进行生产，启动 QC 释放测定，QC 稳定性研究，进行临床前毒理学研究，设计临床试验，并为新药研究申请 (IND) 准备所有信息。