Structure-Based Design of a Broadly Protective Group A Streptococcal Vaccine
基于结构的广泛保护群 A 链球菌疫苗的设计
基本信息
- 批准号:10183147
- 负责人:
- 金额:$ 72.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-08 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsAntibodiesBacteriaBase SequenceBindingBiological AssayCell surfaceCellsCessation of lifeChronicCollectionComplement Factor HComplementarity Determining RegionsComplicationComputer AnalysisDataDevelopmentDiseaseEnsureEnzyme-Linked Immunosorbent AssayEpidemiologyEpitopesFrequenciesGoalsHealthHumanImmuneImmune SeraImmunityImmunizeImmunologicsIn VitroInfectionLifeLinkMachine LearningModelingMusN-terminalNatural ImmunityOrganismOryctolagus cuniculusPeptide VaccinesPeptide antibodiesPeptidesPopulationPreventionProcessPropertyProteinsRecombinant VaccinesRecombinantsRheumatic Heart DiseaseSequence AnalysisStreptococcal InfectionsStreptococcal VaccinesStreptococcus pyogenesStructureSurfaceSystemTestingTransgenic MiceVaccine AntigenVaccine DesignVaccinesbactericidebasecross reactivitydesignexperimental studyflexibilityhybrid proteinimmunogenicimmunogenicityinnovationmolecular dynamicsmultiple myeloma M Proteinnovelnovel strategiespeptide structurepreclinical studypreventprotein aminoacid sequenceprotein structureretinal S antigen peptide Msynthetic peptidetoolvaccination outcomevaccine developmentvaccine evaluation
项目摘要
The overall goal of this project is to develop a safe, broadly effective, and affordable vaccine to prevent group
A streptococcal infections. Antibodies against the N-terminal hypervariable region (HVR) of surface M (Emm)
proteins of GAS are opsonic and are associated with protection against infection. Immunity has classically
been described as “type-specific”, leading to the assumption that natural immunity confers protection against
only one of the more than 200 different emm types of GAS. We now have new information that calls into
question this classic view and serves as the basis for an entirely different approach to GAS vaccine design and
development. A recent comprehensive sequence analysis of M proteins from a global collection of 175 emm
types of GAS resulted in a new emm cluster typing system that classified 96.2% of all contemporary GAS
isolates into 48 emm clusters containing structurally and functionally related M proteins. Moreover, 117 emm
types contained in 16 clusters accounted for 94.4% of GAS infections in the world. Indeed, preclinical studies
indicated that a multivalent vaccine containing N-terminal peptides from 30 prevalent M types cross-opsonized
a significant number of non-vaccine emm types of GAS that co-localized in clusters with vaccine emm types.
The frequency of cross-opsonic antibodies, combined with the emm cluster data, prompted us to conclude that
there is a need for a paradigm shift away from the concept of “type-specific” immunity against GAS infections
to one of “cluster-specific” immunity. Our overall hypothesis is that immunity to GAS infections is the result of
both type-specific and cross-reactive antibodies against the N-terminal regions of M proteins and that a new
approach employing computational predictions of peptide structures will result in a multivalent vaccine that will
induce broadly protective immunity in populations throughout the world. Our preliminary results indicate the
feasibility of using structure-based design to predict the antigenic relatedness of M peptides within a cluster.
The specific aims of this proposal are to: 1) Apply computational structure-based design in an iterative process
with immunological data from Aim 2 to predict the minimal number of M peptide sequences that are most
representative of the structural and physicochemical properties of the peptides in one emm cluster containing
17 GAS emm types, 2) determine the cross-reactive immunogenicity of the selected peptides with all
seventeen emm types of GAS in the cluster, and apply the results to refine the computational design
predictions in Aim 1, 3) apply the refined computational parameters from Aims 1 and 2 to analyze the
remaining epidemiologically important emm clusters, select a comprehensive panel of peptides representing all
emm types, construct four multivalent recombinant vaccine proteins, and assess potential cross-protective
immunogenicity using in vitro bactericidal assays against all 117 emm types of GAS, and 4) determine the
protective immunogenicity of the final multivalent vaccine in unique transgenic mice expressing human C4BP
and factor H that will be immunized and then challenged with multiple emm types of GAS.
该项目的总体目标是开发一种安全、广泛有效和负担得起的疫苗,
链球菌感染。针对表面M(Emm)的N-末端高变区(HVR)的抗体
GAS的蛋白质具有调理作用,与预防感染有关。经典的免疫力
被描述为“类型特异性”,导致天然免疫赋予保护免受
仅是200多种不同的EMM类型的GAS中的一种。我们现在有了新的信息,
质疑这一经典观点,并作为一种完全不同的GAS疫苗设计方法的基础,
发展全球175个emm中M蛋白的最新综合序列分析
GAS类型导致了一种新的EMM聚类分型系统,该系统对所有当代GAS的96.2%进行了分类
分离物分成48个emm簇,包含结构和功能相关的M蛋白。此外,117 emm
16个聚集群所含的GAS型别占全球GAS感染的94.4%。实际上,临床前研究
表明含有来自30种流行M型的N-末端肽的多价疫苗交叉调理
大量非疫苗emm类型的GAS与疫苗emm类型共定位成簇。
交叉调理素抗体的频率,结合emm聚类数据,促使我们得出结论,
需要从针对GAS感染的“类型特异性”免疫的概念转变为
一种是“集群特异性”免疫。我们的总体假设是,对GAS感染的免疫是以下因素的结果:
针对M蛋白N-末端区域的类型特异性和交叉反应性抗体,
采用肽结构的计算预测的方法将产生多价疫苗,
在全世界人群中诱导广泛的保护性免疫。我们的初步结果表明,
使用基于结构的设计来预测簇内M肽的抗原相关性的可行性。
该建议的具体目标是:1)在迭代过程中应用基于计算结构的设计
用来自Aim 2的免疫学数据预测最多的M肽序列的最小数目,
代表一个EMM簇中肽的结构和物理化学性质,
17种GAS emm类型,2)确定所选肽与所有GAS emm类型的交叉反应性免疫原性,
集群中的十七种emm类型的GAS,并将结果应用于改进计算设计
目标1和目标3中的预测)应用目标1和目标2中的精确计算参数来分析
剩余的流行病学上重要的EMM簇,选择代表所有
emm类型,构建四种多价重组疫苗蛋白,并评估潜在的交叉保护性
使用针对所有117种emm类型的GAS的体外杀菌测定的免疫原性,和4)确定
最终多价疫苗在表达人C4 BP的独特转基因小鼠中的保护性免疫原性
以及将被免疫然后用多种emm类型的GAS攻击的因子H。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Immune Cross-Opsonization Within emm Clusters Following Group A Streptococcus Skin Infection: Broadening the Scope of Type-Specific Immunity.
- DOI:10.1093/cid/cix599
- 发表时间:2017-10-16
- 期刊:
- 影响因子:0
- 作者:Frost HR;Laho D;Sanderson-Smith ML;Licciardi P;Donath S;Curtis N;Kado J;Dale JB;Steer AC;Smeesters PR
- 通讯作者:Smeesters PR
Cross-reactive immunogenicity of group A streptococcal vaccines designed using a recurrent neural network to identify conserved M protein linear epitopes.
- DOI:10.1016/j.vaccine.2021.01.075
- 发表时间:2021-03-19
- 期刊:
- 影响因子:5.5
- 作者:Spencer JA;Penfound T;Salehi S;Aranha MP;Wade LE;Agarwal R;Smith JC;Dale JB;Baudry J
- 通讯作者:Baudry J
Caution Indicated in Extrapolating Carditis in Rats to Rheumatic Heart Disease in Humans.
将大鼠心脏炎外推至人类风湿性心脏病时应注意的事项。
- DOI:10.1093/infdis/jiy560
- 发表时间:2019
- 期刊:
- 影响因子:0
- 作者:Dale,JamesB;Shulman,StanfordT
- 通讯作者:Shulman,StanfordT
Design of Broadly Cross-Reactive M Protein-Based Group A Streptococcal Vaccines.
- DOI:10.4049/jimmunol.2100286
- 发表时间:2021-08-15
- 期刊:
- 影响因子:0
- 作者:Aranha MP;Penfound TA;Salehi S;Botteaux A;Smeesters P;Dale JB;Smith JC
- 通讯作者:Smith JC
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JAMES B. DALE其他文献
JAMES B. DALE的其他文献
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{{ truncateString('JAMES B. DALE', 18)}}的其他基金
Group A Streptococcal Vaccine Containing Immunogenic Peptides of Streptolysin S
含有链球菌溶血素S免疫原性肽的A组链球菌疫苗
- 批准号:
9044727 - 财政年份:2015
- 资助金额:
$ 72.93万 - 项目类别:
Chemistry and Immunology of Streptococcal M Proteins
链球菌 M 蛋白的化学和免疫学
- 批准号:
8128102 - 财政年份:2010
- 资助金额:
$ 72.93万 - 项目类别:
17th Lancefield International Symposium on Streptococci and Streptococcal Disease
第十七届兰斯菲尔德国际链球菌和链球菌疾病研讨会
- 批准号:
7483861 - 财政年份:2008
- 资助金额:
$ 72.93万 - 项目类别:
Vaccine Prevention of Group A Streptococcal Infections
A 组链球菌感染的疫苗预防
- 批准号:
8232727 - 财政年份:1996
- 资助金额:
$ 72.93万 - 项目类别:
Chemistry and Immunology of Streptococcal M Proteins
链球菌 M 蛋白的化学和免疫学
- 批准号:
7625116 - 财政年份:1996
- 资助金额:
$ 72.93万 - 项目类别:
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