Cross-reactivity and avidity of antibody responses induced in humans by the oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX
Cross-reactivity and avidity of antibody responses induced in humans by the oral inactivated multivalent enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX
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DOI：
10.1016/j.vaccine.2017.06.006
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发表时间：
2017-07-13
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：
Leach, Susannah;Lundgren, Anna;Svennerholm, Ann-Mari
我们研究了口服多价产肠毒素大肠杆菌(ETEC)灭活疫苗ETVAX，该疫苗由四株过表达定居因子(CFs)CFA/I、CS3、CS5和CS6的大肠杆菌菌株与类毒素LCTBA结合在一起，是否可以诱导与CFA/I和CS5家族相关的CFS的交叉反应抗体。我们还评估了疫苗诱导的针对类毒素和CFs的抗体的亲和力。从两个I期试验中，分析了粘膜(粪便和淋巴细胞上清液中的抗体，ALS)样本中的交叉反应，以及血清和ALS样本中的抗体亲和力：初步疫苗接种研究，其中两剂ETVAX口服双突变不稳定毒素(DmLT)佐剂，间隔两周，以及加强免疫研究，我们发现，在ALS或粪便样本中对CFA/I有反应的受试者中，有65%-90%的人也对相关的CFS产生了交叉反应抗体，即CS1、CS14和CS17，而对CS5有反应的人中，大约有80%对密切相关的CS7也有反应。对于已经产生交叉反应抗体的受试者，对疫苗CFS和相关的非疫苗CFS的反应程度是相似的。采用基于极限抗原稀释的简单抗体亲和力测定方法和杂乱ELISA方法，我们发现后期加强免疫后血清和ALS抗体对关键疫苗抗原的亲和力比初次接种后增加。我们的结果表明，针对多个CFs的交叉反应可能导致ETEC株对ETVAX的覆盖范围扩大，重复接种诱导的疫苗特异性抗体结合能力增加。(C)2017爱思唯尔有限公司。保留所有权利。
We investigated whether the oral inactivated, multivalent enterotoxigenic Escherichia coli (ETEC) vaccine ETVAX, consisting of four E. coli strains over-expressing the colonisation factors (CFs) CFA/I, CS3, CS5 and CS6, combined with the toxoid LCTBA, could induce cross-reactive antibodies to CFs related to the CFA/I and CS5 families. We also evaluated the avidity of vaccine induced antibodies against the toxoid and CFs.Cross-reactivity was analysed in mucosal (faecal and antibodies in lymphocyte supernatants, ALS) samples, and antibody avidity in serum and ALS samples, from two phase I trials: a primary vaccination study, where two oral doses of ETVAX were given the double mutant heat labile toxin (dmLT) adjuvant at a 2-week interval, and a booster vaccination study, where a single booster dose of ETVAX was given 13-23 months after primary vaccinations.We found that 65-90% of subjects who had responded to CFA/I in ALS or faecal specimens also developed cross-reactive antibodies to the related CFs tested, i.e. CS1, CS14 and CS17, and that approximately 80% of those responding to CS5 also responded to the closely related CS7. For subjects who had developed cross-reactive antibodies, the magnitudes of responses against vaccine CFs and related non-vaccine CFs were comparable. Using both a simple method of antibody avidity determination based on limiting antigen dilution, as well as a chaotropic ELISA method, we found that the avidity of serum and ALS antibodies to key vaccine antigens increased after a late booster dose compared to after primary vaccination.Our results suggest that the cross-reactive antibody responses against multiple CFs may result in expanded ETEC strain coverage of ETVAX and that repeated vaccinations induce vaccine-specific antibodies with increased binding capacity. (C) 2017 Elsevier Ltd. All rights reserved.