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.

抽象的 鉴于许多发展中国家的伯宁疟疾非常高，并且继续需要 有效的疫苗，该提案的目的是通过服用恶性疟原虫（PF）疫苗 在过去几年中获得的知识的优势隔离和表征受保护的人 寄生虫蛋白（CS）蛋白的主要外套蛋白特异性抗体。这 目前在诊所，RTS，S和R21中最先进的疟疾疫苗候选者仅针对主要NANP C末端结构域中PFCS蛋白和T细胞表位的重复。 RTS的当前局限 疫苗一直是30-50％的效率和瞬态保护。进一步的潜在并发症是预先存在的 对HBSAG载体的免疫/耐受性，该载体源自人类病原体。绕过这些 我们开发了非人类病原体衍生的载体平台的问题，特别是核心蛋白 来自Woodchuck Hepadnavirus（WHCAG）。修改后的WHCAG VLP用作疫苗平台 几个原因：WHC-CS杂交VLP引起极高的抗CS保护抗体；新的 可以简单地添加保护性表位；并且由于可以在细菌中制成WHC-CS混合VLP，因此疫苗 良好成本将低。在初步研究中，我们开发了一个WHC-CS混合VLP，其中包含两个 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。这个WHC-CS 混合VLP（指定的VLP-162）在小鼠中非常免疫原性，兔子和引起中和抗CS 重复防止贝尔格（P. berghei）/PF混合孢子虫肝感染体内并产生无菌的抗体 在90-100％的小鼠中对血液阶段感染的免疫力。我们的方法是扩大范围和保护性 VLP-162的功效通过添加由受保护的人mabs cis43，313/317，L9和 5D5，加上VLP传递的CS特异性T细胞表位。开发最佳的策略 下一代疟疾疫苗分为3个目的：目标1）建立在VLP-162上，并通过新近的成立 定义的CS衍生的受保护的B细胞表位并扩大了CS特异性T细胞表位的数量；目的 2）通过评估多种小鼠菌株中的调整公式来优化免疫原性；目标3）行为 使用包含PBPF混合孢子虫的PF小鼠挑战模型中的体内保护效率测试 整个PF CS或工程PF CS蛋白，使我们能够测量每个表位对 保护效率。这两种技术的组合，WHCAG平台和PBPF混合动力车 Sporozoite挑战模型将允许在感染模型中确定体内受保护的效率 系统。