IMMUNOGENICITY OF SYNTHETIC POLYOXIME MALARIA VACCINES

疟疾环子孢子（CS）蛋白的重复B细胞表位已形成合成肽疫苗的基础，所述合成肽疫苗旨在引发高水平的体液免疫以阻断感染性子孢子对宿主肝细胞的侵袭。 利用肟键连接技术构建了含有恶性疟原虫CS蛋白的重复B细胞表位（T1 B）与通用T细胞表位（T*）组合的合成肽疫苗。 三表位聚氧肟疫苗的分支模板核心含有内置的合成脂肽佐剂三棕榈酰-S-甘油基半胱氨酸（P3 C）。 最近在日内瓦大学进行了一项小规模I期试验，以测试（T1 BT *）4-P3 C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单倍型的志愿者中引发抗肽抗体应答，而不需要添加外源性佐剂。 目前的资助申请提出分析多肟免疫的志愿者的T细胞和B细胞应答，并测定来自这些志愿者的T细胞系和克隆的遗传限制和效应子功能。 这些研究将提供人类对多肟疫苗反应的第一次免疫学分析，以及第一次有机会研究疟疾通用T细胞表位在定义的II类单倍型个体中的功能。 初步血清学结果还表明，虽然在所有接种者中均引发了抗肽抗体，但抗体应答的幅度是可变的，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和B细胞比率和构型的多肟与人类使用可接受的不同佐剂制剂的组合。将在近交系小鼠以及HLA II类转基因小鼠和Aotus猴中测定免疫原性。 将在约氏疟原虫啮齿动物疟疾模型中研究设计用于引发高水平体液免疫以及细胞免疫的多肟疫苗的保护效力。 （T1 BT *）4-P3 C免疫志愿者T和B细胞应答的分析、多肟疫苗配方的优化以及在啮齿动物疟疾模型中的效力研究将为开发高免疫原性合成肽疟疾疫苗提供实验基础，以及支持多肟疫苗在人类志愿者中的额外I期测试的临床前数据。

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.