MALARIA VACCINE--ATTENUATED INFLUENZA & VACCINIA VECTORS

描述：在上一次授予的过程中，PI描述了 猪瘟病毒诱导的体液免疫和细胞免疫应答 表达选定序列的重组流感和痘苗病毒 或整个CS蛋白或疟疾寄生虫。她的特点是 小鼠连续免疫后的免疫应答 这两种重组病毒表达啮齿动物CS蛋白(P. Yoelii)和人(恶性疟原虫)疟疾寄生虫。这些研究 证明在Py的情况下，与这些疫苗的联合免疫 两种病毒通过疟疾特异性抗体诱导保护性 和T细胞，它们对活的挑战具有广泛的抵抗力 寄生虫。在PF的情况下，体内存在激活的 循环的、保护性的CS特异性T细胞间接地显示为 增强免疫小鼠对脑内复制病毒的抵抗力 表达相同CS特异性表位的重组痘苗病毒。 考虑到将此方法应用于开发的可能性 在人类疟疾疫苗方面，我们目前建议进行以下工作 目标：确定工程的最佳条件 表达a)独特B细胞的免疫原性重组流感病毒 已被证明能诱导有效抗体反应的表位 抗原生寄生虫蛋白，以及b)通用的CD4T细胞 可被具有不同II类的个体识别的表位 MHC分子。以发展安全有效的疟疾为目的 疫苗，她将产生高度减毒的重组病毒 表达一组最优的CS表位。她会用冷适应的 流感病毒和牛痘病毒的MVA株，这两种病毒 已经被用来为大量的人类接种疫苗，没有严重的副作用 效果。这些衰减后的向量将根据其 诱导抗体和CD4、CD8 T细胞的安全性和免疫原性 对疟疾表位/抗原的反应。

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.