Integrating a pre-erythrocytic component into a multistage malaria vaccine

将前红细胞成分整合到多阶段疟疾疫苗中

• 批准号: 10301364
• 负责人: James Matthew Burns
• 金额: $ 18.94万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-12 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301364
• 关键词: Address; Adjuvant; Antibodies; Antibody Response; Antigens; Attention; Attenuated; B-Lymphocyte Epitopes; B-Lymphocytes; Binding Proteins; Blood; C-terminal; CD4 Positive T Lymphocytes; Carrier Proteins; Cessation of life; Child; Clinical; Complex; Development; Drug Combinations; Engineering; Epitopes; Erythrocytes; Falciparum Malaria; Formulation; Foundations; Genetic Polymorphism; Goals; Hepatitis B Surface Antigens; Homologous Protein; Immune response; Immunity; Immunization; Immunoglobulin G; Individual; Infection; Insecticides; International; Knowledge; Left; Maintenance; Malaria; Malaria Vaccines; Measurable; Measures; Membrane Proteins; Merozoite Surface Protein 1; Modeling; Modification; Molecular Conformation; N-terminal; Parasites; Plasmodium berghei; Plasmodium falciparum; Preclinical Testing; Preventive therapy; Production; Recombinant Vaccines; Recombinants; Reporting; Residual state; Reticulocytes; Rodent; Severity of illness; Specificity; Sporozoites; Structure; Subunit Vaccines; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Time; Transgenic Organisms; Vaccine Antigen; Vaccine Design; Vaccine Production; Vaccines; Work; base; circumsporozoite; circumsporozoite protein; design; design and construction; immunogenic; immunogenicity; improved; interest; merozoite surface protein; neutralizing antibody; nonhuman primate; novel; pathogen; phase III trial; programs; protective efficacy; rapid diagnosis; response; success; tool; transmission process; transmission-blocking vaccine; vaccine candidate; vaccine development; vaccine formulation; vaccine immunogenicity; vaccine trial

Malaria control continues to attract international attention. While current integrated control efforts are being maintained, new tools need to be added if further reduction in the global malaria burden is to be realized. The development and introduction of an efficacious vaccine has great potential to be one such tool. However, successes in the malaria vaccine effort to date have been limited. While there are several challenges that must be addressed, two key issues have repeatedly emerged. First, the immunogenicity of subunit vaccines must be improved. Second, there is no indication that immunity to these complex, multi-stage plasmodial parasites is directed toward a single protective antigen. Vaccine candidate antigens will need to be formulated in combination, without any reduction in the immunogenicity of individual components. Our prior efforts have focused on both blood-stage and sexual stage vaccine targets where antibody-dependent mechanisms of immunity are essential, but where immunogenicity of neutralizing B cell epitopes has not been optimal. In our approach, we engineered a well-conserved, highly immunogenic, P. falciparum specific carrier protein based on merozoite surface protein 8 that facilitates vaccine production and induces potent CD4+ T cell help for the production of neutralizing antibodies. We demonstrated its utility as a carrier for P. falciparum blood-stage vaccine candidates including merozoite surface protein 1, merozoite surface protein 2, reticulocyte-binding protein homologue 5 and the 25 kDa sexual stage antigen. Of importance, neutralizing antibody responses to targeted domains were maintained within the context of a multi-antigen, multi-stage formulation. A pre- erythrocytic stage vaccine component is currently lacking from our formulation. In this project, we will test the hypothesis that PfMSP8 is an effective carrier protein for a recombinant P. falciparum circumsporozoite surface protein-based vaccine to elicit potent, durable antibody responses to multiple protective B cell epitopes (repeat and non-repeat domains) that neutralize sporozoites. In aim 1, we will express and purify four recombinant PfCSP-based vaccines designed to increase the breadth of immune responses to relevant epitopes, some of which are lacking in the current PfCSP-based RTS,S vaccine. In aim 2, we will determine the magnitude and epitope specificity of T and B cell responses elicited by each rPfCSP-based vaccine formulated with GLA-SE as adjuvant. Following down-selection, we will evaluate the functionality and durability of vaccine-induced, PfCSP-specific IgG in a rodent challenge model with transgenic Plasmodium berghei parasite expressing P. falciparum CSP. Success in this effort will provide the foundation for subsequent preclinical testing in non- human primates to determine if a rPfCSP* vaccine can be formulated in combination with existing rPfMSP1/8, rPfMSP2/8, rPfRh5/8 and rPfs25/8 vaccines without compromising responses to individual components.

疟疾控制继续引起国际关注。当前的集成控制工作是 在维护的情况下，如果要实现全球疟疾负担的进一步减轻，则需要添加新工具。 有效的疫苗的开发和引入具有成为这样一种工具的巨大潜力。然而， 迄今为止，疟疾疫苗的成功受到了限制。虽然有几个挑战 必须解决，重复出现了两个关键问题。首先，亚基疫苗的免疫原性 必须改进。其次，没有迹象表明对这些复杂的多阶段质学的免疫力 寄生虫针对单一保护抗原。疫苗候选抗原将需要制定 结合起来，单个成分的免疫原性而无需降低。我们先前的努力 专注于血液阶段和性阶段疫苗靶标的抗体依赖性机制 免疫力是必不可少的，但是中和B细胞表位的免疫原性并不是最佳的。在我们的 方法，我们设计了一个保存良好的高度免疫原性的恶性疟原虫特异性载体蛋白 在梅洛唑岩表面蛋白8上，促进疫苗的产生并诱导有效的CD4+ T细胞帮助 中和抗体的产生。我们证明了它作为恶性疟原虫血液阶段的载体的实用性 候选疫苗的候选物，包括梅洛唑岩表面蛋白1，梅罗洛唑表面蛋白2，网状细胞结合 蛋白质同源物5和25 kDa性阶段抗原。重要性，中和抗体反应 在多抗原的多阶段公式的背景下，靶向域维持。预先 目前，我们的制剂目前缺乏红细胞疫苗成分。在这个项目中，我们将测试 假设PFMSP8是重组恶性疟原虫表面的有效载体蛋白 基于蛋白质的疫苗可引起对多种保护性B细胞表位的有效耐用抗体反应（重复 和非重复域）中和孢子虫。在AIM 1中，我们将表达和净化四个重组 基于PFCSP的疫苗旨在增加对相关表位的免疫反应的广度，其中一些 当前基于PFCSP的RTS疫苗缺乏。在AIM 2中，我们将确定大小和 T和B细胞反应的表位特异性由GLA-SE配制的每种基于RPFCSP的疫苗引起 作为佐剂。下调后，我们将评估疫苗诱导的功能和耐用性， 在啮齿动物挑战模型中，PFCSP特异性IgG具有转基因疟原虫表达P。 恶性CSP。这项工作的成功将为非 - 随后的临床前测试提供基础 人类灵长类动物确定是否可以与现有RPFMSP1/8结合配制RPFCSP*疫苗， RPFMSP2/8，RPFRH5/8和RPFS25/8疫苗，没有对单个组件的反应。