Vaccine strategy for broad spectrum protection agains non-typhoidal salmonell

针对非伤寒沙门氏菌的广谱保护疫苗策略

• 批准号: 7669835
• 负责人: Myron Max Levine
• 金额: $ 24.72万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-03 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669835
• 关键词: ATP phosphohydrolase; Adjuvant; Agonist; Antibiotic Resistance; Antibodies; Antibody Formation; Antigens; Area; Aromatic Amino Acids; Attenuated; Attenuated Vaccines; Bacteremia; Carrier Proteins; Cellular Immunity; Cessation of life; Clinical; Clinical Data; Complement component C1s; Conjugate Vaccines; Corynebacterium diphtheriae; Development; Disease; Elderly; Engineering; Enzymes; Flagella; Flagellin; Focal Infection; Future; Gastroenteritis; Genotype; Goals; Grant; Guanine Nucleotides; Heat shock proteins; Hospitalization; Human; Immune response; Immunity; Immunization; Infant; Intestines; Invaded; Investigational New Drug Application; Lead; Licensing; Life; Link; Mastigophora; Measures; Mucosal Immune Responses; Mus; Mutation; Nucleotide Biosynthesis; Oral; Panama; Pathway interactions; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Phase; Phase I Clinical Trials; Placebos; Play; Polysaccharides; Population; Preparation; Proteins; Public Health; Reagent; Research; Research Personnel; Research Proposals; Role; Salmonella; Salmonella Vaccines; Salmonella enterica; Salmonella paratyphi; Salmonella typhi; Salmonella typhimurium; Sepsis; Serine Protease; Serotyping; Serum; Specificity; TLR5 gene; Testing; Translational Research; Treatment Protocols; Typhoid Fever; Typhoid Vaccine; Vaccinated; Vaccination; Vaccines; Virulent; aminoacid biosynthesis; anti-IgG; attenuation; bactericide; base; biodefense; cross reacting material 197; design; experience; feeding; flagellum antigen; gastrointestinal; high risk; immunogenic; immunogenicity; mutant; oral vaccine; pre-clinical; prevent; resistant strain; stress protein; vaccine candidate; volunteer

While non-typhoidal Salmonella (NTS) have long been known to cause gastroenteritis, multiple antibioticresistant highly virulent strains are emerging as important causes of invasive bacteremia and focal infections in the USA and globally, resulting in hospitalizations and deaths. This translational research proposal tests the hypothesis that appropriately engineered attenuated strains of Salmonella enterica serovar Typhimurium and Enteritidis, with attenuating mutations in guaBA (encoding guanine nucleotide biosynthesis enzymes) and either dpX (encoding ATPase) or dpP (encoding a protease), can play an important role in vaccinating against these NTS serovars by: 1) allowing safer, high yield preparation of purified O polysaccharide (OPS) and flagella protein for making conjugate vaccines (dpP and c/pX mutants hyper-express flagella), and 2) by their use in a heterologous mucosal prime/parenteral boost immunization strategy in which mice given the attenuated strains of S. Typhimurium and S. Enteritidis orally are subsequently boosted parenterally with conjugate vaccines consisting of Salmonella Group B and D OPS covalently linked to Phase 1 flagella protein of Typhimurium or Enteritidis, respectively. We hypothesize that this strategy will markedly broaden the immune responses elicited and enhance protection (tested in oral challenge studies in mice) over what can be achieved with either oral vaccines or conjugates alone. We expect SlgA antibodies and cellmediated immunity (CMI) stimulated by the live vaccine to synergize with the serum IgG anti-OPS bactericidal antibodies and anti-flagella antibodies stimulated by the parenteral conjugate vaccines. Two S. Paratyphi A strains, genotypes guaBAc/pXand guaBA.dpP, that have already been constructed, will be fed to volunteers in a Phase 1 clinical trial in grant-year 1 to obtain a preliminary assessment of these attenuations in humans (albeit in Paratyphi A background) and their likely suitability for attenuating NTS. Since Typhimurium and Enteritidis are the most common NTS serovars associated with invasive and severe gastrointestinal NTS clinical disease in the USA (and globally), this research can pave the way for development of a rational, highly effective, broad spectrum vaccine against NTS. If the bivalent vaccines cross protect against other Group B & D serovars and if (in the future) either a group C1 or C2 conjugate is added, coverage will then be provided against the overwhelming majority of NTS associated with invasive and severe disease in the USA and worldwide.

虽然长期以来已知非锥状沙门氏菌（NTS）引起胃炎，但多种抗生素抗药性 高度毒性菌株正在出现，作为侵入性菌血症和局灶性感染的重要原因 在美国和全球，导致住院和死亡。这项翻译研究建议测试 适当地设计的假设减弱了沙门氏菌血清typhimurium 和肠肠菌，并在瓜巴（编码鸟嘌呤核苷酸生物合成酶）中衰减突变。 DPX（编码ATPase）或DPP（编码蛋白酶）可以在接种疫苗中起重要作用 通过以下方式对付这些NTS血清，1）允许纯化的O多糖（OPS）更安全，高产制备 和用于生产结合疫苗的鞭毛蛋白（DPP和C/PX突变体高表达鞭毛），2） 它们在异源粘膜素/肠胃外促进免疫策略中的使用 鼠伤寒链霉菌和肠链球菌口服的菌株随后被育儿促进 共轭疫苗由沙门氏菌组和D OPS组成 鼠伤寒或肠菌的蛋白质。我们假设该策略将显着扩大 免疫反应引起并增强保护（在小鼠口腔挑战研究中测试） 可以单独使用口服疫苗或共轭物来实现。我们期望SLGA抗体和细胞介导 通过活疫苗刺激的免疫（CMI）与血清IgG抗OPS协同作用 肠胃外结合疫苗刺激的杀菌抗体和抗氟脂蛋白抗体。 两个已构建的副链球菌A菌株，基因型guabac/pxand guaba.dpp 将在授予年度1的1阶段临床试验中送给志愿者，以获得对这些的初步评估 人类的衰减（尽管在副本A背景中）及其可能适合衰减NTS。 由于鼠伤寒和肠内虫是与侵入性和 在美国（以及全球），严重的胃肠道NTS临床疾病，这项研究可以为 开发针对NTS的合理，高效，广泛的频谱疫苗。如果二价疫苗 交叉防止其他B＆D血清射击，如果（将来）C1或C2共轭是 添加，将提供覆盖范围，以与与侵入性相关的绝大多数NT提供覆盖范围 以及美国和全球的严重疾病。