ADENOVIRUS--AN EFFICIENT VECTOR OF ANTIMALARIA IMMUNITY

疟疾是一种严重的疾病， 热带地区的流行感染，遍布世界各地。 的 事实上，用辐照过的子孢子进行免疫接种， 只有啮齿类动物，而且人类对这种疾病表明， 开发有效的红细胞前疫苗可能是可行的， 这将是一个有价值的额外工具， 这种疾病。 这项建议的总体目标是使用复制缺陷 重组腺病毒，表达一种或多种疟原虫 抗原，作为表征保护性免疫的模型系统， 针对疟疾寄生虫的肝脏阶段的反应。 我 早期的研究表明，单次免疫剂量的 该载体表达环子孢子（CS）蛋白，不像 这种疟原虫抗原的任何其他形式的呈递，诱导 高水平的CS特异性CD 8+和CD 4 +T细胞，并赋予 对相当大比例的小鼠产生无菌免疫。 我也 确定这种保护作用主要由CD 8 + T细胞介导， 但这种保护机制的分子基础仍然存在 有待阐明。 我建议通过使用遗传学方法来实现这一点。 被操纵的基因敲除小鼠 另一个重要问题，特别是 未来的疫苗开发涉及到对各种 旨在增强亚单位的保护作用的方法 重组腺病毒疫苗。 这些目标将 追求： 1)确定体液和细胞的水平和持久性- 介导的抗疟原虫应答和保护接受 用重组腺病毒载体多次免疫，或 与含CS的其他免疫原联合免疫 蛋白 2)确定是否用腺病毒免疫 共表达两种或多种红细胞前抗原的载体可以 增强免疫后发生的免疫应答 这些抗原之一。 调查是否有可能 这种免疫应答通过给予腺病毒共 表达疟原虫抗原和选择的淋巴因子/共- 3）分析抗疟原虫效应子 CD 8 +T细胞的机制和分子表征 参与CSCD 8+的体内加工和呈递 表位

Malaria is a severe disease that continues to rank among the most prevalent infections in tropical areas, throughout the world. The fact that immunization with irradiated sporozoites can protect not only rodents, but also humans against this disease indicates that it might be feasible to develop an effective pre-erythrocytic vaccine, which would represent a valuable additional tool for the control of this disease. The overall aim of this proposal is to use a replication-defective recombinant adenovirus, expressing one or more plasmodial antigens, as a model system to characterize the protective immune response targeted against the liver stages of malaria parasites. My earlier studies have demonstrated that a single immunizing dose of this vector, expressing the circumsporozoite (CS) protein, unlike any other form of presentation of this plasmodial antigen, induces high levels of CS-specific CD8+ and CD4+T cells, and confers sterile immunity to a considerable percentage of mice. I also determined that this protection is primarily mediated by CD8+ T cells, but the molecular basis of this protective mechanisms remains to be elucidated. This I propose to pursue by the use of genetically manipulated, knock-out mice. Another important issue, particularly for future vaccine development relates to the exploration of various approaches aimed at enhancing the protective effect of a subunit vaccine based on recombinant adenovirus. These objectives will be pursued by: 1)Determining the level and persistence of humoral and cell- mediated anti-plasmodial responses and protection of mice receiving multiple immunizations with recombinant adenovirus vectors, or combined immunization with other immunogens containing the CS protein. 2) Determine whether immunization with an adenoviral vector co-expressing two or more pre-erythrocytic antigens, can potentiate the immune response which occurs upon immunization with one of these antigens. Investigate the possibility of modulating this immune response by administration of an adenovirus co- expressing a plasmodial antigen and a selected lymphokine/co- stimulatory molecule, and 3) Analyze the anti-plasmodial effector mechanisms of CD8+T cells and characterization of the molecules involved in the in vivo processing and presentation of the CSCD8+ epitope.