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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：
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
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：
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

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来预防艾滋病

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：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
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：
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。