MALARIA VACCINE--ATTENUATED INFLUENZA & VACCINIA VECTORS

描述：在上一次资助的过程中，PI 描述了 体液和细胞抗疟疾免疫反应 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 小鼠连续接种疫苗后产生的免疫反应 这两种重组病毒，表达啮齿动物（P. yoelii）和人类（恶性疟原虫）疟疾寄生虫。这些研究 证明在 Py 的情况下，与这些的联合免疫 两种病毒诱导由疟疾特异性抗体介导的保护 和 T 细胞，赋予对活细胞挑战的广泛抵抗力 寄生虫。就 Pf 而言，体内激活的存在 循环的、保护性的 CS 特异性 T 细胞通过 免疫小鼠对脑内复制的抵抗力增加 重组痘苗病毒表达相同的CS特异性表位。 考虑将这种方法应用于开发的可能性 为了开发人类疟疾疫苗，我们目前建议采取以下措施 目标：确定高度工程的最佳条件 表达 a) 独特 B 细胞的免疫原性重组流感病毒 已被证明可诱导有效抗体反应的表位 对抗天然寄生虫蛋白，以及 b) 通用 CD4 T 细胞 可以被不同II类个体识别的表位 MHC 分子。以开发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 表达一组最佳的 CS 表位。她会用冷适应 流感病毒和牛痘病毒 MVA 株，这两种病毒 已被用于对大量人类进行免疫，没有严重的副作用 影响。将评估这些减毒载体的 诱导抗体和 CD4 和 CD8 T 细胞的安全性和免疫原性 针对疟疾表位/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.