An Outpatient, Ambulant-Design, Controlled Human Infection Model Using Escalating Doses of Salmonella Typhi Challenge Delivered in Sodium Bicarbonate Solution
An Outpatient, Ambulant-Design, Controlled Human Infection Model Using Escalating Doses of Salmonella Typhi Challenge Delivered in Sodium Bicarbonate Solution
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DOI：
10.1093/cid/ciu078
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发表时间：
2014-05-01
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：
Waddington, Claire S.;Darton, Thomas C.;Pollard, Andrew J.
背景伤寒是一个主要的全球性健康问题，其控制受到缺乏合适的动物模型来研究伤寒沙门氏菌感染的阻碍。直到1974年，人类挑战模型促进了对伤寒的理解，并用于疫苗开发。我们着手建立一个新的人类挑战模型，并确定S。伤寒（鹌鹑株）接种所需的攻击率为60%-75%的伤寒初治志愿者时，摄入碳酸氢钠溶液。健康同意的成年人组摄入递增剂量水平的S。伤寒和密切监测2周的门诊设置。如果诊断为伤寒（体温>= 38 ℃，持续>= 12小时或菌血症）或未治疗者在第14天开始抗生素治疗。需要两个剂量水平（10（3）或10（4）个集落形成单位）才能达到主要目的，导致发作率分别为55%（11/20）或65%（13/20）。攻毒耐受性良好; 40名参与者中有4名符合预先规定的严重感染标准。绝大多数（87.5%）的诊断是通过血培养确诊的，无症状菌血症和粪便中的沙门氏菌脱落。还观察到伤寒。发生伤寒感染的参与者在第14天表现出对鞭毛蛋白和脂多糖抗原的血清学应答;然而，没有检测到抗Vi抗体应答。用少量的强毒沙门氏菌接种物进行人体挑战。伤寒管理的碳酸氢盐溶液中可以安全地进行使用移动模型设计，以提高对宿主-病原体相互作用和免疫力的理解。这一模式将加快伤寒控制的诊断、疫苗和治疗方法的发展。
Background. Typhoid fever is a major global health problem, the control of which is hindered by lack of a suitable animal model in which to study Salmonella Typhi infection. Until 1974, a human challenge model advanced understanding of typhoid and was used in vaccine development. We set out to establish a new human challenge model and ascertain the S. Typhi (Quailes strain) inoculum required for an attack rate of 60%-75% in typhoid-naive volunteers when ingested with sodium bicarbonate solution.Methods. Groups of healthy consenting adults ingested escalating dose levels of S. Typhi and were closely monitored in an outpatient setting for 2 weeks. Antibiotic treatment was initiated if typhoid diagnosis occurred (temperature >= 38 degrees C sustained >= 12 hours or bacteremia) or at day 14 in those remaining untreated.Results. Two dose levels (10(3) or 10(4) colony-forming units) were required to achieve the primary objective, resulting in attack rates of 55% (11/20) or 65% (13/20), respectively. Challenge was well tolerated; 4 of 40 participants fulfilled prespecified criteria for severe infection. Most diagnoses (87.5%) were confirmed by blood culture, and asymptomatic bacteremia and stool shedding of S. Typhi was also observed. Participants who developed typhoid infection demonstrated serological responses to flagellin and lipopolysaccharide antigens by day 14; however, no anti-Vi antibody responses were detected.Conclusions. Human challenge with a small inoculum of virulent S. Typhi administered in bicarbonate solution can be performed safely using an ambulant-model design to advance understanding of host-pathogen interactions and immunity. This model should expedite development of diagnostics, vaccines, and therapeutics for typhoid control.