Pre-erythrocytic Stage Antigen Discovery for Malaria Vaccine Development

描述（由申请人提供）：研制有效的疟疾疫苗是全球卫生的高度优先事项。疟疾是人类负担最重的寄生虫病，估计每年造成863 000人死亡和2.43亿临床病例。迫切需要一种安全有效的疟疾疫苗。啮齿动物、非人类灵长类动物和人类的大量数据表明，在整个生物体疟疾疫苗中存在保护性抗原，可诱导靶向疟疾寄生虫红细胞前阶段的T细胞。然而，这种保护性免疫的特异性抗原靶点尚不清楚。我们的总体目标是确定用于疟疾疫苗开发的新型、高度保护性的红细胞前抗原。

DESCRIPTION (provided by applicant): The development of an effective malaria vaccine is a high global health priority. Malaria is the most burdensome parasitic disease of man, exacting an estimated toll of 863,000 deaths and 243 million clinical cases per year. There is an urgent need for a safe and effective malaria vaccine. An abundance of data in rodents, non-human primates and humans indicate the existence of protective antigens in whole organism malaria vaccines that induce T cells which target the pre-erythrocytic stages of the malaria parasite. However, the specific antigen targets of this protective immunity are not known. Our overall goal is to identify novel, highly protective, pre-erythrocytic antigens for malaria vaccine development. Our hypothesis is that the pre- erythrocytic P. yoelii antigens that are the targets of protective cell responses induced by immunization with highly protective regimens of live sporozoites under chloroquine prophylaxis will induce robust and protective immune responses in mice when delivered by adenovectors; and that the corresponding P. falciparum orthologues will be good candidate antigens for malaria vaccine development. We propose a rational and systematic approach to identify these novel highly protective, pre-erythrocytic antigens. We have already developed an array of adenovectors that express 300 of the most highly expressed pre-erythrocytic P. yoelii antigens, and will screen this array to identify antigens that recall robust T cell responses from mice immunized with live sporozoites under chloroquine prophylaxis (Specific Aim 1). Adenovectors from the array that recall the strongest T cell responses will be purified and evaluated for their ability to induce protective immune responses in mice (Specific Aim 2). Transitioning to preclinical development, we will build hexon-modified Ad5 vectors expressing the P. falciparum orthologues of the three most protective antigens and evaluate their capacity to induce T cell and antibody responses in mice (Specific Aim 3). Success in achievement of these aims will advance three new pre-erythrocytic antigens to malaria vaccine development.