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。虽然目前的综合控制努力是 如果要进一步减少全球疟疾负担，就需要增加新的工具。 开发和引进一种有效的疫苗具有成为这样一种工具的巨大潜力。然而， 迄今为止，疟疾疫苗努力取得的成功有限。虽然有几个挑战， 必须加以解决，两个关键问题一再出现。第一，亚单位疫苗的免疫原性 必须加以改进。第二，没有迹象表明对这些复杂的、多阶段的疟原虫的免疫力 寄生虫针对的是单一保护性抗原。将需要制定疫苗候选抗原 组合在一起，不会降低单个成分的免疫原性。我们之前的努力已经 重点关注血液期和性期疫苗靶点，其中抗体依赖机制 免疫是必不可少的，但中和B细胞表位的免疫原性并不是最理想的。在我们的 方法，我们设计了一种高度保守、高度免疫原性的恶性疟原虫特异载体蛋白。 在裂殖子表面蛋白8上，促进疫苗生产并诱导强大的CD4+T细胞帮助 产生中和抗体。我们证明了它作为恶性疟原虫血液期载体的有效性。 候选疫苗包括裂殖子表面蛋白1、裂殖子表面蛋白2、网织红细胞结合 蛋白同源物5和25 kDa的性期抗原。重要的是，中和抗体反应 靶向结构域在多抗原、多阶段制剂的背景下保持不变。A Pre- 我们的配方中目前缺少红细胞期疫苗成分。在这个项目中，我们将测试 PfMSP8是重组恶性疟原虫环子孢子表面有效载体蛋白的假设 基于蛋白质的疫苗，可诱导针对多个保护性B细胞表位的有效、持久的抗体反应(重复 和非重复结构域)中和子孢子。在目标1中，我们将表达和纯化四个重组 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 这些都是目前基于PfCSP的RTS、S疫苗所缺乏的。在目标2中，我们将确定震级和 GLA-SE重组PfCSP疫苗诱导T、B细胞应答的表位特异性 作为佐剂。在下选之后，我们将评估疫苗诱导的功能性和持久性， 用表达PfCSP的伯氏疟原虫转基因寄生虫攻击啮齿动物模型。 恶性疟原虫CSP。这一努力的成功将为随后的非临床试验提供基础 以确定rPfCSP*疫苗是否可以与现有的rPfMSP1/8结合使用， RPfMSP2/8、rPfRh5/8和rPfs25/8疫苗，不影响对个别成分的反应。