Tzeng Yih-Ling, Sannigrahi Soma, Stephens David S
Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.
NPJ Vaccines. 2024 Nov 18;9(1):223. doi: 10.1038/s41541-024-01018-4.
The 4CMenB (Bexsero) vaccine contains detergent-extracted outer membrane vesicles (OMVs) from a Neisseria meningitidis (Nm) group B strain NZ98/254 and three recombinant Nm protein antigens: Neisseria adhesin A (NadA), Factor H binding protein (FHbp, as the C-terminal protein in the GNA2091-FHbp fusion), and Neisserial Heparin Binding Antigen (NHBA, as the N-terminal protein in the NHBA-GNA1030 fusion). Previous work has shown that 4CMenB generates serum antibodies to Nm and Neisseria gonorrhoeae (Ng) OMV proteins and lipooligosaccharide (LOS). Mounting evidence indicates 4CMenB can partially protect against mucosal infections with Ng. The immunologic basis for Ng cross protection remains to be fully elucidated. Ten paired human sera obtained pre- and post-immunization with 4CMenB (1 month after a third vaccine dose) were used in ELISAs and in Western blots to determine IgG and IgA serum responses to OMVs from Nm strain NZ98/254 (OMV) and two Ng strains, 1291 and CNG20 (OMV), and gonococcal recombinant NHBA (rNHBA) proteins. Post 4CMenB sera, but not pre-sera, showed strong IgG and variable IgA responses to the OMV but lower (2-11-fold difference in signal intensity) recognition of OMV. All post (not pre) 4CMenB sera showed strong IgG, but variable IgA, recognition of rNHBA by ELISAs and Western blots. Three post 4CMenB sera at 10% (v/v) concentration had serum bactericidal activity (SBA) against Ng strains 1291 and CNG20 (~30-40% killing), not seen in paired pre-sera. These data confirmed 4CMenB-induced cross-reactive functional antibody responses to Ng. In competitive SBA assays, in which sera were pre-incubated with rNHBA, minimal SBA against Nm strain NZ98/254 was titrated away. However, most of the SBA against Ng strains 1291 and CNG20 required NHBA-specific antibodies, and the Δnhba mutants were resistant to killing by post 4CMenB sera. Removing NHBA-specific and LOS-specific OMV antibodies simultaneously decreased SBA significantly more than the sum of removing individual antibodies alone, suggesting synergy between anti-NHBA and anti-OMV antibodies. Anti- NHBA antibodies induced by 4CMenB vaccination cross react with NHBA and substantially contribute to the bactericidal response toward Ng induced by the vaccine.
4CMenB（Bexsero）疫苗包含从B群脑膜炎奈瑟菌（Nm）菌株NZ98/254中通过去污剂提取的外膜囊泡（OMV）以及三种重组Nm蛋白抗原：奈瑟菌粘附素A（NadA）、H因子结合蛋白（FHbp，作为GNA2091-FHbp融合蛋白中的C末端蛋白）和奈瑟菌肝素结合抗原（NHBA，作为NHBA-GNA1030融合蛋白中的N末端蛋白）。先前的研究表明，4CMenB可产生针对Nm和淋病奈瑟菌（Ng）的OMV蛋白及脂寡糖（LOS）的血清抗体。越来越多的证据表明，4CMenB可部分预防Ng引起的黏膜感染。Ng交叉保护的免疫基础仍有待充分阐明。使用10对在接种4CMenB前和接种后（第三次疫苗剂量后1个月）采集的人血清进行酶联免疫吸附测定（ELISA）和蛋白质免疫印迹法，以确定血清中针对Nm菌株NZ98/254的OMV（OMV）、两种Ng菌株1291和CNG20的OMV（OMV）以及淋球菌重组NHBA（rNHBA）蛋白的IgG和IgA反应。接种4CMenB后的血清，而非接种前的血清，对OMV表现出强烈的IgG反应及可变的IgA反应，但对OMV的识别较低（信号强度相差2至11倍）。所有接种4CMenB后的血清（而非接种前的血清）通过ELISA和蛋白质免疫印迹法对rNHBA表现出强烈的IgG反应，但IgA反应可变。三份接种4CMenB后浓度为10%（v/v）的血清对Ng菌株1291和CNG20具有血清杀菌活性（SBA）（约30%至40%的杀菌率），而配对的接种前血清中未观察到这种情况。这些数据证实了4CMenB诱导的针对Ng的交叉反应性功能性抗体反应。在竞争性SBA测定中，血清与rNHBA预孵育后，针对Nm菌株NZ98/254的最小SBA被滴定去除。然而，针对Ng菌株1291和CNG20的大多数SBA需要NHBA特异性抗体，并且Δnhba突变体对接种4CMenB后的血清杀伤具有抗性。同时去除NHBA特异性和LOS特异性OMV抗体导致SBA显著降低，幅度超过单独去除单个抗体的总和，表明抗NHBA和抗OMV抗体之间存在协同作用。由4CMenB疫苗接种诱导的抗NHBA抗体与NHBA交叉反应，并在很大程度上促成了疫苗诱导的针对Ng的杀菌反应。
