Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model
Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model
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DOI：
10.1093/cid/cix042
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发表时间：
2017-04-15
影响因子：
11.8
通讯作者：
Pollard, Andrew J.
中科院分区：
文献类型：
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作者：
Dobinson, Hazel C.;Gibani, Malick M.;Pollard, Andrew J.
背景为了加快对副伤寒疫苗的评价，我们的目的是建立甲型副伤寒沙门氏菌感染的第一个人类攻击模型。两组20名受试者接受了S.以2个剂量水平之一（第1组：1-5 x 10（3）菌落形成单位[CFU]，第2组：0.5-1 x 10（3）CFU）进行碳酸氢钠预处理后的甲型副伤寒。参与者在门诊接受监测，每天进行临床回顾并收集血液和粪便培养。当符合预先规定的诊断标准（体温≥ 38 ℃持续≥ 12小时和/或菌血症）或在攻毒后第14天开始抗生素治疗。用1-5 x 10（3）CFU（第1组）攻毒后达到了主要研究目标，攻毒率为12/20（60%）。与伤寒攻毒相比，副伤寒的亚临床菌血症发生率较高（在该剂量下，11/20 [55%]）。尽管症状有限，但抗生素治疗后菌血症持续长达96小时（菌血症的中位持续时间为53小时[四分位距为24-85小时]）。S.粪便中甲型副伤寒通常先于菌血症发作。挑战S。甲型副伤寒在1-5 × 10（3）CFU的剂量下耐受性良好，并具有可接受的安全性。在没有临床症状的情况下，菌血症的频率和持续性是显著的，并且与先前伤寒攻毒研究中观察到的显著不同。我们得出结论，副伤寒攻毒模型适用于使用包括菌血症和/或细菌学在内的终点评估疫苗有效性。
Background. To expedite the evaluation of vaccines against paratyphoid fever, we aimed to develop the first human challenge model of Salmonella enterica serovar Paratyphi A infection.Methods. Two groups of 20 participants underwent oral challenge with S. Paratyphi A following sodium bicarbonate pretreatment at 1 of 2 dose levels (group 1: 1-5 x 10(3) colony-forming units [CFU] and group 2: 0.5-1 x 10(3) CFU). Participants were monitored in an outpatient setting with daily clinical review and collection of blood and stool cultures. Antibiotic treatment was started when prespecified diagnostic criteria were met (temperature >= 38 degrees C for >= 12 hours and/or bacteremia) or at day 14 postchallenge.Results. The primary study objective was achieved following challenge with 1-5 x 10(3) CFU (group 1), which resulted in an attack rate of 12 of 20 (60%). Compared with typhoid challenge, paratyphoid was notable for high rates of subclinical bacteremia (at this dose, 11/20 [55%]). Despite limited symptoms, bacteremia persisted for up to 96 hours after antibiotic treatment (median duration of bacteremia, 53 hours [interquartile range, 24-85 hours]). Shedding of S. Paratyphi A in stool typically preceded onset of bacteremia.Conclusions. Challenge with S. Paratyphi A at a dose of 1-5 x 10(3) CFU was well tolerated and associated with an acceptable safety profile. The frequency and persistence of bacteremia in the absence of clinical symptoms was notable, and markedly different from that seen in previous typhoid challenge studies. We conclude that the paratyphoid challenge model is suitable for the assessment of vaccine efficacy using endpoints that include bacteremia and/or symptomatology.