Effect of colonisation with Neisseria lactamica on cross-reactive anti-meningococcal B-cell responses: a randomised, controlled, human infection trial.
Effect of colonisation with Neisseria lactamica on cross-reactive anti-meningococcal B-cell responses: a randomised, controlled, human infection trial.
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DOI：
10.1016/s2666-5247(22)00283-x
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发表时间：
2022-12
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影响因子：
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通讯作者：
Read RC
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作者：
Dale AP;Theodosiou AA;Gbesemete DF;Guy JM;Jones EF;Hill AR;Ibrahim MM;de Graaf H;Ahmed M;Faust SN;Gorringe AR;Polak ME;Laver JR;Read RC
无害共生内酰胺奈瑟菌（Nlac）的咽定植抑制脑膜炎奈瑟菌（Nmen）定植，并与脑膜炎球菌病呈负相关的流行病学关系。支持这种关系的机制仍未解释，但可能是由于诱导交叉反应性免疫。在这项研究中，我们评估了Nlac定殖是否会诱导Nlac特异性B细胞反应与Nmen交叉反应。在英国南安普顿大学医院临床研究中心进行的一项随机、安慰剂对照的人类感染实验中，年龄在18-45岁的健康成年人被随机分为2:1，接受105个菌落形成单位的Nlac在1ml磷酸盐缓冲盐水（PBS）中鼻内接种，或单独1ml PBS。参与者和进行参与者抽样和免疫分析的研究人员对分配都是盲目的。主要终点是Nlac接种后（第7-28天）循环Nlac特异性浆细胞（BPLAS）和记忆B细胞（BMEM）频率与基线（第0天）的比较，使用酶联免疫斑点（ELISpot）测定。次要终点是测量nmen特异性BPLAS和BMEM的频率。该试验已在ClinicalTrials.gov注册（NCT03633474），目前已结束。在2018年9月5日至2019年3月3日期间评估资格的参与者中，随机分配n= 31/50 （n=20 Nlac, n=11 PBS）。在nlac定植的参与者（n=17）中，与定植后峰值nlac特异性BPLAS频率（每105个外周血单个核细胞）相比，中位基线为0 (IQR为0.0-0.0)，而分泌iga的BPLAS为5 (1.5-10.5)(P <0.0001)，分泌igg的BPLAS为0（0.0-0.0）和3 (1.5-9.5)（P <0.0001）。nlac特异性IgG BMEM的中位频率（占总IgG BMEM的%）从基线时的0.0024%（0.000 -0.0097）增加到第28天的0.0384% (0.0275-0.0649)（P <0.0001）。nmen特异性分泌IgA和IgG的BPLAS和IgG BMEM的频率在nlac定殖的参与者中也显著增加。Nlac和nmen特异性BPLAS和BMEM在对照组中没有变化。n=10/20名接种了nlac的参与者和n=6/11名接种了pbs的参与者报告了上呼吸道症状（P < 0.99）。另有3例不良事件，无严重不良事件发生。Nlac定植后对Nmen的自然免疫可能是由于交叉反应性适应性反应。利用转基因活载体开发这种微生物机制可以防止Nmen定植和疾病。
Pharyngeal colonisation by the harmless commensal Neisseria lactamica (Nlac) inhibits Neisseria meningitidis (Nmen) colonisation and has an inverse epidemiological association with meningococcal disease. The mechanisms underpinning this relationship remain unexplained, but could be due to induction of cross-reactive immunity. In this study, we evaluated whether colonisation with Nlac induces Nlac-specific B cell responses cross-reactive with Nmen. In a randomised, placebo-controlled, human infection experiment at University Hospital Southampton Clinical Research Facility, UK, healthy adults, aged 18-45 years, were randomised 2:1 to receive intra-nasal inoculation with either 105 colony-forming units of Nlac in 1 ml phosphate buffered saline (PBS), or 1 ml PBS alone. Participants, and researchers performing participant sampling and immunological assays, were all blinded to allocation. The primary endpoint was a comparison of circulating Nlac-specific plasma cell (BPLAS) and memory B cell (BMEM) frequencies post Nlac inoculation (day 7-28), as compared to baseline (day 0), measured using Enzyme-Linked ImmunoSpot (ELISpot) assays. The secondary endpoint was to measure the frequency of Nmen-specific BPLAS and BMEM. The trial is registered with ClinicalTrials.gov (NCT03633474) and is now closed. n = 31/50 of participants assessed for eligibility between Sep 5, 2018, and Mar 3, 2019, were randomly assigned (n=20 Nlac, n=11 PBS). Amongst Nlac-colonised participants (n=17), median baseline compared to peak post-colonisation Nlac-specific BPLAS frequencies (per 105 Peripheral Blood Mononuclear Cells) were 0 (IQR 0.0-0.0) versus 5 (1.5-10.5) for IgA-secreting BPLAS (P <0.0001), and 0 (0.0-0.0) versus 3 (1.5-9.5) for IgG-secreting BPLAS (P <0.0001). Median Nlac-specific IgG BMEM frequencies (% of total IgG BMEM) increased from 0.0024% (0.0000-0.0097) at baseline to 0.0384% (0.0275-0.0649) at day 28 (P <0.0001). The frequency of Nmen-specific IgA- and IgG-secreting BPLAS and IgG BMEM also increased significantly amongst Nlac-colonised participants. Nlac- and Nmen-specific BPLAS and BMEM were unchanged amongst controls. Upper respiratory tract symptoms were reported amongst n=10/20 Nlac-inoculated and n=6/11 PBS-inoculated participants (P >0.99). There were 3 additional adverse events and no serious adverse events. Natural immunity to Nmen following Nlac colonisation may be due to cross-reactive adaptive responses. Exploitation of this microbial mechanism with a genetically modified live vector could protect against Nmen colonisation and disease.