Induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia coli vaccine
Induction of long term mucosal immunological memory in humans by an oral inactivated multivalent enterotoxigenic Escherichia coli vaccine
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DOI：
10.1016/j.vaccine.2016.04.055
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发表时间：
2016-06-08
期刊：
影响因子：
5.5
通讯作者：
Svennerholm, Ann-Mari
中科院分区：
文献类型：
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作者：
Lundgren, Anna;Jertborn, Marianne;Svennerholm, Ann-Mari
我们评价了口服多价产肠毒素大肠杆菌(ETEC)疫苗(MEV)诱导粘膜免疫记忆的能力。MEV由四株过表达主要定植因子CFA/I、CS3、CS5和CS6以及LTB相关类毒素LCTBA的灭活大肠杆菌组成。在第一阶段试验中，通过比较三组成年瑞典志愿者(每组16-19名受试者)对单剂量MEV的肠源性抗体分泌细胞反应的幅度和动力学来分析记忆反应：未免疫对照组(I)和在13-23个月前的第一阶段试验中接受了两次双周剂量MEV(II)或MEV+双突变LT(DmLT)佐剂(III)的受试者。免疫前(0天)、免疫后4/5和7天采集外周血单个核细胞淋巴细胞分泌物(ALS)中的抗体，分析抗CFs和LTB的反应。我们还研究了单剂疫苗接种时存在的特异性循环记忆B细胞，以确定这些细胞是否反映了粘膜记忆。与未免疫的志愿者相比，单剂疫苗接种组诱导的针对所有CFS和LTB的IgA ALS反应明显更高和更频繁。此外，在大多数既往免疫的受试者中，对所有抗原的IgA-ALS反应在第4/5天达到高峰，而在第7天之前，只有少数未免疫的受试者有反应。佐剂免疫不影响记忆反应。免疫后13~23个月未检测到循环疫苗特异性的IgA记忆B细胞，而在免疫后13~23个月可检测到抗毒素的免疫记忆B细胞，提示MEV可诱导至少1~2年的黏膜功能记忆。此外，我们的结果支持，分析加强免疫后的抗体分泌细胞反应可能是评估人类长期存在的粘膜免疫记忆的有用方法。临床试验注册：ISRCTN27096290。(C)2016年提交人。爱思唯尔有限公司出版。
We have evaluated the capacity of an oral multivalent enterotoxigenic Escherichia call (ETEC) vaccine (MEV) to induce mucosal immunological memory. MEV consists of four inactivated E. coli strains over expressing the major colonization factors (CFs) CFA/I, CS3, CS5 and CS6 and the LTB-related toxoid LCTBA. Memory responses were analyzed by comparing the magnitudes and kinetics of intestine-derived antibody-secreting cell responses to a single dose of MEV in three groups of adult Swedish volunteers (n = 16-19 subjects per group) in a Phase I trial: non-immunized controls (I) and subjects who in a previous Phase I trial 13-23 months earlier had received two biweekly doses of MEV (II) or MEV + double mutant LT (dmLT) adjuvant (III). Responses against CFs and LTB were analyzed in antibodies in lymphocyte secretions (ALS) of blood mononuclear cells collected before (day 0) and 4/5 and 7 days after immunization. Specific circulating memory B cells present at the time of the single dose vaccination were also studied to determine if such cells may reflect mucosal memory.Considerably higher and significantly more frequent IgA ALS responses against all CFs and LTB were induced by the single vaccine dose in the previously immunized than in non-immunized volunteers. Furthermore, peak IgA ALS responses against all antigens were observed on days 4/5 in most of the previously immunized subjects whereas only a few previously non-vaccinated individuals responded before day 7. Priming with adjuvant did not influence memory responses. Circulating vaccine specific IgA memory B cells were not detected, whereas anti-toxin IgG memory B cells were identified 13-23 months after priming vaccination.We conclude that MEV induces functional mucosal immunological memory which remains at least 1-2 years. Furthermore, our results support that analysis of antibody-secreting cell responses after booster vaccination may be a useful approach to evaluate longstanding mucosal immunological memory in humans.Clinical trials registration: ISRCTN27096290. (C) 2016 The Authors. Published by Elsevier Ltd.