PHOP/PHOQ DELETED S TYPHI VACCINE STRAINS

PHOP/PHOQ 删除伤寒疫苗株

• 批准号: 2856110
• 负责人: ELIZABETH L. HOHMANN
• 金额: $ 24.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-15 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856110
• 关键词: Escherichia coli; Helicobacter; Salmonella typhi; Salmonella vaccines; active immunization; antigen antibody reaction; attenuated microorganism; bacterial antigens; chimeric proteins; clinical research; clinical trials; enterotoxins; genetic strain; heterophile antigens; human subject; human therapy evaluation; humoral immunity; immunomodulators; laboratory mouse; live vaccine; lymphocyte proliferation; mucosal immunity; urease; vector vaccine; virulence

Vaccination is an effective and economical method of preventing disease, and multivalent, orally administered vaccines will have the widest clinical application. Attenuated Salmonella have been successfully studied in murine models as live vectors for delivery of heterologous antigens to the gastrointestinal immune system. Studies in humans have been limited, and variables important for immunogenicity in humans have not been clearly defined. A Salmonella typhi strain (Ty800) deleted for the phoP/phoQ virulence regulon of Salmonellae is very safe and immunogenic in human volunteers, and this strain has been modified to express clinically relevant heterologous antigens. This proposal describes a program of translational research designed to evaluate Salmonella-based vaccine regimens in humans utilizing bivalent S. typhi vaccine strains. These studies emphasize rational modification of clinically acceptable human vaccine strains and vaccination regimens which may alter immunogenicity of heterologous antigens such as type of antigen, location of antigen within the bacterial cell and mechanism of expression or secretion. Using an established IRB-approved human study protocol, adult volunteers are vaccinated, followed for safety and vaccine shedding, and intensively evaluated for evidence of mucosal, humoral and cellular immune-responses to both S. typhi antigens and the relevant heterologous antigens. A sequential oral vaccination regimen consisting of a S. typhi vaccine strain expressing cytoplasmic Helicobacter pylori urease followed by purified recombinant urease and E. coli heat labile toxin adjuvant will be tested in adult volunteers seronegative for H. pylori. An S. typhi strain expressing a fusion antigen of E. coli hemolysin A linked to urease B which is secreted from the bacterial cell will be studied to determine whether secretion alters immunogenicity in this system. Additional constructs will be generated which express either an E. coli heat labile toxin mutant or an E. coli colonization factor antigen (CFA/I). These new strains will be evaluated in vitro and subsequently tested in volunteers to determine whether these molecules with different structures or subcellular location can engender systemic and/or mucosal immune responses. These studies are designed to provide novel human safety and immunogenicity data which is vital to the clinical development of live bacterial vaccine vectors.

疫苗接种是预防疾病有效且经济的方法， 多价口服疫苗将具有最广泛的应用 临床应用。 沙门氏菌减毒已成功 在小鼠模型中作为活载体进行异源传递研究 胃肠道免疫系统的抗原。 对人类的研究有 是有限的，对人类免疫原性重要的变量已经 没有被明确定义。 伤寒沙门氏菌菌株 (Ty800) 被删除 沙门氏菌的 phoP/phoQ 毒力调节非常安全 在人类志愿者中具有免疫原性，并且该菌株已被修改为 表达临床相关的异源抗原。这个提议 描述了旨在评估的转化研究计划 利用二价伤寒沙门氏菌的人类疫苗方案 疫苗株。 这些研究强调合理修改 临床上可接受的人类疫苗株和疫苗接种方案 这可能会改变异源抗原的免疫原性，例如 抗原、抗原在细菌细胞内的定位及其机制 表达或分泌。 使用 IRB 批准的既定人体研究 根据协议，成年志愿者接种疫苗，并遵循安全和 疫苗脱落，并深入评估粘膜的证据， 对伤寒沙门氏菌抗原和 相关异源抗原。 序贯口服疫苗接种方案 由表达细胞质的伤寒沙门氏菌疫苗株组成 幽门螺杆菌脲酶，然后是纯化的重组脲酶和 大肠杆菌不耐热毒素佐剂将在成年志愿者中进行测试 幽门螺杆菌血清阴性。 表达融合体的伤寒沙门氏菌菌株 与尿素酶 B 连接的大肠杆菌溶血素 A 抗原，由 将研究细菌细胞以确定分泌是否改变 该系统的免疫原性。 将生成额外的构造 表达大肠杆菌不耐热毒素突变体或大肠杆菌 定植因子抗原（CFA/I）。 这些新菌株将 进行体外评估并随后在志愿者中进行测试以确定 这些分子是否具有不同的结构或亚细胞 位置可以引起全身和/或粘膜免疫反应。 这些 研究旨在提供新的人类安全性和免疫原性 对于活细菌的临床开发至关重要的数据 疫苗载体。