IMMUNOGENICITY OF SYNTHETIC POLYOXIME MALARIA VACCINES

合成多肟疟疾疫苗的免疫原性

• 批准号: 6534146
• 负责人: Elizabeth H Nardin
• 金额: $ 39.68万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534146
• 关键词: Aotus; Plasmodium; active immunization; clinical research; clinical trials; human subject; laboratory mouse; malaria; malaria vaccines; synthetic vaccines; vaccine development

The repeat B cell epitopes of the malaria circumsporozoite (CS) protein have formed the basis of synthetic peptide vaccines aimed at eliciting high levels of humoral immunity to block the invasion of the host hepatocytes by the infectious sporozoite. A synthetic peptide vaccine, containing repeat B cell epitopes (T1 B) combined with a universal T cell epitope (T*) of the P. falciparum CS protein, has been constructed using oxime bond ligation technology. The branched template core of the tri-epitope polyoxime vaccine contains the built-in synthetic lipopeptide adjuvant tripalmitoyl-S-glyceryl cysteine (P3C). A small-scale phase I trial to test the safety and immunogenicity of the (T1BT*)4-P3C polyoxime malaria vaccine has recently been carried out at the University of Geneva. The multicomponent polyoxime malaria vaccine was found to elicit anti-peptide antibody responses in 10/10 volunteers of diverse HLA haplotypes, without requiring the addition of exogenous adjuvant. The current grant application proposes to analyze the T cell and B cell responses of the polyoxime immunized volunteers and to assay the genetic restriction and effector functions of T cell lines and clones derived from these volunteers. These studies will provide the first immunological analysis of the human response to a polyoxime vaccine, as well as the first opportunity to investigate the function of a malaria universal T cell epitope in individuals of defined class II haplotypes. The preliminary serological results also demonstrate that, while anti-peptide antibodies were elicited in all the vaccinees, the magnitude of the antibody response was variable, reaching high antibody titers (greater than 5120) in 5/10 of the volunteers. To optimize humoral immunity, polyoximes containing varying T and B cell ratios and configurations would be tested in combination with different adjuvant formulations acceptable for human use. Immunogneicity would be assayed in inbred strains of mice, as well as HLA class II transgenic mice and in Aotus monkeys. The protective efficacy of polyoxime vaccines designed to elicit high levels of humoral, as well as cellular, immunity would be studied in the P. yoelii rodent malaria model. The analysis of the T and B cell responses of the (T1BT*)4-P3C immunized volunteers, the optimization of polyoxime vaccine formulation and the efficacy studies in the rodent malaria model will provide the experimental basis for the development of highly immunogenic synthetic peptide malaria vaccines as well as the preclinical data to support additional Phase I testing of polyoxime vaccines in human volunteers.

疟疾环孢子子（CS）蛋白的重复B细胞表位构成了合成肽疫苗的基础，旨在激发高水平的体液免疫，以阻止传染性孢子子对宿主肝细胞的入侵。利用肟键连接技术构建了一种含有重复B细胞表位（T1 B）和恶性疟原虫CS蛋白通用T细胞表位（T*）的合成肽疫苗。三表位多肟疫苗的支链模板核心含有内嵌的合成脂肽佐剂三棕榈酰- s -甘油半胱氨酸（P3C）。最近在日内瓦大学进行了一项小规模一期试验，以测试（T1BT*）4-P3C多肟疟疾疫苗的安全性和免疫原性。发现多组分多肟疟疾疫苗在10/10的不同HLA单倍型志愿者中引起抗肽抗体应答，而无需添加外源性佐剂。目前的拨款申请建议分析多肟免疫志愿者的T细胞和B细胞反应，并分析来自这些志愿者的T细胞系和克隆的遗传限制和效应功能。这些研究将首次对人类对多肟疫苗的反应进行免疫学分析，并首次有机会研究疟疾通用T细胞表位在确定的II类单倍型个体中的功能。初步的血清学结果还表明，虽然抗肽抗体在所有疫苗接种者中被激发，但抗体反应的大小是可变的，在5/10的志愿者中达到高抗体滴度（大于5120）。为了优化体液免疫，将测试含有不同T细胞和B细胞比例和结构的多肟与人类可接受的不同佐剂配方的组合。免疫原性将在近交系小鼠、HLAⅱ类转基因小鼠和猕猴中进行检测。多肟疫苗设计用于引起高水平的体液免疫和细胞免疫，其保护功效将在约氏疟原虫啮齿动物疟疾模型中进行研究。分析（T1BT*）4-P3C免疫志愿者的T细胞和B细胞应答、优化多肟疫苗配方以及在啮齿动物疟疾模型中的疗效研究，将为开发高免疫原性合成多肽疟疾疫苗提供实验依据，并为多肟疫苗在人体志愿者中的额外I期试验提供临床前数据支持。