MODULAR CHIMERIC VACCINES TAILORED FOR MALARIA PARASITES

针对疟疾寄生虫的模块化嵌合疫苗

• 批准号: 8357458
• 负责人: Alberto Moreno
• 金额: $ 4.12万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357458
• 关键词: Anemia; Antibodies; Blood; CD8B1 gene; Chimera organism; Chimeric Proteins; Clinical; Development; Dose; Drug Formulations; Erythrocytes; Funding; Grant; Immune response; Immunity; Life Cycle Stages; Malaria; Methodology; Modeling; Mus; National Center for Research Resources; Parasitemia; Parasites; Passive Immunization; Phase; Plasmodium yoelii; Play; Primates; Principal Investigator; Proteins; Recombinant Proteins; Reporting; Research; Research Infrastructure; Resources; Rodent; Role; Source; Sporozoites; Staging; T-Lymphocyte; United States National Institutes of Health; Vaccines; base; comparative; cost; design; immunogenic; polyclonal antibody; potency testing; research study; vaccine candidate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The complexity of the malaria parasite life cycle and the poor efficacy reported for vaccines candidates that have reached Phase 2 of clinical development has encouraged the search of alternative methodologies to elicit protective immunity. We have designed and expressed several pre-erythrocytic and erythrocytic chimeric recombinant proteins in the search of an optimal formulation capable of inducing long-term protection against malaria. Proof of principle studies have been done in mice using the rodent malaria parasite model Plasmodium yoelii. Potency tests have confirmed that the chimeric protein is highly immunogenic and able to induce robust immune responses against different components of the chimera. Most relevantly, the vaccine construct confers protection at very low doses to both hyper-parasitemia and severe anemia after experimental challenge with P. yoelii sporozoites. Delay in the prepatent period and low parasite burden after experimental challenge suggested that both, anti-pre-erythrocytic immunity and anti-blood stage immunity played a role in protection. To evaluate the impact of antibodies in protection, passive immunization experiments were done using polyclonal antibodies elicited against the two major components of the chimeric protein. These comparative experiments confirmed that functional antibodies against the blood stage component are essential for protection. We also established that CD4+ but not CD8+ T cells are required. This is the first evidence that a multi-stage protein-based vaccine can elicit protective immunity in malaria. Experiments are in progress to design a chimeric vaccine that also incorporates a sexual stage vaccine component.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 疟疾寄生虫生命周期的复杂性以及已达到临床开发第二阶段的候选疫苗的报告效力较差，鼓励人们寻找替代方法来获得保护性免疫。我们设计并表达了几种红细胞前和红细胞嵌合重组蛋白，以寻找能够诱导对疟疾的长期保护的最佳配方。已经使用啮齿动物疟疾寄生虫模型约氏疟原虫在老鼠身上进行了原理验证研究。效力测试证实，该嵌合蛋白具有高度的免疫原性，并能够针对嵌合体的不同成分诱导强大的免疫反应。最相关的是，疫苗结构在用约氏疟原虫子孢子进行实验性攻击后，以非常低的剂量对高寄生虫血症和严重贫血都提供了保护。感染后潜伏期延迟，寄生虫负担低，提示抗红细胞前免疫和抗血液期免疫均起到保护作用。为了评估抗体在保护中的影响，使用针对嵌合蛋白的两个主要成分的多克隆抗体进行了被动免疫实验。这些对比实验证实，针对血液期成分的功能性抗体对于保护至关重要。我们还确定了需要的是CD4+T细胞，而不是CD8+T细胞。这是首次有证据表明，基于蛋白质的多阶段疫苗可以在疟疾中引发保护性免疫。目前正在进行实验，以设计一种嵌合疫苗，该疫苗还包括有性阶段疫苗的成分。