DEVELOPMENT OF A LIVE ORAL CHOLERA VACCINE

口服霍乱活疫苗的开发

• 批准号: 6137120
• 负责人: JAMES B KAPER
• 金额: $ 37.51万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-01-01 至 2001-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137120
• 关键词: Bacillus subtilis; Vibrio cholerae; active immunization; antibacterial antibody; bacterial proteins; bacterial toxins; cholera toxin; cholera vaccine; disease /disorder model; drug screening /evaluation; gastrointestinal epithelium; gene deletion mutation; human tissue; immunogenetics; laboratory mouse; live vaccine; membrane proteins; molecular cloning; nucleic acid sequence; oral administration; phospholipase A2; southern blotting; vaccine development; virulence

DESCRIPTION (Adapted from applicant's abstract): An ideal vaccine for the prevention of cholera is not yet available. Previous work by the investigator resulted in development of an attenuated live oral cholera vaccine, V. cholerae CVD103-HgR. This vaccine confers strong protective immunity against experimental challenge with virulent V. cholerae O1 after a single dose. However, this vaccine is limited in that it does not protect against the El Tor biotype as well as it does against the classical biotype and it offers no protection against the recently emerged V. cholerae O139 serogroup. Additional vaccine candidates have been developed by deleting genes encoding cholera toxin and other toxins of V. cholerae but these other strains produce varying amounts of diarrhea and non-diarrheal symptoms such as headache, fever, abdominal cramps, and malaise in many individuals. The proposed project will develop additional vaccine candidates for O139 V. cholerae by deletion of specific genes encoding toxins and other virulence factors from a toxigenic O139 parent strain and by transferring genes encoding important antigens of O139 to CVD 103-HgR. In addition, the investigator will study previously uncharacterized virulence factors that may be involved in the reactogenicity of vaccine candidates other than CVD 103-HgR. Additional vaccine candidates for O139 V. cholerae will be constructed by deletion of specific genes encoding toxins and other virulence factors from a toxigenic O139 parent strain and by transferring genes encoding important antigens of O139 to CVD 103-HgR. In addition, previously uncharacterized virulence factors that may be involved in the reactogenicity of vaccine candidates other than CVD 103-HgR will be studied. The investigator has recently cloned the genes for the OmpU outer membrane protein and the phospholipase of V. cholerae. He has shown that OmpU has adhesive properties and that altered expression of this protein may be responsible for the diminished intestinal colonization which is associated with diminished vaccine reactogenicity. The phospholipase may be involved in a recently recognized inflammatory response to V. cholerae infection. The phospholipase may act on epithelial cells and break down membrane phospholipids, thereby releasing chemoattractants to trigger an inflammatory response that may be involved in vaccine reactogenicity.

描述（改编自申请人的摘要）：一种理想的疫苗 尚未预防霍乱。 以前的工作 研究人员导致了衰减的活口腔霍乱的发展 疫苗，V。CholeraeCVD103-HGR。 这种疫苗赋予强大保护性 对毒性V.霍乱O1的实验挑战的免疫力 单剂量后。但是，这种疫苗受到限制，因为它没有 防止El tor Biotype以及它的影响 古典生物型，它没有防止最近 出现了V.霍乱O139血清群。其他候选疫苗 通过删除编码霍乱毒素和其他毒素的基因开发 V.霍乱，但这些其他菌株产生了不同的数量 腹泻和非乳腺炎症状，例如头痛，发烧，腹部 许多人抽筋和不适。 拟议的项目将 通过删除为O139 V.霍乱的O139 V开发其他疫苗 来自毒素和其他毒力因子的特定基因 毒素O139母体菌株并通过转移编码重要的基因 O139至CVD 103-HGR的抗原。 此外，调查员还将 研究以前可能涉及的未表征的毒力因子 在CVD 103-HGR以外的疫苗候选物的反应生成性中。 将建造O139 V.霍乱的其他疫苗候选物 通过缺失编码毒素和其他毒力因子的特定基因 从毒素O139母体菌株和通过转移编码的基因 O139至CVD 103-HGR的重要抗原。另外，以前 可能涉及的未表征的毒力因子 CVD 103-HGR以外的其他疫苗的反应生成性将是 研究。 研究者最近将OMPU的基因克隆 外膜蛋白和V.霍乱的磷脂酶。 他有 表明oppu具有粘合特性，并且改变了 该蛋白可能导致肠道减少 定植与疫苗反应生成降低有关。 磷脂酶可能参与最近公认的炎症 对霍乱感染的反应。 磷脂酶可能作用于 上皮细胞并分解膜磷脂，从而释放 化学吸引剂以触发可能涉及的炎症反应 在疫苗反应生成中。