Modular Chimeric Vaccines tailored for malaria parasites

描述(申请人提供)：这项研究提案的总体目标是优化疟疾模块嵌合疫苗(MCV)的设计、组成和配方，作为在流行地区控制疾病的有效干预措施。MCV是一种合成基因，旨在表达一系列保护性抗原，这些抗原来自几种蛋白质和一些疟原虫通用T细胞表位。疟疾通用T细胞表位将促进辅助性T细胞反应，克服与多种疟疾抗原相关的遗传限制，并促进自然暴露于疟疾寄生虫所产生的增强效应。MCV将使用计算机辅助算法在电子计算机中设计，以预测分子构象和稳定性特征，并诱导对寄生虫生命周期的几个阶段的免疫反应。这些嵌合结构的氨基酸序列将被反向翻译、密码子优化并组装成合成基因。合成的基因将被克隆，插入到大肠杆菌中，并表达和纯化蛋白质。这些抗原将被评估分子稳定性和抗原性，然后测试免疫原性和保护性。第一个具体目标将集中在开发战略，以构建和提供稳定和有效的MCV，以保护恒河猴免受猴疟疾寄生虫食蟹猴的实验挑战。这种寄生虫在恒河猴身上复制了人类感染间日疟原虫的几个临床特征。该项目的第二个目标将建立在设计具有潜在保护人类免受间日疟原虫感染的MCV所获得的经验的基础上。这些间日疟原虫MCV将在Aotus猴子身上进行免疫原性和保护性测试，Aotus猴子是一种非人类灵长类动物模型，被认为是测试疟疾候选疫苗的金标准。我们在严格的保护模型中对MCV的严格评估将为推动该疫苗平台的开发用于临床试验提供关键数据。关联性。由间日疟原虫引起的疟疾是一个主要的世界性健康问题，估计每年有8000万病例。在非洲以外，间日疟原虫是分布最广的疟疾寄生虫。间日疟正在死灰复燃，在已经根除的地区，它现在是一个严重的威胁。间日疟原虫、氯喹和伯氨喹抗药性菌株的出现使人们更加强调需要有替代的预防和治疗策略来控制这种感染。

DESCRIPTION (provided by applicant): The overall goal of this research proposal is to optimize the design, composition and formulation of malaria Modular Chimeric Vaccines (MCVs) as effective intervention measures to control the disease in endemic areas. MCVs are synthetic genes designed to express an array of protective antigens derived from several proteins and a number of Plasmodium universal T cell epitopes. Malaria universal T cell epitopes will promote helper T-cell responses, overcome the genetic restriction associated with several malaria antigens and facilitate the boosting effect induced by natural exposure to malaria parasites. MCVs will be designed in silico using computer-assisted algorithms to predict molecular conformation and stability characteristics and to induce immune responses to several stages of the parasite life cycle. The amino acid sequences of these chimeric constructs will be reverse translated, codon optimized and assembled into synthetic genes. The synthetic genes will be cloned, inserted into E. coli, and the proteins expressed and purified. These antigens will be assessed for molecular stability and antigenicity, and then tested for immunogenicity and protection. The first specific aim will focus on developing strategies to construct and deliver stable and efficacious MCVs that can protect rhesus macaques against the experimental challenge with a simian malaria parasite Plasmodium cynomolgi. This parasite reproduces in rhesus monkeys several clinical features of the infection of humans with P. vivax. The second aim of the project will build on the experience gained to design MCVs with the potential to protect humans against P. vivax. These P. vivax MCVs will be tested for immunogenicity and protection in Aotus monkeys, a non-human primate model considered the gold standard for testing malaria vaccine candidates. Our rigorous evaluation of MCVs in stringent models of protection will provide critical data to advance the development of this vaccine platform for use in clinical trials. Relevance. Malaria caused by P. vivax is a major worldwide health problem with an estimated 80 million cases annually. Outside Africa, P. vivax is the most widely distributed malaria parasite. P. vivax malaria is resurging and now represents a serious threat in areas where it had been eradicated. The emergence of P. vivax chloroquine and primaquine drug resistant strains has brought increased emphasis to the need for alternative prophylactic and therapeutic strategies to control this infection.