Salmonella Group C as part of a multivalent Salmonella vaccine

C 组沙门氏菌作为多价沙门氏菌疫苗的一部分

• 批准号: 8652661
• 负责人: Sharon Mei Tennant
• 金额: $ 78.02万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8652661
• 关键词: Accounting; Address; Adult; Antibiotics; Attenuated; Attenuated Live Virus Vaccine; Bacteria; Chemicals; Clinical Trials; Conjugate Vaccines; Disease; Drug Formulations; Elderly; Engineering; Enteral; Family suidae; Flagella; Flagellin; Funding; Future; Gastroenteritis; Genetic Engineering; Gnotobiotic; Goals; Infant; Infection; Investigational New Drug Application; Life; Link; Macaca mulatta; Mediating; Meningitis; Modeling; Molecular Weight; Mus; Oral; Organism; Pathway interactions; Phase; Phase I Clinical Trials; Phenotype; Polysaccharides; Preparation; Proteins; Reagent; Recombinants; Research Proposals; Resistance; Salmonella; Salmonella Vaccines; Salmonella enterica; Salmonella typhimurium; Sepsis; Testing; Translational Research; Translations; United States Food and Drug Administration; Vaccine Production; Vaccines; aged; immunogenic; immunogenicity; oral vaccine; pathogen; prevent; senescence

Non-typhoidal Salmonella (NTS) are increasingly being recognized as important causes of invasive disease (e.g. sepsis, meningitis) in the very young and the elderly in the USA. The growing resistance of NTS strains to multiple antibiotics further complicates treatment. NTS disease in the USA is accounted for primarily by serovars belonging to three serogroups (B, C and D). Our overall goal is to develop a broad-spectrum vaccine against these invasive NTS serogroups. We have already developed live oral and conjugate vaccines against Group B {Salmonella enterica subspecies enterica serovar Typhimurium) and D (S. Enteritidis) serovars that can protect against invasive NTS disease with the wild-type homologous pathogen. Although less common than strains of Salmonella Groups B and D, Group C organisms represent a significant proportion of NTS cases, and some Group C serovars (e.g. S. Choleraesuis) are highly invasive. The purpose of this translational research proposal is to develop Salmonella Group C live attenuated and conjugate vaccines. Our central hypothesis is that appropriately engineered attenuated strains of Salmonella enterica Group Cl and C2 serovars can: 1) allow safe, high yield preparation of core-0 polysaccharide (COPS) and flagella protein for making conjugate vaccines, and 2) serve as protective live attenuated vaccines. We will select suitable Salmonella Group Cl and C2 strains and genetically engineer them so that they are attenuated and secrete large amounts of Phase 1 flagellin protein into the supernatant. We will purify COPS and flagellin from these strains and construct COPS-FliC conjugate vaccines using various chemical strategies. These conjugates will be evaluated in adult and aged mice. Live attenuated Salmonella Group Cl and C2 vaccine strains will also be evaluated for their ability to protect adult and aged mice. We will also determine whether gnotobiotic piglets can be protected from invasive disease by S. Choleraesuis conjugate and live oral vaccines. We will ascertain whether NTS vaccines can also protect against gastroenteritis by testing our live attenuated S. Typhimurium vaccine CVD 1931 in the rhesus macaque model of Salmonella gastroenteritis. Finally, we will determine whether a multivalent formulation of live oral or conjugate Group B, C and D Salmonella vaccines can prevent invasive disease caused by Group B, C and D serovars. If we are successful, these results will pave the way for initiating future Phase 1 clinical trials and we will have addressed three ofthe four broad objectives of this multi-center research proposal.

非伤寒沙门氏菌 (NTS) 越来越多地被认为是美国幼儿和老年人侵袭性疾病（例如败血症、脑膜炎）的重要原因。 NTS 菌株对多种抗生素的耐药性不断增强，使治疗进一步复杂化。在美国，NTS 疾病主要由属于三个血清群（B、C 和 D）的血清型引起。我们的总体目标是开发针对这些侵入性 NTS 血清群的广谱疫苗。我们已经开发出针对 B 组（肠沙门氏菌亚种、鼠伤寒沙门氏菌）和 D（肠炎沙门氏菌）血清型的口服活疫苗和结合疫苗，可以预防野生型同源病原体侵袭性 NTS 疾病。尽管不如 B 组和 D 组沙门氏菌菌株常见，但 C 组微生物在 NTS 病例中占很大比例，并且一些 C 组血清型（例如猪霍乱沙门氏菌）具有高度侵袭性。该转化研究计划的目的是开发沙门氏菌 C 组减毒活疫苗和结合疫苗。我们的中心假设是，适当工程化的肠道沙门氏菌 Cl 组和 C2 血清型减毒菌株可以：1) 能够安全、高产地制备 core-0 多糖 (COPS) 和鞭毛蛋白，用于制造结合疫苗，以及 2) 作为保护性活疫苗减毒疫苗。我们将选择合适的沙门氏菌Cl组和C2组菌株，并对它们进行基因改造，使其减毒并分泌大量的1相鞭毛蛋白到上清液中。我们将从这些菌株中纯化 COPS 和鞭毛蛋白，并使用各种化学策略构建 COPS-FliC 结合疫苗。这些缀合物将在成年和老年小鼠中进行评估。活的减毒沙门氏菌C1组和C2组疫苗株也将评估其保护成年和老年小鼠的能力。我们还将确定猪霍乱结合物和口服活疫苗是否可以保护无菌仔猪免受侵袭性疾病的影响。我们将通过在沙门氏菌胃肠炎恒河猴模型中测试我们的减毒鼠伤寒沙门氏菌活疫苗 CVD 1931 来确定 NTS 疫苗是否也能预防胃肠炎。最后，我们将确定口服活疫苗或 B、C 和 D 组沙门氏菌结合疫苗的多价制剂是否可以预防 B、C 和 D 组血清型引起的侵袭性疾病。如果我们成功，这些结果将为启动未来的一期临床试验铺平道路，我们将解决这个多中心研究提案的四个广泛目标中的三个。