Multi-ligand merozoite invasion blocking malaria vaccine

描述（由申请人提供）：恶性疟原虫（Pf）引起的疟疾每年导致超过2.5亿例临床病例，近100万人死亡。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学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开始。阻断寄生虫侵入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侵入红细胞。因此，通过诱导干扰寄生虫受体-配体相互作用的抗体来阻断寄生虫侵入红细胞是疟疾疫苗开发的重要方法。一种研究充分的Pf配体是EBA-175，其结合血型糖蛋白A上的受体唾液酸。EBA-175的抗体可以阻断寄生虫的入侵。不幸的是，有Pf菌株通过不涉及唾液酸的替代途径侵入。因此，有效阻断入侵的疫苗的开发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 已鉴定蛋白质的结合同源蛋白家族（PfRH）通过除唾液酸之外的替代途径在红细胞的结合和侵入中起主要作用。我们的目的是评估当与针对EBA-175的抗体组合时，由PfRH蛋白免疫诱导的抗体是否可以有效地阻断寄生虫侵入红细胞。将使用红细胞结合阻断和寄生虫生长侵袭抑制试验系统进行评估。我们将首先表达重组候选蛋白质，以在兔子中产生针对这些候选蛋白质的抗体。将对候选物PfRH 1、2b、4和5以及EBA-175进行评估。我们的近期目标是使用多配体疫苗的策略有效地干扰寄生虫结合和侵入红细胞，所述多配体疫苗诱导阻断多种侵入途径的抗体。在多个方面对红细胞侵入这一关键步骤进行干预是我们创新和方法的核心。我们将选择最佳的候选组合，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II期，我们将产生所选重组候选物的生产者克隆，并在恒河猴中用适合人类使用的多种佐剂制剂系统地评估它们，向下选择最佳佐剂制剂，并在cGMP下生产材料，以准备临床试验，该临床试验旨在确定这种多配体裂殖子侵入阻断疫苗的功效。 公共卫生相关性：疟疾每年造成4 - 5亿临床病例和近100万人死亡，每年造成非洲GDP损失>1%，是旅行者和军事人员的严重关切。Protein Potential的目标是为主要市场开发和商业化一种保护性>90%的疟疾疫苗，年收入可能超过10亿美元; 1）来自发达国家的旅行者，2）发展中国家的婴儿，幼儿和少女。该项目的成功将大大降低开发成本，缩短有效疟疾疫苗上市时间。

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.