ANTIMALARIA VACCINE BASED ON AN INFLUENZA VIRUS VECTOR

基于流感病毒载体的抗疟疾疫苗

• 批准号: 2072859
• 负责人: Ruth S Nussenzweig
• 金额: $ 28.75万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2072859
• 关键词: B lymphocyte; Plasmodium falciparum; T lymphocyte; cellular immunity; cytotoxic T lymphocyte; drug delivery systems; drug design /synthesis /production; epitope mapping; humoral immunity; laboratory mouse; malaria vaccines; nonhuman therapy evaluation; protozoal antigen

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.

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。 具体来说，我们生成了表达 CTL 的重组流感病毒 和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 随后是表达整个 CS 蛋白的重组痘苗病毒， 诱导针对这种鼠疟疾的保护性免疫力。 我们现在提议 扩大这种方法并将其扩展到由疟原虫引起的人类疟疾。 恶性疟原虫。 这项工作应该生成定义所需的数据 重组病毒的优化设计，以供未来用作疫苗 对抗疟疾，也可能对抗其他传染病。 为了 为此，我们计划： 1.构建重组流感病毒，表达B和T细胞 人类疟原虫恶性疟原虫的 CS 蛋白表位。 2. 确定这些构建体在小鼠中的衰减程度，以及 表征暴露于流感病毒的动物的流感特异性免疫反应 病毒载体。 3. 表征体液和 T 细胞介导的抗疟疾免疫 用重组流感-CS病毒免疫小鼠的反应。 4. 构建表达选定序列的额外流感病毒 第二种恶性疟原虫抗原，Trombospondin 相关匿名者 蛋白（TRAP），并评估其在小鼠中的免疫原性。还定义 对同时表达 CS 和 TRAP 表位的流感病毒的免疫反应。 5. 尝试通过启动和加强来增强这些免疫反应 具有两种流感病毒亚型的转染子，或两种完全 不同的病毒载体，都表达相同的外源表位。