Refinement of a Human Challenge Model for Evaluation of Enterotoxigenic Escherichia coli Vaccines
Refinement of a Human Challenge Model for Evaluation of Enterotoxigenic Escherichia coli Vaccines
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DOI：
10.1128/cvi.05194-11
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发表时间：
2011-10-01
影响因子：
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通讯作者：
Sack, David A.
中科院分区：
文献类型：
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作者：
Harro, Clayton;Chakraborty, Subhra;Sack, David A.
在≥ 10（9）CFU的剂量下，产肠毒素性大肠杆菌（ETEC）菌株H10407（血清型O 78：H11，产生不耐热毒素[LT]、热稳定毒素[ST]和定植因子I [CFA/I]）在人体攻毒模型中诱导可靠的高结肠炎发作率（AR）。通过改变标准禁食时间和缓冲液配方进行了剂量递减挑战研究，寻求允许较低接种量同时保持可重现高AR的条件。在队列1中，20例受试者禁食过夜，并以1：1：1：1的比例随机接受H10407，剂量为10（8）CFU（含碳酸氢盐）、10（8）CFU（含CeraVacx）、10（7）CFU（含碳酸氢盐）或10（7）CFU（含CeraVacx）。随后的队列在相似的空腹条件下接受H10407（含碳酸氢盐的10（7）CFU）。队列2包括15名ETEC初治志愿者。队列3包括10例ETEC初治志愿者和10例再激发志愿者。总体而言，25/35（71%）ETEC初治的10（7）CFU H10407接受者发生中度或重度腹泻（平均最大粪便排出量/24 h = 1，042 g），大多数（97%）排出H10407（最大几何平均滴度= 7.5 x 10（7）CFU/g粪便）。10名再激发志愿者中只有1名发生腹泻。这些再激发受试者的肠道定植减少，反映在粪便样本的定量微生物学上。在35例ETEC初治者中，抗脂多糖（LPS）O 78血清抗体应答显著，伊加和IgG抗体应答分别为33/35（94%）和25/35（71%）。分别在19/35（54%）和14/35（40%）例受试者中产生了抗不耐热肠毒素（LTB）血清伊加和IgG应答。在15/35（43%）和8/35（23%）例受试者中检测到抗CFA/I血清伊加和IgG应答。在第二次挑战后，参与者表现出钝化的抗LPS和抗LTB反应，但对CFA/I的增强反应。该ETEC模型应证明在未来ETEC候选疫苗的评价中是有用的。
Enterotoxigenic Escherichia coli (ETEC) strain H10407 (serotype O78:H11 producing heat-labile toxin [LT], heat-stable toxin [ST], and colonization factor I [CFA/I]) induces reliably high diarrheal attack rates (ARs) in a human challenge model at doses of >= 10(9) CFU. A descending-dose challenge study was conducted with changes to the standard fasting time and buffer formulation, seeking conditions that permit lower inocula while maintaining reproducibly high ARs. In cohort 1, 20 subjects were fasted overnight and randomized 1:1:1:1 to receive H10407 at doses of 10(8) CFU with bicarbonate, 10(8) CFU with CeraVacx, 10(7) CFU with bicarbonate, or 10(7) CFU with CeraVacx. Subsequent cohorts received H10407 (10(7) CFU with bicarbonate) with similar fasting conditions. Cohort 2 included 15 ETEC-naive volunteers. Cohort 3 included 10 ETEC-naive volunteers and 10 rechallenged volunteers. In all, 25/35 (71%) ETEC-naive recipients of 10(7) CFU of H10407 developed moderate or severe diarrhea (average maximum stool output/24 h = 1,042 g), and most (97%) shed H10407 (maximum geometric mean titer = 7.5 x 10(7) CFU/gram of stool). Only one of 10 rechallenged volunteers developed diarrhea. These rechallenged subjects had reduced intestinal colonization, reflected by quantitative microbiology of fecal samples. Among the 35 ETEC-na ve subjects, anti-lipopolysaccharide (LPS) O78 serum antibody responses were striking, with positive IgA and IgG antibody responses in 33/35 (94%) and 25/35 (71%), respectively. Anti-heat-labile enterotoxin (LTB) serum IgA and IgG responses developed in 19/35 (54%) and 14/35 (40%) subjects, respectively. Anti-CFA/I serum IgA and IgG responses were detected in 15/35 (43%) and 8/35 (23%) subjects. After the second challenge, participants exhibited blunted anti-LPS and -LTB responses but a booster response to CFA/I. This ETEC model should prove useful in the future evaluation of ETEC vaccine candidates.