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.

摘要： 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。的理由 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 特别是在抗疟药物耐药性日益增强的情况下。核心动机 因为这个建议是由抗原的结构-功能分析的洞察力驱动的免疫原的设计 将导致疟疾疫苗开发的纵向飞跃，鉴于最近疟疾疫苗的激增， 结构疫苗学技术和关键疟疾抗原中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， 将免疫反应集中在血液期寄生虫的中和表位上，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在一个独特的多阶段抗原， 在疟原虫属（Plasmodium spp.）并且是感染和传播所必需的。第二个目标是考察两个 红细胞侵入配体，是中和抗体的目标，是血液阶段生长所需的。的 第三个目标提出了联合收割机免疫原设计，以引发对生命多个阶段的中和反应 循环同时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。这项建议是创新的，因为我们的综合和互补性 研究团队非常适合测试疟疾疫苗设计的新概念，并应用多学科 全面设计免疫原的技术创新。这项研究意义重大，因为 每年有2亿多人患疟疾，导致至少50万人死亡， 120亿美元的医疗保健相关费用。在美国，每年发生1,500至2,000例疟疾病例。 仅在美国，并报告给CDC，约10%是严重的，并导致死亡。既往疫苗 由于抗原变异性，靶向免疫显性但非中和表位， 抗原，只关注生命周期的一个阶段。这项研究是有影响力的，因为 迭代方法将：（1）将免疫应答集中于现有的结构上确定的中和表位， 疟疾抗原通过产生具有柔性骨架的表位支架免疫原，（2）使用多个结构- 确定的中和表位，以提供多管齐下的保护性应答，（3）评估所有 在已建立的测定和小鼠模型中，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性。

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.