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

• 批准号: 10183147
• 负责人: JAMES B. DALE
• 金额: $ 72.93万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10183147
• 关键词: Animals; Antibodies; Bacteria; Base Sequence; Binding; Biological Assay; Cell surface; Cells; Cessation of life; Chronic; Collection; Complement Factor H; Complementarity Determining Regions; Complication; Computer Analysis; Data; Development; Disease; Ensure; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epitopes; Frequencies; Goals; Health; Human; Immune; Immune Sera; Immunity; Immunize; Immunologics; In Vitro; Infection; Life; Link; Machine Learning; Modeling; Mus; N-terminal; Natural Immunity; Organism; Oryctolagus cuniculus; Peptide Vaccines; Peptide antibodies; Peptides; Population; Prevention; Process; Property; Proteins; Recombinant Vaccines; Recombinants; Rheumatic Heart Disease; Sequence Analysis; Streptococcal Infections; Streptococcal Vaccines; Streptococcus pyogenes; Structure; Surface; System; Testing; Transgenic Mice; Vaccine Antigen; Vaccine Design; Vaccines; bactericide; base; cross reactivity; design; experimental study; flexibility; hybrid protein; immunogenic; immunogenicity; innovation; molecular dynamics; multiple myeloma M Protein; novel; novel strategies; peptide structure; preclinical study; prevent; protein aminoacid sequence; protein structure; retinal S antigen peptide M; synthetic peptide; tool; vaccination outcome; vaccine development; vaccine evaluation

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的蛋白质是调理的，并且与抗感染的保护有关。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

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: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 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: Vaccine
• 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: The Journal of infectious diseases
• 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: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Aranha MP;Penfound TA;Salehi S;Botteaux A;Smeesters P;Dale JB;Smith JC
• 通讯作者: Smith JC