MALARIA VACCINE--ATTENUATED INFLUENZA & VACCINIA VECTORS

描述：在先前授予的过程中，PI表征了 诱导的体液和细胞抗疟疾免疫应答 表达选定序列的重组流感病毒和牛痘病毒 或整个CS蛋白或疟疾寄生虫。她描述了 小鼠的免疫应答由其连续接种 这两种重组病毒均表达啮齿类动物（P. 约氏疟原虫（P. yoelii）和人（恶性疟原虫（P. falciparum））疟原虫。这些研究 证明了在Py的情况下，与这些的联合免疫 两种病毒诱导保护，由疟疾特异性抗体介导 和T细胞，其赋予对活的 寄生虫在Pf的情况下，体内激活的 循环，保护性CS特异性T细胞间接显示了 免疫小鼠对脑内复制的 表达相同CS特异性表位的重组牛痘病毒。 考虑到将这种方法应用于发展的可能性， 关于人类疟疾疫苗，我们目前建议开展以下工作： 目的：确定工程的最佳条件， 表达a）独特B细胞免疫原性重组流感病毒 表位，其已显示诱导有效的抗体应答 抗天然寄生虫蛋白，和B）通用CD 4 + T细胞 表位可以被携带不同II类抗原的个体识别 MHC分子。为了开发安全有效的疟疾疫苗 疫苗，她将产生高度减毒的重组病毒， 表达CS表位的最佳集合。她将使用冷适应 流感病毒和牛痘病毒的MVA株，两者都 已经被用于免疫大量的人类，没有严重的副作用， 方面的影响.将评价这些减毒载体的 诱导抗体和CD 4+和CD 8 + T细胞的安全性和免疫原性 针对疟疾表位/抗原的应答。

DESCRIPTION: During the course of the previous grant the PI characterized the humoral and cellular anti-malaria immune responses induced by recombinant influenza and vaccinia viruses expressing selected sequences or the entire CS protein or malaria parasites. She characterized the immune responses of mice resulting from their successive vaccination with these two recombinant viruses, expressing the CS protein of rodent (P. yoelii) and human (P. falciparum) malaria parasites. These studies demonstrated that in the case of Py, the combined immunization with these two viruses induces protecting, mediated by malaria-specific antibodies and T cells which confer extensive resistance to challenge with viable parasites. In the case of Pf, the presence of in vivo activated circulating, protective CS-specific T cells was shown indirectly by the increased resistance of immunized mice to the intracerebral replication of recombinant vaccinia virus expressing the same CS-specific epitope. Considering the possibility of applying this approach to the development of a human malaria vaccine, we currently propose to pursue the following aims: Determine the optimal conditions for the engineering of highly immunogenic recombinant influenza viruses expressing a) a unique B cell epitope which has been shown to induce effective antibody responses against the native parasite protein, and b) a universal CD4+ T cell epitope which can be recognized by individuals bearing different class II MHC molecules. With the purpose of developing safe and effective malaria vaccines, she will generate highly attenuated recombinant viruses expressing an optimal set of CS epitopes. She will use cold adapted influenza viruses and the MVA strain of vaccinia viruses, both of which have been used to immunize large numbers of humans, without severe side effects. These attenuated vectors will be evaluated with regard to their safety and immunogenicity to induce antibodies and CD4+ and CD8+ T cell responses against malaria epitopes/antigens.