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

基本信息

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
项目类别：
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

项目摘要

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工作正在如果要进一步减少全球疟疾负担，就需要增加新的工具。有效疫苗的开发和引入具有成为此类工具的巨大潜力。然而，迄今为止，疟疾疫苗工作取得的成功有限。虽然存在一些挑战必须解决，两个关键问题反复出现。一、亚单位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、多阶段的疟原虫的免疫力寄生虫针对单一保护性抗原。需要配制疫苗候选抗原组合使用，不会降低单个成分的免疫原性。我们之前的努力已经专注于血液阶段和性阶段疫苗目标，其中抗体依赖性机制免疫是必不可少的，但中和 B 细胞表位的免疫原性尚未达到最佳。在我们的通过这种方法，我们设计了一种保守的、高度免疫原性的、基于恶性疟原虫特异性载体蛋白的裂殖子表面蛋白 8 促进疫苗生产并诱导有效的 CD4+ T 细胞帮助中和抗体的产生。我们展示了其作为恶性疟原虫血期载体的实用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 性阶段抗原。重要的是，中和抗体反应目标结构域保持在多抗原、多阶段制剂的背景下。一个预目前我们的配方中缺乏红细胞阶段疫苗成分。在这个项目中，我们将测试假设 PfMSP8 是重组恶性疟原虫环子孢子表面的有效载体蛋白基于蛋白质的疫苗，可引发针对多个保护性 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，我们将表达并纯化四种重组体基于 PfCSP 的疫苗旨在增加对相关表位的免疫反应的广度，其中一些目前基于 PfCSP 的 RTS,S 疫苗缺乏这些功能。在目标 2 中，我们将确定规模和由 GLA-SE 配制的每种基于 rPfCSP 的疫苗引发的 T 和 B 细胞反应的表位特异性作为佐剂。向下选择后，我们将评估疫苗诱导的功能和耐久性，啮齿动物攻击模型中的 PfCSP 特异性 IgG，其中转基因伯氏疟原虫表达伯氏疟原虫。恶性疟原虫 CSP。这项工作的成功将为后续非临床前测试奠定基础。人类灵长类动物以确定是否可以与现有的 rPfMSP1/8 组合配制 rPfCSP* 疫苗， rPfMSP2/8、rPfRh5/8 和 rPfs25/8 疫苗不会影响对单个成分的反应。