Laboratory of Bacterial Polysaccharides, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Laboratory of Bacterial Polysaccharides, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA.
Vaccine. 2018 Jan 29;36(5):644-652. doi: 10.1016/j.vaccine.2017.12.045. Epub 2017 Dec 26.
The Neisseria meningitidis factor H binding protein (FHbp) is an important virulence factor and vaccine antigen contained in both USA licensed serogroup B meningococcal vaccines. Recent studies in human factor H (hFH) transgenic mice suggest that hFH-FHbp interactions lower FHbp-elicited immunogenicity. To provide tools with which to characterize and potentially improve FHbp immunogenicity, we developed an FHbp-cholera holotoxin-like chimera vaccine expression system in Escherichia coli that utilizes cholera toxin B (CTB) as both a scaffold and adjuvant for FHbp. We developed FHbp-CTB chimeras using a wild-type (WT) FHbp and a low hFH-binding FHbp mutant R41S. Both chimeras bound to G ganglioside and were recognized by the FHbp-specific monoclonal antibody JAR4. The R41S mutant had greatly reduced hFH binding compared to the WT FHbp-CTB chimera. WT and R41S FHbp-CTB chimeric antigens were compared to equimolar amounts of FHbp admixed with CTB or FHbp alone in mouse immunogenicity studies. The chimeras were significantly more immunogenic than FHbp alone or mixed with CTB, and elicited bactericidal antibodies against a panel of MenB isolates. This study demonstrates a unique and simple method for studying FHbp immunogenicity. The chimeric approach may facilitate studies of other protein-based antigens targeting pathogenic Neisseria and lay groundwork for the development of new protein based vaccines against meningococcal and gonococcal disease.
脑膜炎奈瑟菌因子 H 结合蛋白（FHbp）是一种重要的毒力因子和疫苗抗原，包含在美国许可的 B 群脑膜炎球菌疫苗中。最近在人因子 H（hFH）转基因小鼠中的研究表明，hFH-FHbp 相互作用降低了 FHbp 激发的免疫原性。为了提供用于表征和可能改善 FHbp 免疫原性的工具，我们在大肠杆菌中开发了 FHbp-霍乱全毒素样嵌合疫苗表达系统，该系统利用霍乱毒素 B（CTB）作为 FHbp 的支架和佐剂。我们使用野生型（WT）FHbp 和低 hFH 结合 FHbp 突变体 R41S 开发了 FHbp-CTB 嵌合体。两种嵌合体都与 G 神经节苷脂结合，并被 FHbp 特异性单克隆抗体 JAR4 识别。与 WT FHbp-CTB 嵌合体相比，R41S 突变体与 hFH 的结合大大降低。在小鼠免疫原性研究中，将 WT 和 R41S FHbp-CTB 嵌合抗原与等量的 FHbp 与 CTB 混合或单独的 FHbp 进行比较。嵌合体比单独的 FHbp 或与 CTB 混合更具免疫原性，并针对一组 MenB 分离株产生杀菌抗体。这项研究证明了一种研究 FHbp 免疫原性的独特而简单的方法。嵌合方法可能有助于研究针对致病性奈瑟菌的其他基于蛋白质的抗原，并为开发针对脑膜炎球菌和淋病奈瑟菌疾病的新型基于蛋白质的疫苗奠定基础。
