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.

虽然人们早就知道非伤寒沙门氏菌 (NTS) 会引起胃肠炎，但对多种抗生素具有耐药性 高毒力菌株正在成为侵袭性菌血症和局灶性感染的重要原因 在美国和全球范围内，导致住院和死亡。该转化研究计划测试 适当改造肠道沙门氏菌鼠伤寒血清型减毒菌株的假设 和肠炎球菌，具有 guaBA（编码鸟嘌呤核苷酸生物合成酶）的减毒突变 dpX（编码 ATP 酶）或 dpP（编码蛋白酶）在疫苗接种中发挥重要作用 通过以下方式对抗这些 NTS 血清型：1) 可以更安全、高产率地制备纯化 O 多糖 (OPS) 和鞭毛蛋白用于制备结合疫苗（dpP和c/pX突变体超表达鞭毛），以及2) 它们在异源粘膜初免/肠胃外加强免疫策略中的应用，其中小鼠给予 口服鼠伤寒沙门氏菌和肠炎沙门氏菌减毒菌株随后通过肠胃外加强 由与 1 期鞭毛共价连接的 B 组和 D 组沙门氏菌 OPS 组成的结合疫苗 分别是鼠伤寒杆菌或肠炎杆菌的蛋白质。我们假设该策略将显着拓宽 免疫反应引发并增强保护（在小鼠口服攻击研究中进行测试） 可以通过口服疫苗或单独的结合物来实现。我们预计 SlgA 抗体和细胞介导 活疫苗刺激的免疫（CMI）与血清 IgG 抗 OPS 协同作用 肠外结合疫苗刺激的杀菌抗体和抗鞭毛抗体。 已构建的两个甲型副伤寒沙门氏菌菌株，基因型为 guaBAc/pX 和 guaBA.dpP， 将在资助第一年的第一阶段临床试验中提供给志愿者，以获得对这些的初步评估 人类的减毒（尽管是在甲型副伤寒背景下）及其对 NTS 减毒的可能适用性。 由于鼠伤寒菌和肠炎菌是与侵袭性和侵袭性相关的最常见的 NTS 血清型。 美国（以及全球）严重的胃肠道 NTS 临床疾病，这项研究可以为 开发合理、高效、广谱的 NTS 疫苗。如果是二价疫苗 交叉保护免受其他 B 组和 D 组血清型的影响，并且如果（将来）C1 组或 C2 组结合物是 补充说，随后将针对绝大多数与侵入性相关的 NTS 提供承保 以及美国和世界各地的严重疾病。