The effect of human factor H on immunogenicity of meningococcal native outer membrane vesicle vaccines with over-expressed factor H binding protein.
The effect of human factor H on immunogenicity of meningococcal native outer membrane vesicle vaccines with over-expressed factor H binding protein.
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DOI：
10.1371/journal.ppat.1002688
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Granoff DM
中科院分区：
文献类型：
--
作者：
Beernink PT;Shaughnessy J;Pajon R;Braga EM;Ram S;Granoff DM
人补体抑制剂与疫苗抗原在体内的结合可降低其免疫原性。补体下调因子H（fH）的脑膜炎球菌配体是fH结合蛋白（fHbp），对人fH具有特异性。含有重组fHbp或来自具有过表达fHbp的突变株的天然外膜囊泡（NOMV）的疫苗正在临床开发中。在先前的转基因小鼠研究中，人fH的存在损害了重组fHbp疫苗的免疫原性。在本研究中，我们从具有过表达野生型fHbp的突变体组B菌株或没有可检测的fH结合的R41 S突变体fHbp制备了两种NOMV疫苗。在其中小鼠fH不结合任一疫苗中的fHbp的野生型小鼠中，具有野生型fHbp的NOMV疫苗引起比具有突变体fHbp的NOMV高2倍的血清IgG抗fHbp滴度（P = 0.001）和高4倍的针对PorA异源菌株的补体介导的杀菌滴度（P = 0.003）。 通过吸附，显示杀菌抗体针对fHbp。在其中人fH结合野生型fHbp但不结合R41S fHbp的转基因小鼠中，具有突变体fHbp的NOMV疫苗引起比具有野生型fHbp的NOMV疫苗高5倍的血清IgG抗fHbp滴度（P = 0.002）和高19倍的杀菌滴度（P = 0.001）。 因此，在仅存在人fH的小鼠中，两种疫苗的相应结果相反。在存在人fH的情况下，突变fHbp疫苗引起的杀菌活性增强远远超过了野生型动物中突变蛋白免疫原性的损失。因此，工程改造fHbp使其不与其同源补体抑制剂结合可能会增加疫苗在人体中的免疫原性。正在开发含有因子H结合蛋白（fHbp）的疫苗，用于预防脑膜炎球菌引起的细菌性脑膜炎和败血症。该抗原是从基因组序列中鉴定出来的，后来才发现它与人补体蛋白H因子（fH）结合，但不与非人物种的fH结合。在先前的研究中，来自具有过表达fHbp的突变体的天然外膜囊泡（NOMV）疫苗在小鼠中引起广泛的保护性血清抗体，所述小鼠的fH不结合疫苗中的fHbp。在这项研究中，作者免疫了转基因小鼠，并表明人fH的存在降低了对具有结合人fH的fHbp的NOMV疫苗的血清杀菌抗体应答。相比之下，含有具有消除fH结合的单个氨基酸取代的fHbp的NOMV疫苗引发了近20倍的保护性抗体应答。因此，简单改变疫苗抗原以消除与宿主蛋白质的结合可增加免疫原性。
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. Vaccines containing factor H-binding protein (fHbp) are being developed for protection against bacterial meningitis and sepsis caused by meningococci. The antigen was identified from genomic sequences and only later found to bind a human complement protein, factor H (fH), but not fH from non-human species. In previous studies, native outer membrane vesicle (NOMV) vaccines from mutants with over-expressed fHbp elicited broadly protective serum antibodies in mice whose fH did not bind to fHbp in the vaccine. In this study, the authors immunized transgenic mice and showed that the presence of human fH decreased serum bactericidal antibody responses to a NOMV vaccine with fHbp that bound human fH. In contrast, a NOMV vaccine containing fHbp with a single amino acid substitution that eliminated fH binding elicited nearly twenty-fold higher protective antibody responses. Thus, a simple change in a vaccine antigen to eliminate binding to a host protein can increase immunogenicity.
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DOI：
10.1084/jem.20021911
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Masignani V;Comanducci M;Giuliani MM;Bambini S;Adu-Bobie J;Arico B;Brunelli B;Pieri A;Santini L;Savino S;Serruto D;Litt D;Kroll S;Welsch JA;Granoff DM;Rappuoli R;Pizza M
通讯作者：
Pizza M
脑膜炎球菌因子H结合蛋白在非洲流行病中的结合蛋白：对疫苗发育的影响。
影响因子：
3.8
作者：
Pajon R;Fergus AM;Koeberling O;Caugant DA;Granoff DM
通讯作者：
Granoff DM
影响因子：
6.4
作者：
Hou, VC;Koeberling, O;Granoff, DM
通讯作者：
Granoff, DM
影响因子：
6.4
作者：
Beernink, P. T.;Caugant, D. A.;Granoff, D. M.
通讯作者：
Granoff, D. M.
DOI：
10.1086/589308
发表时间：
2008-07-15
期刊：
The Journal of infectious diseases
影响因子：
--
作者：
Koeberling O;Seubert A;Granoff DM
通讯作者：
Granoff DM