Structural Vaccinology and Design of Novel Imunogens for Malaria Vaccine Development

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。该计划的基本原理 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 与这种疾病有关，特别是在面对日益增长的抗疟疾药物耐药性的情况下。其核心动机 因为这个提议是由来自抗原结构-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垂直飞跃，鉴于最近 结构疫苗学技术和关键疟疾抗原中和表位的结构定义。 在强劲的初步数据指导下，这项建议将追求三个独立但相互补充的具体目标： 1)设计红细胞前感染阻断和传播阻断疫苗，2)开发免疫原以 将免疫反应集中在血液期寄生虫的中和表位，以及3)组合设计一种 多阶段、跨物种保护性免疫原。第一个目标将集中在一种独特的多级抗原上，即 在疟原虫中保守。是感染和传播所必需的。第二个目标是检查两个 红细胞侵入配体，是中和抗体的目标，是血液阶段生长所必需的。这个 第三个目标是结合免疫原设计，以引起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。这项建议是创新的，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概念，并应用多学科 技术创新，全面设计免疫原。这项拟议的研究具有重要意义，因为 每年有2亿多人罹患疟疾，导致至少50万人死亡，据估计 120亿美元的医疗保健相关成本。美国每年发生1500至2000例疟疾病例 仅在各州，并向疾控中心报告，约10%的病例病情严重，并导致死亡。以前的疫苗 疟疾由于抗原可变性而失败，目标是免疫主导但非中和的表位 抗原，并且只专注于生命周期的一个阶段。拟议的研究之所以有影响力，是因为 迭代方法将：(1)集中对现有结构定义的中和表位的免疫反应 疟疾抗原通过创建具有柔性骨架的表位支架免疫原，(2)在结构上使用多个 确定中和表位以提供多管齐下的保护性反应，(3)评估所有 已建立的分析方法和小鼠模型中疟疾生命周期的各个阶段，(4)利用功能分析方法指导 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 提高免疫原性和保护性。

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.