Structural Vaccinology and Design of Novel Imunogens for Malaria Vaccine Development

用于疟疾疫苗开发的结构疫苗学和新型免疫原设计

• 批准号: 10330551
• 负责人: Daniel E. Goldberg
• 金额: $ 71.36万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330551
• 关键词: Address; Anti-malarial drug resistance; Antibody Formation; Antigenic Variation; Antigens; B-Lymphocyte Epitopes; B-Lymphocytes; Biological Assay; Blood; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Culicidae; Data; Development; Disease; Economic Burden; Economic Development; Epitopes; Erythrocytes; Explosion; Foundations; Generations; Growth; Healthcare; Human; Immune response; Immunity; Immunization; In Vitro; Infection; Intervention; Knowledge; Lead; Life Cycle Stages; Ligands; Liver; Malaria; Malaria Vaccines; Methods; Mission; Modification; Monoclonal Antibodies; Motivation; Mus; Parasites; Parasitology; Persons; Plasmodium; Plasmodium falciparum; Play; Process; Public Health; Publishing; Reporting; Research; Role; Social Development; Sporozoites; Sterility; Structure; Surface Antigens; Symptoms; T-Lymphocyte; Technology; Testing; Therapeutic; United States; United States National Institutes of Health; Vaccine Design; Vaccines; Vertebral column; Work; acquired immunity; base; combinatorial; cost; design; flexibility; global health; health economics; human disease; human monoclonal antibodies; immunogenicity; improved; in vivo; innovation; insight; malaria infection; mouse model; multidisciplinary; neutralizing antibody; neutralizing monoclonal antibodies; next generation; novel; novel vaccines; response; scaffold; socioeconomics; technological innovation; transmission process; transmission-blocking vaccine; vaccine development; vaccinology

ABSTRACT: Malaria is a major global health problem for which a viable vaccine is desperately needed. The rationale for the proposed research is an effective vaccine for malaria will alleviate the health and socio-economic burden associated with the disease, especially in the face of growing antimalarial drug resistance. The central motivation for this proposal is that design of immunogens driven by insights from the structure-function analysis of antigens will result in a vertical leap in malaria vaccine development, and is now possible given the recent explosion in technology for structural vaccinology and the structural definition of neutralizing epitopes in key malaria antigens. Guided by strong preliminary data, this proposal will pursue three independent yet complementary specific aims: 1) Design pre-erythrocytic infection-blocking and transmission-blocking vaccines, 2) Develop immunogens to focus the immune responses to neutralizing epitopes in blood-stage parasites, and 3) Combinatorially design a multi-stage, cross-species protective immunogen. The first aim will focus on a unique multi-stage antigen that is conserved in Plasmodium spp. and is required for infection and transmission. The second aim examines two red-cell invasion ligands that are targets for neutralizing antibodies and required for blood-stage growth. The third aim proposes to combine immunogen designs to elicit neutralizing responses to multiple stages of the life cycle simultaneously. These aims will be achieved through structural vaccinology, immuno-parasitology, and therapeutic design of novel vaccines. This proposal is innovative because our integrated and complementary research team is well-suited to test novel concepts in vaccine design for malaria, and apply multi-disciplinary technological innovation to comprehensively design immunogens. The proposed research is significant because more than 200 million people every year suffer from malaria, leading to at least 500,000 deaths and an estimated $12 billion of healthcare-related costs. Between 1,500 and 2,000 cases of malaria occur each year in the United States alone and are reported to the CDC, with ~10% being severe and resulting in death. Prior vaccines for malaria have failed due to antigenic variability, targeting immunodominant but non-neutralizing epitopes of antigens, and focusing solely on a single stage of the life cycle. The proposed research is impactful because the iterative approach will: (1) focus the immune response to existing structurally-defined neutralizing epitopes in malaria antigens by creating epitope scaffold immunogens with flexible backbones, (2) use multiple structurally- defined neutralizing epitopes to provide a multi-pronged protective response, (3) assess neutralization for all stages of the malaria life cycle in established assays and mouse models, (4) utilize functional assays to guide and validate protective immunogenicity of epitope targets, and (5) use structure-based modification of antigens to improve immunogenicity and protection.

抽象的： 疟疾是全球主要的健康问题，迫切需要一种可行的疫苗。理由 拟议的研究是疟疾的有效疫苗，可以减轻健康和社会经济负担 与疾病有关，尤其是面对增长的抗疟疾耐药性。中心动机 对于该建议，是由抗原结构功能分析驱动的免疫原的设计 将导致疟疾疫苗发育的垂直飞跃，现在有可能 结构性疫苗学的技术和主要疟疾抗原中和表位的结构定义。 在强大的初步数据的指导下，该提案将追求三个独立但互补的特定目的： 1）设计前肉毒细胞感染阻滞和传播阻断疫苗，2）向 将免疫反应集中在血液阶段寄生虫中中和表位，3）组合设计 多阶段，跨物种保护性免疫原。第一个目标将重点放在独特的多阶段抗原上 在疟原虫中保守。并且是感染和传播所必需的。第二个目标检查两个 红细胞浸润配体是中和抗体的靶标，并且需要进行血液阶段生长。这 第三目的建议将免疫原设计结合起来，以引起对生活多个阶段的中和反应 同时循环。这些目标将通过结构性疫苗学，免疫传播学和 新型疫苗的治疗设计。该建议具有创新性，因为我们的综合和互补 研究团队非常适合测试疟疾疫苗设计中的新颖概念，并应用多学科 全面设计免疫原的技术创新。拟议的研究很重要，因为 每年有超过2亿人患疟疾，导致至少500,000人死亡，估计 120亿美元与医疗保健有关的费用。美国每年发生1,500至2,000例疟疾病例 单独的状态并报告给疾病预防控制中心，约有10％严重并导致死亡。先前的疫苗 疟疾由于抗原可变性而失败 抗原，仅专注于生命周期的单个阶段。拟议的研究具有影响力，因为 迭代方法将：（1）将免疫反应集中在现有的结构定义的中和表位上 疟疾抗原通过创建具有柔性骨架的表位支架免疫原子，（2）在结构上使用多个 定义的中和表位以提供多管齐下的保护反应，（3）评估所有人的中和 疟疾生命周期的阶段已建立的测定和鼠标模型，（4）利用功能测定指导 并验证表位目标的保护性免疫原性，（5）使用基于结构的抗原的修饰 改善免疫原性和保护。

项目成果

Blood-Stage Malaria Parasite Antigens: Structure, Function, and Vaccine Potential.

血期疟疾寄生虫抗原：结构、功能和疫苗潜力。

• DOI: 10.1016/j.jmb.2019.05.018
• 发表时间: 2019
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Salinas,NicholeD;Tang,WaiKwan;Tolia,NirajH
• 通讯作者: Tolia,NirajH

Progress towards the development of a P. vivax vaccine.

• DOI: 10.1080/14760584.2021.1880898
• 发表时间: 2021-03
• 期刊: Expert review of vaccines
• 影响因子: 6.2
• 作者: De SL;Ntumngia FB;Nicholas J;Adams JH
• 通讯作者: Adams JH

Implications of conformational flexibility, lipid binding, and regulatory domains in cell-traversal protein CelTOS for apicomplexan migration.

• DOI: 10.1016/j.jbc.2022.102241
• 发表时间: 2022-09
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Kumar, Hirdesh;Jimah, John R.;Misal, Santosh A.;Salinas, Nichole D.;Fried, Michal;Schlesinger, Paul H.;Tolia, Niraj H.
• 通讯作者: Tolia, Niraj H.