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Live Recombinant Salmonella Typhi Vaccines Constructed to Investigate the Role of rpoS in Eliciting Immunity to a Heterologous Antigen

机译:活重组鼠伤寒沙门氏菌疫苗旨在研究rpoS在提高异源抗原免疫力中的作用

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摘要

We hypothesized that the immunogenicity of live Salmonella enterica serovar Typhi vaccines expressing heterologous antigens depends, at least in part, on its rpoS status. As part of our project to develop a recombinant attenuated S. Typhi vaccine (RASTyV) to prevent pneumococcal diseases in infants and children, we constructed three RASTyV strains synthesizing the Streptococcus pneumoniae surface protein PspA to test this hypothesis. Each vector strain carried ten engineered mutations designed to optimize safety and immunogenicity. Two S. Typhi vector strains (χ9639 and χ9640) were derived from the rpoS mutant strain Ty2 and one (χ9633) from the RpoS+ strain ISP1820. In χ9640, the nonfunctional rpoS gene was replaced with the functional rpoS gene from ISP1820. Plasmid pYA4088, encoding a secreted form of PspA, was moved into the three vector strains. The resulting RASTyV strains were evaluated for safety in vitro and for immunogenicity in mice. All three RASTyV strains were similar to the live attenuated typhoid vaccine Ty21a in their ability to survive in human blood and human monocytes. They were more sensitive to complement and were less able to survive and persist in sewage and surface water than their wild-type counterparts. Adult mice intranasally immunized with any of the RASTyV strains developed immune responses against PspA and Salmonella antigens. The RpoS+ vaccines induced a balanced Th1/Th2 immune response while the RpoS− strain χ9639(pYA4088) induced a strong Th2 immune response. Immunization with any RASTyV provided protection against S. pneumoniae challenge; the RpoS+ strain χ9640(pYA4088) provided significantly greater protection than the ISP1820 derivative, χ9633(pYA4088). In the pre-clinical setting, these strains exhibited a desirable balance between safety and immunogenicity and are currently being evaluated in a Phase 1 clinical trial to determine which of the three RASTyVs has the optimal safety and immunogenicity profile in human hosts.
机译:我们假设表达异源抗原的活肠沙门氏菌血清型鼠伤寒疫苗的免疫原性至少部分取决于其rpoS的状态。作为开发预防婴幼儿肺炎球菌疾病的重组减毒伤寒沙门氏菌疫苗(RASTyV)的项目的一部分,我们构建了三株RASTyV菌株,它们合成了肺炎链球菌表面蛋白PspA,以检验这一假设。每个载体菌株均带有十个工程突变,旨在优化安全性和免疫原性。两种S. Typhi载体菌株(χ9639和χ9640)来源于rpoS突变菌株Ty2,一种(χ9633)来自RpoS +菌株ISP1820。在χ9640中,将非功能性rpoS基因替换为ISP1820中的功能性rpoS基因。将编码PspA分泌形式的质粒pYA4088移入这三个载体菌株中。评价所得的RASTyV毒株的体外安全性和小鼠的免疫原性。所有三种RASTyV毒株在人血和人单核细胞中的存活能力均与减毒活伤疫苗Ty21a相似。与野生型同类动物相比,它们对补体更敏感,在污水和地表水中的存活和存活能力较弱。用任何RASTyV菌株经鼻内免疫的成年小鼠均产生针对PspA和沙门氏菌抗原的免疫反应。 RpoS +疫苗诱导了平衡的Th1 / Th2免疫反应,而RpoS-菌株χ9639(pYA4088)诱导了强烈的Th2免疫反应。接种任何RASTyV疫苗均可抵抗肺炎链球菌的攻击; RpoS +菌株χ9640(pYA4088)提供的保护作用明显大于ISP1820衍生物χ9633(pYA4088)。在临床前阶段,这些菌株在安全性和免疫原性之间表现出理想的平衡,目前正在1期临床试验中进行评估,以确定三种RASTyV中哪一种在人宿主中具有最佳的安全性和免疫原性。

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