Epitope-Based CSP Vaccines Optimized to Achieve Long-Term Sterile Immunity

经过优化的基于表位的 CSP 疫苗可实现长期无菌免疫

• 批准号: 10637778
• 负责人: David R. Milich
• 金额: $ 71万
• 依托单位: VACCINE RESEARCH INSTITUTE OF SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637778
• 关键词: Active Immunization; Adjuvant; Affinity; Anopheles Genus; Antibodies; Antigens; B-Lymphocyte Epitopes; B-Lymphocytes; Bacteria; Binding; Biological Models; Blood; C-terminal; CD4 Positive T Lymphocytes; Capsid Proteins; Carrier Proteins; Cessation of life; Clinic; Clinical; Complication; Contracts; Core Protein; Developing Countries; Development; Disease; Dose; Engineering; Epitopes; Formulation; Generations; Hepadnaviridae; Hepatitis; Hepatitis B Surface Antigens; Housing; Human; Hybrids; Immune Sera; Immunity; Immunize; Immunoglobulin G; Immunologics; In Vitro; Individual; Infection; Insecticide Resistance; Knock-in; Knock-out; Knowledge; Laboratory Animals; Length; Malaria; Malaria Vaccines; Measures; Minor; Modeling; Monitor; Mouse Strains; Multi-Drug Resistance; Mus; Nature; Oryctolagus cuniculus; Parasites; Parasitic Diseases; Plasmodium falciparum; Plasmodium falciparum vaccine; Preventive vaccine; Production; Proteins; Recombinants; Selection Criteria; Site; Specificity; Sporozoites; Sterility; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Universities; Vaccines; Virus-like particle; Woodchuck; animal care; circumsporozoite; circumsporozoite protein; cost; design; efficacy testing; human monoclonal antibodies; human pathogen; immunogenic; immunogenicity; in vivo; liver infection; next generation; pathogen; prevent; protective efficacy; screening; sex; timeline; vaccine candidate; vaccine efficacy; vaccine evaluation; vaccine platform; vector mosquito

Abstract Given the very high burden malaria imposes on many developing countries and the continued need for an effective vaccine, the objective of this proposal is to develop a Plasmodium falciparum (Pf) vaccine by taking advantage of the knowledge gained in the last few years isolating and characterizing protective human monoclonal antibodies specific for major coat protein of the parasite, circumsporozoite (CS) protein. The malaria vaccine candidates currently most advanced in the clinic, RTS,S and R21, target only the major NANP repeat of the PfCS protein plus T cell epitopes in the C-terminal domain. Current limitations of the RTS,S vaccine have been the 30-50% efficacy and transient protection. A further potential complication is pre-existing immunity/tolerance to the HBsAg carrier, which is derived from a human pathogen. To circumvent these problems we have developed a non-human pathogen-derived carrier platform, specifically the core protein from the woodchuck hepadnavirus (WHcAg). Modified WHcAg VLPs are used as the vaccine platform for several reasons: WHc-CS hybrid VLPs elicit extremely high levels of anti-CS protective antibodies; new protective epitopes can be added simply; and since WHc-CS hybrid VLPs can be made in bacteria, the vaccine will have a low cost-of-goods. In preliminary studies we developed a WHc-CS hybrid VLP that contains two neutralizing Pf-CS repeat B cell epitopes and three “universal” malaria-specific T cell domains. This WHc-CS hybrid VLP (designated VLP-162) is very immunogenic in mice and rabbits and elicits neutralizing anti-CS repeat antibodies that prevent P. berghei/Pf hybrid sporozoite liver infection in vivo and produces sterile immunity to blood stage infection in 90-100% of mice. Our approach is to expand the scope and protective efficacy of VLP-162 by adding B cell epitopes defined by the protective human Mabs CIS43, 313/317, L9 and 5D5, plus expand the CS-specific T cell epitopes delivered by the VLP. The strategy for developing an optimal next-generation malaria vaccine is divided into 3 aims: Aim 1) build on VLP-162 by incorporation of the newly defined CS-derived protective B cell epitopes and broadening the number of CS-specific T cell epitopes; Aim 2) optimize immunogenicity by assessing adjuvant formulations in multiple mouse strains; and Aim 3) conduct in vivo protective efficacy tests in Pf mouse challenge models using PbPf hybrid sporozoites that contain the entire Pf CS or engineered Pf CS proteins that allow us to measure the contribution of each epitope to protective efficacy. Combination of these two technologies, the WHcAg platform and the PbPf hybrid sporozoite challenge models, will allow in vivo protective efficacy to be determined in infectious model systems.

摘要 鉴于疟疾给许多发展中国家带来的沉重负担， 有效的疫苗，这项建议的目的是开发一种恶性疟原虫（Pf）疫苗， 利用过去几年中获得的知识， 对寄生虫的主要外壳蛋白，环子孢子（CS）蛋白具有特异性的单克隆抗体。的 目前临床上最先进的疟疾候选疫苗RTS、S和R21只针对主要的NANP PfCS蛋白的重复加上C端结构域中的T细胞表位。RTS，S的当前限制 疫苗有30-50%的效力和短暂的保护。另一个潜在的并发症是预先存在的 - 对HBsAg携带者的免疫力/耐受性，所述HBsAg携带者来源于人类病原体。为了规避这些 我们已经开发了一种非人类病原体衍生的载体平台，特别是核心蛋白， 土拨鼠嗜肝DNA病毒（woodchuck hepadnavirus，WHcAg）修饰的WHcAg VLP用作疫苗平台， 几个原因：WHc-CS杂交VLP引起极高水平的抗CS保护性抗体;新的 可以简单地添加保护性表位;并且由于WHc-CS杂合VLP可以在细菌中制备， 将有一个低成本的商品。在初步研究中，我们开发了一种WHc-CS混合VLP， 中和Pf-CS重复B细胞表位和三个“通用”疟疾特异性T细胞结构域。这种WHc-CS 杂合VLP（命名为VLP-162）在小鼠和兔中具有很强的免疫原性， 在体内预防伯氏疟原虫/Pf杂合子子孢子肝感染并产生无菌的重复抗体 90-100%小鼠对血液阶段感染的免疫力。我们的做法是扩大保护范围， 通过添加由保护性人单克隆抗体CIS 43、313/317、L9和 5D 5，加上扩增由VLP递送的CS特异性T细胞表位。制定最佳战略 下一代疟疾疫苗分为3个目标：目标1）在VLP-162基础上， 确定CS衍生的保护性B细胞表位，并扩大CS特异性T细胞表位的数量;目的 2)通过在多种小鼠品系中评估佐剂制剂来优化免疫原性;以及 在Pf小鼠攻击模型中使用含有以下的PbPf杂交子孢子的体内保护效力测试： 完整的Pf CS或工程化的Pf CS蛋白，使我们能够测量每个表位对 保护功效WHcAg平台和PbPf Hybrid这两种技术的组合 子孢子攻击模型将允许在感染模型中确定体内保护效力 系统.