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
基本信息
- 批准号:10330551
- 负责人:
- 金额:$ 71.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAnti-malarial drug resistanceAntibody FormationAntigenic VariationAntigensB-Lymphocyte EpitopesB-LymphocytesBiological AssayBloodCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeClinicalCulicidaeDataDevelopmentDiseaseEconomic BurdenEconomic DevelopmentEpitopesErythrocytesExplosionFoundationsGenerationsGrowthHealthcareHumanImmune responseImmunityImmunizationIn VitroInfectionInterventionKnowledgeLeadLife Cycle StagesLigandsLiverMalariaMalaria VaccinesMethodsMissionModificationMonoclonal AntibodiesMotivationMusParasitesParasitologyPersonsPlasmodiumPlasmodium falciparumPlayProcessPublic HealthPublishingReportingResearchRoleSocial DevelopmentSporozoitesSterilityStructureSurface AntigensSymptomsT-LymphocyteTechnologyTestingTherapeuticUnited StatesUnited States National Institutes of HealthVaccine DesignVaccinesVertebral columnWorkacquired immunitybasecombinatorialcostdesignflexibilityglobal healthhealth economicshuman diseasehuman monoclonal antibodiesimmunogenicityimprovedin vivoinnovationinsightmalaria infectionmouse modelmultidisciplinaryneutralizing antibodyneutralizing monoclonal antibodiesnext generationnovelnovel vaccinesresponsescaffoldsocioeconomicstechnological innovationtransmission processtransmission-blocking vaccinevaccine developmentvaccinology
项目摘要
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
疟疾生命周期的各个阶段,(4)利用功能性测定来指导
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
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
- 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:
- 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:
- 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.
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Daniel E. Goldberg其他文献
Characterization of Membrane Contact Sites for the Facilitation of Lipid Exchange at the Malaria Parasite - Red Blood Cell Interface
- DOI:
10.1016/j.bpj.2019.11.3119 - 发表时间:
2020-02-07 - 期刊:
- 影响因子:
- 作者:
Matthias Garten;Josh Beck;Robyn Roth;John E. Heuser;Tatyana Tenkova-Heuser;Christopher K.E. Bleck;Daniel E. Goldberg;Joshua Zimmerberg - 通讯作者:
Joshua Zimmerberg
The structure of Ascaris hemoglobin domain I at 2.2 A resolution: molecular features of oxygen avidity.
2.2 A 分辨率下蛔虫血红蛋白结构域 I 的结构:氧亲合力的分子特征。
- DOI:
- 发表时间:
1995 - 期刊:
- 影响因子:11.1
- 作者:
Jian Yang;A. P. Kloek;Daniel E. Goldberg;F. Mathews - 通讯作者:
F. Mathews
When the Host Is Smarter Than the Parasite
当宿主比寄生虫更聪明时
- DOI:
- 发表时间:
2002 - 期刊:
- 影响因子:56.9
- 作者:
Daniel E. Goldberg - 通讯作者:
Daniel E. Goldberg
Malaria parasites require a divergent heme oxygenase for apicoplast gene expression and biogenesis
疟疾寄生虫需要不同的血红素加氧酶来进行顶质体基因表达和生物合成
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Amanda Mixon Blackwell;Y. Jami;Armiyaw S. Nasamu;S. Kudo;A. Senoo;Celine Slam;Kouhei Tsumoto;James A. Wohlschlegel;J. Caaveiro;Daniel E. Goldberg;P. Sigala - 通讯作者:
P. Sigala
ColE1 hybrid plasmids for Escherichia coli genes of glycolysis and the hexose monophosphate shunt
用于大肠杆菌糖酵解和己糖单磷酸分流基因的 ColE1 杂交质粒
- DOI:
10.1128/jb.137.1.502-506.1979 - 发表时间:
1979 - 期刊:
- 影响因子:3.2
- 作者:
Jennifer Thomson;T. P. D. Gerstenberger;Daniel E. Goldberg;Eva Gociar;Arminda Orozco DE Silva;D. Fraenkel - 通讯作者:
D. Fraenkel
Daniel E. Goldberg的其他文献
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{{ truncateString('Daniel E. Goldberg', 18)}}的其他基金
Specificity of Plasmodium falciparum protein export
恶性疟原虫蛋白输出的特异性
- 批准号:
10632093 - 财政年份:2022
- 资助金额:
$ 71.36万 - 项目类别:
Defining the resistome in P. falciparum: evolution and mechanism
恶性疟原虫抗性组的定义:进化和机制
- 批准号:
10608899 - 财政年份:2022
- 资助金额:
$ 71.36万 - 项目类别:
Specificity of Plasmodium falciparum protein export
恶性疟原虫蛋白输出的特异性
- 批准号:
10508060 - 财政年份:2022
- 资助金额:
$ 71.36万 - 项目类别:
Plasmepsin X function in Plasmodium
Plasmodium 中 Plasmepsin X 的功能
- 批准号:
10322714 - 财政年份:2018
- 资助金额:
$ 71.36万 - 项目类别:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
胃酶抑素酯抗疟靶点的鉴定
- 批准号:
8734676 - 财政年份:2014
- 资助金额:
$ 71.36万 - 项目类别:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
PFHO-1 在恶性疟原虫红细胞内发育中的作用
- 批准号:
8802857 - 财政年份:2014
- 资助金额:
$ 71.36万 - 项目类别:
ROLE OF PFHO-1 IN P. FALCIPARUM INTRAERYTHROCYTIC DEVELOPMENT
PFHO-1 在恶性疟原虫红细胞内发育中的作用
- 批准号:
8662416 - 财政年份:2014
- 资助金额:
$ 71.36万 - 项目类别:
IDENTIFICATION OF THE ANTIMALARIAL TARGET OF PEPSTATIN ESTERS
胃酶抑素酯抗疟靶点的鉴定
- 批准号:
8852545 - 财政年份:2014
- 资助金额:
$ 71.36万 - 项目类别:
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