ANTIMALARIA VACCINE BASED ON AN INFLUENZA VIRUS VECTOR

我们已经证明，表达外源表位的活流感病毒可以 诱导有效的抗体和细胞毒性T细胞(CTL)反应。 具体地说，我们制造了表达CTL的重组流感病毒 约氏疟原虫环子孢子(CS)蛋白的B细胞表位。 用这些重组流感病毒单独或 然后是表达整个CS蛋白的重组牛痘病毒， 诱导对这种小鼠疟疾的保护性免疫。我们现在提议 为了将这一方法推广到由P. 恶性疟原虫。这项工作应该生成定义 重组病毒未来用作疫苗的优化设计 防治疟疾，可能还防治其他传染病。为 为此，我们计划： 1.构建表达B、T细胞的重组流感病毒 人恶性疟原虫CS蛋白表位的研究 2.测定这些结构在小鼠体内的衰减程度，以及 描述暴露在流感病毒中的动物的流感特异性免疫反应 病毒载体。 3.体液和T细胞介导的抗疟疾免疫的特性 重组流感-CS病毒免疫小鼠的免疫应答 4.构建额外的流感病毒，表达选定的 另一种恶性疟原虫抗原--弓形虫相关匿名抗原 蛋白(TRAP)，并评估其在小鼠体内的免疫原性。还定义了 对同时表达CS和TRAP表位的流感病毒的免疫应答。 5.尝试通过启动和增强来增强这些免疫反应 用两种亚型流感病毒的转染体，或完全两种 不同的病毒载体，都表达相同的外源表位。

We have shown that live influenza viruses expressing foreign epitopes can induce an efficient antibody and cytotoxic T cell (CTL) response. Specifically, we generated recombinant influenza viruses expressing CTL and B cell epitopes of the circumsporozoite (CS) protein of P. yoelii. Immunization of mice with these recombinant influenza viruses, alone or followed by a recombinant vaccinia virus expressing the entire CS protein, induced protective immunity against this murine malaria. We now propose to expand this approach and extend it to human malaria caused by P. falciparum. This work should generate data necessary for defining the optimal design of recombinant viruses for their future use as vaccines against malaria and possibly also against other infectious diseases. For this purpose we plan to: 1. Construct recombinant influenza viruses, expressing B and T cell epitopes of the CS protein of the human malaria parasite, P. falciparum. 2. Determine the degree of attenuation of these constructs in mice, and characterize the influenza-specific immune responses of animals exposed to the viral vectors. 3. Characterize the humoral and T cell mediated anti-malaria immune responses of mice immunized with recombinant influenza-CS viruses. 4. Construct additional influenza viruses expressing selected sequences of a second P. falciparum antigen, the Trombospondin Related Anonymous Protein (TRAP), and assess their immunogenicity in mice. Also define the immune response to influenza viruses expressing both CS and TRAP epitopes. 5. Attempt to potentiate these immune responses by priming and boosting with transfectants of two subtypes of influenza viruses, or two entirely different viral vectors, both expressing the same foreign epitopes.