Novartis Vaccines and Diagnostics, Siena, Italy.
mBio. 2013 Jun 11;4(3):e00163-13. doi: 10.1128/mBio.00163-13.
Neisseria meningitidis, one of the major causes of bacterial meningitis and sepsis, is a member of the genus Neisseria, which includes species that colonize the mucosae of many animals. Three meningococcal proteins, factor H-binding protein (fHbp), neisserial heparin-binding antigen (NHBA), and N. meningitidis adhesin A (NadA), have been described as antigens protective against N. meningitidis of serogroup B, and they have been employed as vaccine components in preclinical and clinical studies. In the vaccine formulation, fHbp and NHBA were fused to the GNA2091 and GNA1030 proteins, respectively, to enhance protein stability and immunogenicity. To determine the possible impact of vaccination on commensal neisseriae, we determined the presence, distribution, and conservation of these antigens in the available genome sequences of the genus Neisseria, finding that fHbp, NHBA, and NadA were conserved only in species colonizing humans, while GNA1030 and GNA2091 were conserved in many human and nonhuman neisseriae. Sequence analysis showed that homologous recombination contributed to shape the evolution and distribution of both NHBA and fHbp, three major variants of which have been defined. fHbp variant 3 was probably the ancestral form of meningococcal fHbp, while fHbp variant 1 from N. cinerea was introduced into N. meningitidis by a recombination event. fHbp variant 2 was the result of a recombination event inserting a stretch of 483 bp from variant 1 into the variant 3 background. These data indicate that a high rate of exchange of genetic material between neisseriae that colonize the human upper respiratory tract exists. IMPORTANCE The upper respiratory tract of healthy individuals is a complex ecosystem colonized by many bacterial species. Among these, there are representatives of the genus Neisseria, including Neisseria meningitidis, a major cause of bacterial meningitis and sepsis. Given the close relationship between commensal and pathogenic species, a protein-based vaccine against N. meningitidis has the potential to impact the other commensal species of Neisseria. For this reason, we have studied the distribution and evolutionary history of the antigen components of a recombinant vaccine, 4CMenB, that recently received approval in Europe under the commercial name of Bexsero®. We found that fHbp, NHBA, and NadA can be found in some of the human commensal species and that the evolution of these antigens has been essentially shaped by the high rate of genetic exchange that occurs between strains of neisseriae that cocolonize the same environment.
脑膜炎奈瑟菌是细菌性脑膜炎和败血症的主要病因之一，属于奈瑟菌属，该属包括定植于许多动物黏膜的物种。三种脑膜炎奈瑟菌蛋白，即因子 H 结合蛋白（fHbp）、奈瑟菌肝素结合抗原（NHBA）和脑膜炎奈瑟菌粘附素 A（NadA），已被描述为针对 B 群脑膜炎奈瑟菌的保护性抗原，并且已作为疫苗成分在临床前和临床研究中使用。在疫苗配方中，fHbp 和 NHBA 分别与 GNA2091 和 GNA1030 蛋白融合，以增强蛋白稳定性和免疫原性。为了确定疫苗接种对共生奈瑟菌的可能影响，我们确定了这些抗原在可获得的奈瑟菌属基因组序列中的存在、分布和保守性，发现 fHbp、NHBA 和 NadA 仅在定植于人类的物种中保守，而 GNA1030 和 GNA2091 在许多人类和非人类奈瑟菌中保守。序列分析表明，同源重组有助于塑造 NHBA 和 fHbp 的进化和分布，已定义了三个主要变体。fHbp 变体 3 可能是脑膜炎奈瑟菌 fHbp 的原始形式，而来自 N. cinerea 的 fHbp 变体 1 通过重组事件被引入脑膜炎奈瑟菌。fHbp 变体 2 是通过将来自变体 1 的 483 个碱基对插入变体 3 背景中的重组事件产生的。这些数据表明，定植于人类上呼吸道的奈瑟菌之间存在高频率的遗传物质交换。
健康个体的上呼吸道是一个复杂的生态系统，定植着许多细菌物种。其中包括脑膜炎奈瑟菌，这是细菌性脑膜炎和败血症的主要病因。鉴于共生和致病物种之间的密切关系，针对脑膜炎奈瑟菌的基于蛋白质的疫苗有可能影响其他共生的奈瑟菌物种。出于这个原因，我们研究了最近在欧洲获得批准并以 Bexsero®的商品名上市的重组疫苗 4CMenB 的抗原成分的分布和进化历史。我们发现 fHbp、NHBA 和 NadA 可在一些人类共生种中找到，并且这些抗原的进化基本上是由定植于同一环境的奈瑟菌菌株之间发生的高遗传交换率所塑造的。
