We studied population genomics of 486 Neisseria meningitidis isolates causing meningitis in the Netherlands during the period 1979–2003 and 2006–2013 using whole-genome sequencing to evaluate the impact of a hyperendemic period of serogroup B invasive disease. The majority of serogroup B isolates belonged to ST-41/44 (41 %) and ST-32 complex (16 %). Comparing the time periods, before and after the decline of serogroup B invasive disease, there was a decrease of ST-41/44 complex sequences (P=0.002). We observed the expansion of a sub-lineage within ST-41/44 complex sequences being associated with isolation from the 1979–2003 time period (P=0.014). Isolates belonging to this sub-lineage expansion within ST-41/44 complex were marked by four antigen allele variants. Presence of these allele variants was associated with isolation from the 1979–2003 time period after correction for multiple testing (Wald test, P=0.0043 for FetA 1–5; P=0.0035 for FHbp 14; P=0.012 for PorA 7–2.4 and P=0.0031 for NHBA two peptide allele). These sequences were associated with 4CMenB vaccine coverage (Fisher’s exact test, P<0.001). Outside of the sub-lineage expansion, isolates with markedly lower levels of predicted vaccine coverage clustered in phylogenetic groups showing a trend towards isolation in the 2006–2013 time period (P=0.08). In conclusion, we show the emergence and decline of a sub-lineage expansion within ST-41/44 complex isolates concurrent with a hyperendemic period in meningococcal meningitis. The expansion was marked by specific antigen peptide allele combinations. We observed preliminary evidence for decreasing 4CMenB vaccine coverage in the post-hyperendemic period.

中文翻译：

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侵袭性脑膜炎球菌的选择压力导致免疫原性基因多样化。

我们使用全基因组测序研究了 1979-2003 年和 2006-2013 年期间在荷兰引起脑膜炎的 486株脑膜炎奈瑟菌的群体基因组学，以评估血清群 B 侵袭性疾病高流行期的影响。大多数血清组 B 分离株属于 ST-41/44 (41 %) 和 ST-32 复合物 (16 %)。比较时间段，B群侵袭性疾病下降前后ST-41/44复合序列减少（P =0.002）。我们观察到 ST-41/44 复杂序列中亚谱系的扩展与 1979-2003 年时期的隔离有关（P =0.014)。属于 ST-41/44 复合物中这种亚谱系扩增的分离物由四个抗原等位基因变体标记。这些等位基因变体的存在与多次测试校正后的 1979-2003 年时间段的隔离相关（Wald 测试，对于 FetA 1-5， P = 0.0043；对于 FHbp 14， P = 0.0035；对于 PorA 7-2.4， P = 0.012 和对于 NHBA 两个肽等位基因，P = 0.0031）。这些序列与 4CMenB 疫苗覆盖率相关（Fisher 精确检验，P <0.001）。在亚谱系扩展之外，预测疫苗覆盖率明显较低的分离株聚集在系统发育组中，显示出 2006-2013 年期间分离的趋势（P=0.08）。总之，我们展示了 ST-41/44 复合物分离株中亚谱系扩张的出现和下降，同时脑膜炎球菌性脑膜炎的高流行期。扩增以特异性抗原肽等位基因组合为标志。我们观察到在高流行后时期降低 4CMenB 疫苗覆盖率的初步证据。