Koeberling Oliver, Seubert Anja, Granoff Dan M
Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.
J Infect Dis. 2008 Jul 15;198(2):262-70. doi: 10.1086/589308.
Outer membrane vesicle (OMV) vaccines from mutant Neisseria meningitidis strains engineered to overexpress factor H-binding protein (fHbp) have elicited broadly protective serum antibody responses in mice. The vaccines investigated were not treated with detergents to avoid extracting fHbp, which is a lipoprotein. Because of their high endotoxin content, the vaccines would not be safe to administer to humans.
We prepared a native OMV vaccine from a strain engineered to overexpress fHbp and in which the gene encoding LpxL1 was inactivated, which reportedly decreases endotoxin activity.
The OMV vaccine from the mutant had a similar or lower ability to induce the expression of proinflammatory cytokines by human peripheral blood mononuclear cells, compared with a detergent-extracted wild-type OMV, and 1000-10,000-fold lower activity than a native wild-type OMV. In mice, the OMV vaccine from the mutant elicited higher serum bactericidal antibody responses to a panel of heterologous N. meningitidis strains than did a control multicomponent recombinant protein vaccine or a detergent-extracted OMV vaccine that has been demonstrated to confer protection against meningococcal disease in humans.
The data illustrate the potential to develop a broadly immunogenic native OMV vaccine that has decreased endotoxin activity and is potentially suitable for testing in humans.
经基因工程改造以过表达因子H结合蛋白（fHbp）的突变型脑膜炎奈瑟菌菌株的外膜囊泡（OMV）疫苗，已在小鼠中引发了广泛的保护性血清抗体反应。所研究的疫苗未用去污剂处理，以避免提取作为脂蛋白的fHbp。由于其高内毒素含量，这些疫苗对人类给药不安全。
我们从一株经基因工程改造以过表达fHbp且编码LpxL1的基因失活的菌株制备了一种天然OMV疫苗，据报道这会降低内毒素活性。
与经去污剂提取的野生型OMV相比，来自突变体的OMV疫苗诱导人外周血单核细胞表达促炎细胞因子的能力相似或更低，且活性比天然野生型OMV低1000 - 10000倍。在小鼠中，来自突变体的OMV疫苗对一组异源脑膜炎奈瑟菌菌株引发的血清杀菌抗体反应比对照多组分重组蛋白疫苗或已证明能在人类中提供针对脑膜炎球菌病保护作用的经去污剂提取的OMV疫苗更高。
数据表明开发一种具有降低的内毒素活性且可能适合在人体中进行测试的广泛免疫原性天然OMV疫苗的潜力。
