Improving Malaria Pre-Erythrocytic Vaccines

改进疟疾前红细胞疫苗

基本信息

批准号：
7647714
负责人：
MORIYA TSUJI
金额：
$ 46.05万
依托单位：
AARON DIAMOND AIDS RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-15 至 2010-01-31
项目状态：
已结题

项目摘要

6. Project Summary Malaria infection starts when mosquitoes inject sporozoites into the skin. The parasites enter the bloodstream, and after reaching the liver, they develop into exoerythrocytic forms (EEFs) inside hepatocytes. The EEFs mature and then divide rapidly to form thousands of merozoites that re-enter the blood and infect erythrocytes causing the disease we recognize as malaria. Sterile immunity against malaria infection has been achieved by vaccination with irradiated sporozoites (IrSp) or with Genetically Attenuated Sporozoites (GAS) obtained by targeting their uis3, or uis4 or P52/36 genes. Using CStransgenic mice that are unable to make antibodies, we have shown that circumsporozoite (CS) antigen alone accounts for close to 90% of the protection elicited by immunization with IrSp of a rodent malaria parasite, Plasmodium yoelii. However, we have found that hyper-immunizing these mice with IrSp could induce a very strong protective anti-malaria immunity, which is mainly mediated by CD8+ T cells. This finding underscores the presence of sub-dominant ¿minor¿ protective antigens in IrSp. Therefore, in this proposal, we seek 1) To identify CD8+ T cell responses against some of the non-CS ¿minor¿ protective antigens generated by immunization with IrSp, and 2) To compare the mechanisms of T cell-mediated protection induced by GAS and IrSp. The identification of novel malaria antigen(s) should facilitate the development of preerythrocytic malaria vaccines. In addition, the systematic comparison of the role of non- CS-specific CD8+ T cells induced by GAS versus by IrSp should contribute to our understanding of the nature of sporozoite-based vaccines against malaria.

六、项目概要当蚊子将子孢子注入皮肤时，疟疾感染就开始了。进入血液，到达肝脏后，发育成外红细胞肝细胞内的 EEF 成熟，然后迅速分裂形成。数以千计的裂殖子重新进入血液并感染红细胞，导致我们认为疟疾是一种针对疟疾感染的无菌免疫力。通过用辐照子孢子 (IrSp) 或基因减毒疫苗接种来实现通过使用 CStransgenic 靶向其 uis3、uis4 或 P52/36 基因获得子孢子 (GAS)。对于无法产生抗体的小鼠，我们已经证明仅环子孢子 (CS) 抗原就占了近 90% 的保护作用然而，我们通过用 IrSp 免疫啮齿动物疟原虫约氏疟原虫。发现用 IrSp 对这些小鼠进行超级免疫可以诱导非常强的免疫反应保护性抗疟疾免疫，主要由 CD8+ T 细胞介导。强调次主导的存在 ¿次要的IrSp 中的保护性抗原。因此，在本提案中，我们寻求 1) 确定 CD8+ T 细胞对某些非 CS 的 ¿次要的通过 IrSp 免疫产生的保护性抗原，以及 2) 比较 GAS 和 IrSp 诱导的 T 细胞介导的保护机制。新型疟疾抗原的鉴定应促进前红细胞的发育此外，还对非疟疾疫苗的作用进行了系统比较。 GAS 与 IrSp 诱导的 CS 特异性 CD8+ T 细胞应该有助于我们了解基于子孢子的疟疾疫苗的性质。