Multi-ligand merozoite invasion blocking 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都是由寄生虫生命周期的红细胞阶段引起的，因此疟疾的所有后遗症都是从寄生虫侵入红细胞开始的。阻断寄生虫对红细胞的侵袭，可以防止寄生虫的复制和所有的临床疾病。Pf寄生虫通过结合特定的红细胞受体侵入红细胞。因此，在疟原虫入侵过程中，通过诱导干扰疟原虫受体-配体相互作用的抗体来阻断疟原虫对红细胞的入侵是开发疟疾疫苗的重要途径。一个被充分研究的Pf配体是EBA-175，它将其受体唾液酸结合在糖蛋白A上。EBA-175的抗体可以阻止寄生虫的入侵。不幸的是，有些菌株通过不涉及唾液酸的替代途径侵入。因此，开发有效阻断入侵的疫苗必须诱导针对多种配体的抗体、干扰唾液酸的抗体和替代入侵途径。网织红细胞的

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.