Pre-erythrocytic Stage Antigen Discovery for Malaria Vaccine Development

描述(由申请人提供)：开发有效的疟疾疫苗是全球卫生的高度优先事项。疟疾是人类最沉重的寄生虫病，估计每年造成86.3万人死亡和2.43亿临床病例。迫切需要一种安全有效的疟疾疫苗。在啮齿动物、非人类灵长类动物和人类中的大量数据表明，在整个机体的疟疾疫苗中存在保护性抗原，这种疫苗诱导针对疟疾寄生虫红细胞期前阶段的T细胞。然而，这种保护性免疫的特定抗原靶标尚不清楚。我们的总体目标是为疟疾疫苗开发寻找新的、高度保护性的前红细胞抗原。 我们的假设是，红系前约氏疟原虫抗原是氯喹预防下的活子孢子免疫诱导的保护性细胞反应的靶标，当腺载体递送时，将在小鼠中诱导强大的保护性免疫反应；相应的恶性疟原虫同源物将成为疟疾疫苗开发的良好候选抗原。我们提出了一种合理和系统的方法来鉴定这些新的高度保护性的红细胞前抗原。我们已经开发了一组腺载体，可以表达300种最高表达的约氏疟原虫前红细胞抗原，并将对该阵列进行筛选，以识别 回忆在氯喹预防下用活子孢子免疫的小鼠的强大T细胞反应(特定目标1)。来自该阵列的能回忆起最强T细胞反应的腺病毒载体将被提纯，并评估它们在小鼠中诱导保护性免疫反应的能力(特定目标2)。过渡到临床前开发，我们将构建表达恶性疟原虫三种最具保护性抗原的同源基因的六邻体修饰Ad5载体，并评估它们在小鼠中诱导T细胞和抗体反应的能力(特定目标3)。这些目标的成功实现将推动三种新的红细胞前抗原用于疟疾疫苗的开发。

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.