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： 疟疾是一个重大的全球健康问题，迫切需要一种可行的疫苗。理由如下： 拟议的研究是一种有效的疟疾疫苗，将减轻健康和社会经济负担 与疾病相关，特别是面对日益增长的抗疟药物耐药性。中心动机 该提案的目的是根据抗原结构功能分析的见解驱动免疫原的设计 将导致疟疾疫苗开发的垂直飞跃，鉴于最近疟疾疫苗的爆炸性增长，现在这是可能的 结构疫苗学技术和关键疟疾抗原中和表位的结构定义。 在强有力的初步数据的指导下，该提案将追求三个独立但互补的具体目标： 1) 设计红细胞前感染阻断和传播阻断疫苗，2) 开发免疫原 将免疫反应集中于血液阶段寄生虫的中和表位，以及 3) 组合设计 多阶段、跨物种保护性免疫原。第一个目标将集中于一种独特的多阶段抗原，即 保存在疟原虫属中。并且是感染和传播所必需的。第二个目标检查两个 红细胞侵袭配体是中和抗体的靶标并且是血液阶段生长所需的。这 第三个目标建议结合免疫原设计来引发对生命多个阶段的中和反应 同时循环。这些目标将通过结构疫苗学、免疫寄生虫学和 新型疫苗的治疗设计。这个提议是创新的，因为我们的综合性和互补性 研究团队非常适合测试疟疾疫苗设计中的新概念，并应用多学科 技术创新，全面设计免疫原。拟议的研究意义重大，因为 每年有超过 2 亿人患有疟疾，导致至少 50 万人死亡，估计 120 亿美元的医疗保健相关成本。美国每年发生 1,500 至 2,000 例疟疾病例 仅各州并向 CDC 报告，约 10% 的情况严重并导致死亡。之前接种过的疫苗 疟疾由于抗原变异性而失败，针对免疫显性但非中和性表位 抗原，并仅关注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）将免疫反应集中于现有结构定义的中和表位 通过创建具有柔性骨架的表位支架免疫原来制备疟疾抗原，（2）使用多种结构- 定义中和表位以提供多管齐下的保护反应，（3）评估所有中和作用 在已建立的测定和小鼠模型中确定疟疾生命周期的各个阶段，(4) 利用功能测定来指导 并验证表位靶标的保护性免疫原性，以及 (5) 使用基于结构的抗原修饰 以提高免疫原性和保护作用。

项目成果

Progress towards the development of a P. vivax vaccine.

间日疟原虫疫苗的开发取得进展。

• 发表时间: 2021
• 作者: De, Sai Lata;Ntumngia, Francis B;Nicholas, Justin;Adams, John H
• 通讯作者: Adams, John H

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

细胞穿越蛋白 CelTOS 中的构象灵活性、脂质结合和调节域对 apicomplexan 迁移的影响。

• 发表时间: 2022-09
• 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

Getting in: The structural biology of malaria invasion.

进入：疟疾入侵的结构生物学。

• 发表时间: 2019
• 影响因子: 6.7
• 作者: Kumar, Hirdesh;Tolia, Niraj H
• 通讯作者: Tolia, Niraj H

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。

• 发表时间: 2019
• 影响因子: 5.6
• 作者: Salinas, Nichole D;Tang, Wai Kwan;Tolia, Niraj H
• 通讯作者: Tolia, Niraj H

Structural basis for neutralization of Plasmodium vivax by naturally acquired human antibodies that target DBP.

通过自然获得的针对 DBP 的人类抗体中和间日疟原虫的结构基础。

• 发表时间: 2019-09
• 影响因子: 28.3
• 作者: Urusova, Darya;Carias, Lenore;Huang, Yining;Nicolete, Vanessa C;Popovici, Jean;Roesch, Camille;Salinas, Nichole D;Dechavanne, Sebastien;Witkowski, Benoit;Ferreira, Marcelo U;Adams, John H;Gross, Michael L;King, Christopher L;Tolia, Niraj H
• 通讯作者: Tolia, Niraj H