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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 疟原虫生命周期的复杂性和对已达到临床发育第二阶段疫苗的候选疫苗的不良疗效，这鼓励了寻找替代方法的搜索方法来引起保护性免疫。我们已经设计并表达了几种肉毒芽孢杆菌和红细胞嵌合重组蛋白，以寻找能够诱导长期保护疟疾的最佳配方。使用啮齿动物疟原虫模型质子质质子质质质体在小鼠中进行了原理研究证明。效力测试已经证实，嵌合蛋白具有高度免疫原性，能够诱导对嵌合体的不同成分的强大免疫反应。最相关的是，疫苗构建体在对Yoelii P. yoelii Sporozoites进行实验性挑战之后，以非常低剂量的高剂量和严重的贫血为保护。在实验挑战之后的延迟和寄生虫负担低的延迟表明，抗疫苗的免疫力和抗血液阶段的免疫力都在保护中起作用。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引起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抗体对于保护至关重要。我们还确定需要CD4+，但不需要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起保护性免疫。正在进行实验以设计一种嵌合疫苗，该嵌合疫苗还结合了性阶段疫苗成分。