Multi-ligand merozoite invasion blocking malaria vaccine

多配体裂殖子侵袭阻断疟疾疫苗

• 批准号: 8251428
• 负责人: B. KIM LEE SIM
• 金额: $ 30万
• 依托单位: PROTEIN POTENTIAL, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251428
• 关键词: Address; Adjuvant; Africa; Antibodies; Binding; Biochemical; Biological Assay; Blocking Antibodies; Cessation of life; Child; Clinical; Clinical Trials Design; Cyclic GMP; Development; Disease; Drug Formulations; Effectiveness; Erythrocytes; Falciparum Malaria; Female Adolescents; Gene Expression; Generations; Glycophorin A; Goals; Growth; Hand; Homologous Gene; Human; Immunization; Infant; Intervention; Invaded; Life Cycle Stages; Ligand Binding; Ligands; Macaca mulatta; Malaria; Malaria Vaccines; Marketing; Military Personnel; Morbidity - disease rate; Oryctolagus cuniculus; Parasites; Pathology; Pathway interactions; Phase; Pichia; Plasmodium falciparum; Plasmodium falciparum vaccine; Play; Preparation; Protein Family; Proteins; Recombinant Proteins; Recombinants; Reticulocytes; Role; Serum; Sialic Acids; Staging; Time; Use Effectiveness; Vaccines; Yeasts; cost; erythrocyte receptor; innovation; mortality; parasite invasion; prevent; receptor; sialic acid receptor; success; vaccine development

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 would prevent 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 binding and 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 >1% 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 >90% protective malaria vaccine for primary markets with a potential for >$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.

描述（由申请人提供）：由恶性疟原虫 (Pf) 引起的疟疾每年导致超过 2.5 亿临床病例，近百万人死亡。疫苗将是降低疟疾发病率和死亡率的理想干预措施。疟疾的所有临床表现和病理都是由寄生虫生命周期的红细胞阶段引起的，因此疟疾疾病的所有后遗症都是在寄生虫侵入红细胞时开始的。阻止寄生虫入侵红细胞将防止寄生虫复制和所有临床疾病。 Pf 寄生虫通过与特定的红细胞受体结合来侵入红细胞。因此，通过诱导在入侵过程中干扰寄生虫受体-配体相互作用的抗体来阻断寄生虫对红细胞的入侵是疟疾疫苗开发的重要方法。一种经过充分研究的 Pf 配体是 EBA-175，它与其糖蛋白 A 上的受体唾液酸结合。EBA-175 的抗体可以阻止寄生虫入侵。不幸的是，有些 Pf 菌株通过不涉及唾液酸的替代途径入侵。因此，开发有效阻止入侵的疫苗必须诱导针对多种配体的抗体、干扰唾液酸和替代入侵途径的抗体。网织红细胞 已确定蛋白质的结合同源蛋白家族 (PfRH) 通过除唾液酸以外的替代途径在红细胞的结合和侵袭中发挥重要作用。我们的目的是评估 PfRH 蛋白免疫诱导的抗体与 EBA-175 抗体结合是否可以有效阻止寄生虫侵入红细胞。将使用红细胞结合阻断和寄生虫生长侵袭抑制测定来系统地进行评估。我们将首先表达重组候选蛋白，以在兔子中产生针对这些候选蛋白的抗体。候选药物 PfRH 1、2b、4 和 5 以及 EBA-175 将接受评估。我们的近期目标是使用多配体疫苗策略来有效干扰寄生虫结合和侵入红细胞，该疫苗诱导阻断多种入侵途径的抗体。从多个方面干扰红细胞侵袭的单个关键步骤是我们创新和方法的核心。我们将选择最佳的候选药物组合，并建议在第二阶段将其开发为多配体、入侵阻断疫苗。因此，在第二阶段，我们将创建所选重组候选物的生产者克隆，并使用适合人类使用的多种佐剂配方在恒河猴中系统评估它们，筛选出最佳佐剂配方，并根据 cGMP 生产材料，为临床试验做准备旨在确定这种多配体裂殖子入侵阻断疫苗的功效。 公共卫生相关性：疟疾每年造成 400-5 亿临床病例和近 100 万人死亡，每年造成非洲 GDP 损失超过 1%，是旅行者和军事人员严重关切的问题。 Protein Potential 的目标是为初级市场开发并商业化一种 > 90% 的保护性疟疾疫苗，年收入潜力 > 10 亿美元； 1) 来自发达国家的旅行者，以及 2) 发展中国家的婴儿、幼儿和少女。该项目的成功将显着降低有效疟疾疫苗的开发成本并缩短上市时间。