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.
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
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
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
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.这
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.
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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