Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, United States of America.
PLoS Pathog. 2012;8(5):e1002688. doi: 10.1371/journal.ppat.1002688. Epub 2012 May 10.
The binding of human complement inhibitors to vaccine antigens in vivo could diminish their immunogenicity. A meningococcal ligand for the complement down-regulator, factor H (fH), is fH-binding protein (fHbp), which is specific for human fH. Vaccines containing recombinant fHbp or native outer membrane vesicles (NOMV) from mutant strains with over-expressed fHbp are in clinical development. In a previous study in transgenic mice, the presence of human fH impaired the immunogenicity of a recombinant fHbp vaccine. In the present study, we prepared two NOMV vaccines from mutant group B strains with over-expressed wild-type fHbp or an R41S mutant fHbp with no detectable fH binding. In wild-type mice in which mouse fH did not bind to fHbp in either vaccine, the NOMV vaccine with wild-type fHbp elicited 2-fold higher serum IgG anti-fHbp titers (P = 0.001) and 4-fold higher complement-mediated bactericidal titers against a PorA-heterologous strain than the NOMV with the mutant fHbp (P = 0.003). By adsorption, the bactericidal antibodies were shown to be directed at fHbp. In transgenic mice in which human fH bound to the wild-type fHbp but not to the R41S fHbp, the NOMV vaccine with the mutant fHbp elicited 5-fold higher serum IgG anti-fHbp titers (P = 0.002), and 19-fold higher bactericidal titers than the NOMV vaccine with wild-type fHbp (P = 0.001). Thus, in mice that differed only by the presence of human fH, the respective results with the two vaccines were opposite. The enhanced bactericidal activity elicited by the mutant fHbp vaccine in the presence of human fH far outweighed the loss of immunogenicity of the mutant protein in wild-type animals. Engineering fHbp not to bind to its cognate complement inhibitor, therefore, may increase vaccine immunogenicity in humans.
人类补体抑制剂与疫苗抗原在体内的结合可能会降低其免疫原性。一种脑膜炎球菌补体下调因子 H（fH）的配体是 fH 结合蛋白（fHbp），它特异性结合人 fH。含有重组 fHbp 或源自高表达 fHbp 的突变株的天然外膜囊泡（NOMV）的疫苗正在临床开发中。在之前的转基因小鼠研究中，人 fH 的存在会损害重组 fHbp 疫苗的免疫原性。在本研究中，我们制备了两种源自高表达野生型 fHbp 或无 fH 结合检测的 R41S 突变型 fHbp 的突变 B 群菌株的 NOMV 疫苗。在野生型小鼠中，两种疫苗中的 fH 均不与 fHbp 结合，含有野生型 fHbp 的 NOMV 疫苗引起的血清 IgG 抗 fHbp 滴度高 2 倍（P = 0.001），对 PorA-异源株的补体介导杀菌滴度高 4 倍（P = 0.003）。通过吸附，杀菌抗体被证明是针对 fHbp 的。在可以结合野生型 fHbp 但不结合 R41S fHbp 的转基因小鼠中，含有突变型 fHbp 的 NOMV 疫苗引起的血清 IgG 抗 fHbp 滴度高 5 倍（P = 0.002），对含有野生型 fHbp 的 NOMV 疫苗的杀菌滴度高 19 倍（P = 0.001）。因此，在仅因存在人 fH 而不同的小鼠中，两种疫苗的结果相反。在人 fH 存在的情况下，突变型 fHbp 疫苗引起的增强杀菌活性远远超过野生型动物中突变蛋白免疫原性的丧失。因此，不使 fHbp 结合其同源补体抑制剂的工程化可能会增加人类疫苗的免疫原性。
