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
• 负责人: JAMES B. DALE
• 金额: $ 18.9万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-02 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9044727
• 关键词: Acute; Affinity; Amino Acids; Animal Model; Antibodies; Antibody Repertoire; Antigens; Biological Assay; Cessation of life; Chronic; Clinical; Clinical Trials; Codon Nucleotides; Complex; Complication; Conserved Sequence; Country; Coupled; Cytolysis; Data; Development; Disease; Enzyme-Linked Immunosorbent Assay; Epidemiology; Epithelial; Epitopes; Escherichia coli; Genes; Goals; Health; Hybrids; Immune Sera; Immunity; Immunization; In Vitro; Infection; Iron; Keyhole Limpet Hemocyanin; Life; Link; Mediating; Messenger RNA; Modeling; Molecular Structure; Mus; N-terminal; Nickel; North America; Operon; Organism; Oryctolagus cuniculus; Pathogenesis; Peptide antibodies; Peptides; Phagocytes; Phagocytosis; Play; Prevention; Production; Proteins; Recombinant Proteins; Recombinants; Research Personnel; Resources; Rheumatic Fever; Rheumatic Heart Disease; Role; Serotyping; Streptococcal Infections; Streptococcal Vaccines; Streptolysins; Structure; Testing; Toxic effect; Toxin; Vaccine Antigen; Vaccines; Virulence; Western Europe; aluminum sulfate; bactericide; base; design; expression vector; hybrid protein; immunogenic; immunogenicity; intraperitoneal; low and middle-income countries; mouse model; multiple myeloma M Protein; neutralizing antibody; prevent; protective efficacy; recombinant peptide; research study; retinal S antigen peptide M; sensor; soft tissue; synthetic peptide; vaccine efficacy

 DESCRIPTION (provided by applicant): The overall goal of goal of this project is to determine the protective immunogenicity of a non-toxic peptide of group A streptococcal streptolysin S (SLS) and to assess its potential to enhance the efficacy of vaccines containing M and M-related proteins (Mrp). SLS is a virulence determinant of GAS that has not previously been considered as a vaccine component because the toxin is not immunogenic following GAS infection. SLS is expressed by 99% of all GAS and there is considerable evidence supporting its prominent role in the pathogenesis of GAS infections. SLS contributes to virulence of GAS by causing soft tissue damage, lysing phagocytes, mediating translocation of the organism across epithelial boundaries, facilitating iron acquisition through lysis of RBCs, acting as a quorum sensor that upregulates itself, and potentially functioning as a global regulator of other virulenc genes via untranslated mRNA. The active toxin is a 30-amino acid heterocyclic peptide that is the product of the nine-gene Sag operon. We have previously shown that a non-toxic synthetic peptide copying amino acid residues 10-30 of the SLS propeptide coupled to KLH evoked antibodies in rabbits that completely neutralized the activity of the toxin in vitro. The SLS antibodies were non-opsonic but when combined with M protein antisera, the SLS antibodies significantly enhanced phagocytosis of GAS that was mediated by M antibodies. SLS peptides have not previously been assessed for protective immunogenicity in animal models of infection. Our hypothesis is that the addition of an immunogenic peptide of SLS to M protein and Mrp-based GAS vaccines will enhance their overall efficacy by neutralizing the cytolytic toxicity of SLS, thus resulting in decreased bacterial virulence coupled with more effective antibody-mediated clearance of the organism. The aims of this proposal are: 1) To construct recombinant multivalent hybrid proteins containing N- terminal M and Mrp peptides with and without SLS peptides and to assay immune sera against both vaccine proteins for in vitro bactericidal activity against selected serotypes of GAS, and 2) To compare the protective immunogenicity of hybrid vaccine proteins containing the SLS peptide to those without the SLS peptide in mouse models of GAS infections. Of the shared virulence determinants that are considered "universal" GAS vaccine antigens, we hypothesize that an immunogenic peptide of SLS that evokes neutralizing antibodies has the greatest potential to impact overall vaccine efficacy by thwarting one of the prominent stealth tactics involved in streptococcal pathogenesis.

 描述（由适用提供）：该项目目标的总体目标是确定A组链球菌链霉菌素S（SLS）的无毒肽的受保护的免疫原性，并评估其潜在的潜力，以提高含有M和M-M-MELCEAL蛋白（MRP）的疫苗效率。 SLS是气体的病毒确定剂，以前尚未被视为疫苗成分，因为毒素在气体感染后不是免疫原性。 SLS由所有气体的99％表示，有大量证据支持其在气体感染发病机理中的重要作用。 SLS通过造成软组织损伤，裂解吞噬细胞，介导有机体跨上皮边界的易位，通过裂解RBC来支持铁的易化，起到逐渐上调的Quorum传感器来支持铁的获取，从而充当自身的法规传感器，并潜在地将其他Via via Via via via via via -n. viales的全球定制函数来支持，从而支持铁的易用。活性毒素是一种30个氨基酸杂环肽，是9种基因sag Operaon的乘积。我们先前已经表明，非毒性合成肽复制氨基酸复制了10-30的SLS丙肽蛋白偶联的SLS丙肽偶联的兔子中诱发的抗体，这些抗体完全中和毒素在体外的活性。 SLS抗体是非osponic的，但是当与M蛋白抗血清结合时，SLS抗体显着增强了由M抗体介导的气体吞噬作用。先前未评估SLS Petides在动物感染模型中的免疫原性。我们的假设是，将SLS的免疫原性肽添加到M蛋白和基于MRP的气体疫苗将通过中和SLS的细胞溶解毒性来提高其整体效率，从而导致细菌病毒与更有效的生物体的抗体介导的清除率降低。该提案的目的是：1）构建含有和不带有SLS辣椒的N-末端M和MRP的重组的多价杂化蛋白，并构建具有和不具有SLS的Pepperides的MRP蛋白质，并在两种疫苗蛋白上组装免疫蛋白，以使体外细菌活性相比，以抗气体的蛋白质型，以及2），以及2），以比较耐盐水的蛋白质，以抗衡的蛋白质，并与抗疫苗的抗性量相比。气体感染小鼠模型中的SLS肽。在被认为是“通用”气体疫苗抗原的共享病毒决定剂中，我们假设SLS的免疫原性肽会引起中和中和抗体具有最大的潜力来影响整体疫苗效率，从而通过侵犯链球菌发病机制涉及的重要的坚固策略。