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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的首席研究员可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 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不良疗效鼓励人们寻找替代方法来引发保护性免疫。我们设计并表达了几种前红细胞和红细胞嵌合重组蛋白，以寻找能够诱导长期预防疟疾的最佳制剂。使用啮齿动物疟疾寄生虫模型约氏疟原虫在小鼠中进行了原理研究验证。效力测试证实，嵌合蛋白具有高度免疫原性，能够诱导针对嵌合体不同成分的强烈免疫反应。最相关的是，在用约氏疟原虫子孢子进行实验攻击后，该疫苗构建体以非常低的剂量即可对高寄生虫血症和严重贫血提供保护。潜伏期的延迟和实验攻击后的低寄生虫负荷表明，抗红细胞前免疫和抗血期免疫都发挥了保护作用。为了评估抗体的保护作用，使用针对嵌合蛋白的两个主要成分引发的多克隆抗体进行了被动免疫实验。这些比较实验证实，针对血液阶段成分的功能性抗体对于保护至关重要。我们还确定需要 CD4+ T 细胞，而不是 CD8+ T 细胞。这是第一个证据表明多阶段蛋白质疫苗可以在疟疾中引发保护性免疫力。设计嵌合疫苗的实验正在进行中，该疫苗还包含有性阶段疫苗成分。