Improving Malaria Pre-Erythrocytic Vaccines

6.项目摘要 当蚊子将子孢子注入皮肤时，疟疾就开始感染了。寄生虫 进入血液，到达肝脏后，它们发展成红细胞外的 在肝细胞内形成EEFs。EEFs成熟后迅速分裂形成 成千上万的裂殖子重新进入血液并感染红细胞， 我们称之为疟疾。针对疟疾感染的无菌免疫已经被 通过用辐照的子孢子（IrSp）或用遗传减毒的 通过靶向其uis 3或uis 4或P52/36基因获得的子孢子（GAS）。使用CS转基因 不能产生抗体的小鼠，我们已经证明， 环子孢子（CS）抗原单独占近90%的保护引起的 通过用啮齿类疟疾寄生虫约氏疟原虫的IrSp免疫。但我们 他们发现，用IrSp对这些小鼠进行超免疫接种， 保护性抗疟疾免疫，主要由CD 8 + T细胞介导。这一发现 强调了IrSp中亚显性保护性抗原的存在。 因此，在本提案中，我们寻求1）鉴定针对某些免疫缺陷病毒的CD 8 + T细胞应答。 通过IrSp免疫产生的非CS次要保护性抗原，和2） 比较GAS和IrSp诱导T细胞介导的保护作用机制。 新的疟疾抗原的鉴定将促进红细胞前 疟疾疫苗此外，系统地比较了非 GAS与IrSp诱导的CS特异性CD 8 + T细胞应该有助于我们的研究。 了解基于子孢子的疟疾疫苗的性质。

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.