Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model.
Homologous and heterologous re-challenge with Salmonella Typhi and Salmonella Paratyphi A in a randomised controlled human infection model.
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DOI：
10.1371/journal.pntd.0008783
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发表时间：
2020-10
影响因子：
3.8
通讯作者：
Pollard AJ
中科院分区：
文献类型：
--
作者：
Gibani MM;Jin C;Shrestha S;Moore M;Norman L;Voysey M;Jones E;Blackwell L;Thomaides-Brears H;Hill J;Blohmke CJ;Dobinson HC;Baker P;Jones C;Campbell D;Mujadidi YF;Plested E;Preciado-Llanes L;Napolitani G;Simmons A;Gordon MA;Angus B;Darton TC;Cerundulo V;Pollard AJ
肠热病是由伤寒沙门氏菌或甲型副伤寒沙门氏菌引起的一种全身性感染，在许多流行地区，这些血清型共同循环，可导致儿童时期的多次感染发作。以前的接触被认为对随后的肠热病攻击提供了部分但不完整的保护。支持这一假说的经验数据有限，而且很少有研究描述这些密切相关的血清型之间发生异源保护的情况。我们使用受控人类感染模型(CHIM)进行了一项挑战-再挑战研究，以调查感染衍生免疫对伤寒沙门氏菌或甲型副伤寒杆菌感染的程度。我们招募了健康志愿者分为两组：未接触伤寒/甲型副伤寒沙门氏菌的天真志愿者和在早期CHIM研究中接触过伤寒或甲型副伤寒的志愿者。在每组中，参与者被随机分为1：1口服伤寒沙门氏菌(104cfu)或甲型副伤寒(103cfu)。主要目标是比较幼稚和以前挑战的个体的发病率，定义为每组参与者符合≥38°C持续≥12小时和/或沙门氏菌/副伤寒菌血症直到挑战后第14天的诊断标准的比例。在接受伤寒沙门氏菌同源再次攻击的参与者中，与受到挑战的天真对照组相比，发病率降低了，尽管这种降低没有统计学意义(12/27[44%]比12/19[63%]；相对风险0.70；95%可信区间0.41-1.21；p=0.24)。与甲型副伤寒沙门氏菌同源的再次攻击也导致了比被挑战的天真对照组更低的发病率(3/12[25%]比10/18[56%]；RR0.45；95%CI 0.16-1.30；p=0.14)。保护的证据得到了一项特别分析的支持，在该分析中，以前的暴露与再次挑战时伤寒或副伤寒的风险分别降低了约36%和57%。与初次接触时发生疾病的个体相比，初次接触时未发生肠热病的个体在再次挑战时更有可能获得保护。用伤寒沙门氏菌或甲型副伤寒沙门氏菌再次攻击与攻击后发病率的降低无关。在该模型的背景下，先前的暴露与疾病严重程度的降低、微生物特征的改变或体液免疫反应的增强无关。我们得出结论，先前的伤寒沙门氏菌和甲型副伤寒沙门氏菌暴露可能对后续感染提供部分但不完全的保护，但具有类似的临床和微生物学表型。这些血清型之间没有明显的交叉保护，这与伤寒沙门氏菌和甲型副伤寒的共同循环一致。总体而言，这些数据与监测和模拟研究相一致，这些研究表明，在高传播环境中可能发生多重感染，这支持了疫苗的必要性，以减轻儿童时期的疾病负担并实现疾病控制。试验注册NCT02192008；Clinicaltrials.gov。在这项研究中，我们评估了以前感染伤寒沙门氏菌和甲型副伤寒沙门氏菌是否能预防二次感染。在早期的人类挑战研究中，先前感染了这些细菌的健康志愿者被第二次挑战。我们比较了再次挑战组和第一次挑战的健康志愿者的感染率。我们发现，以前的感染与较低的二次感染率和较长的患病时间有关，但与完全预防疾病无关。在这两种情况下，一些人似乎对感染更有抵抗力。以前感染伤寒沙门氏菌似乎不能预防后来感染副伤寒沙门氏菌，反之亦然。第一次感染和第二次感染之间的抗体反应和临床症状相似。这些结果和未来的研究可以帮助我们更好地了解对这些细菌的免疫力，并有助于开发针对伤寒和副伤寒的新疫苗。
Enteric fever is a systemic infection caused by Salmonella Typhi or Paratyphi A. In many endemic areas, these serovars co-circulate and can cause multiple infection-episodes in childhood. Prior exposure is thought to confer partial, but incomplete, protection against subsequent attacks of enteric fever. Empirical data to support this hypothesis are limited, and there are few studies describing the occurrence of heterologous-protection between these closely related serovars. We performed a challenge-re-challenge study using a controlled human infection model (CHIM) to investigate the extent of infection-derived immunity to Salmonella Typhi or Paratyphi A infection. We recruited healthy volunteers into two groups: naïve volunteers with no prior exposure to Salmonella Typhi/Paratyphi A and volunteers previously-exposed to Salmonella Typhi or Paratyphi A in earlier CHIM studies. Within each group, participants were randomised 1:1 to oral challenge with either Salmonella Typhi (104 CFU) or Paratyphi A (103 CFU). The primary objective was to compare the attack rate between naïve and previously challenged individuals, defined as the proportion of participants per group meeting the diagnostic criteria of temperature of ≥38°C persisting for ≥12 hours and/or S. Typhi/Paratyphi bacteraemia up to day 14 post challenge. The attack-rate in participants who underwent homologous re-challenge with Salmonella Typhi was reduced compared with challenged naïve controls, although this reduction was not statistically significant (12/27[44%] vs. 12/19[63%]; Relative risk 0.70; 95% CI 0.41–1.21; p = 0.24). Homologous re-challenge with Salmonella Paratyphi A also resulted in a lower attack-rate than was seen in challenged naïve controls (3/12[25%] vs. 10/18[56%]; RR0.45; 95% CI 0.16–1.30; p = 0.14). Evidence of protection was supported by a post hoc analysis in which previous exposure was associated with an approximately 36% and 57% reduced risk of typhoid or paratyphoid disease respectively on re-challenge. Individuals who did not develop enteric fever on primary exposure were significantly more likely to be protected on re-challenge, compared with individuals who developed disease on primary exposure. Heterologous re-challenge with Salmonella Typhi or Salmonella Paratyphi A was not associated with a reduced attack rate following challenge. Within the context of the model, prior exposure was not associated with reduced disease severity, altered microbiological profile or boosting of humoral immune responses. We conclude that prior Salmonella Typhi and Paratyphi A exposure may confer partial but incomplete protection against subsequent infection, but with a comparable clinical and microbiological phenotype. There is no demonstrable cross-protection between these serovars, consistent with the co-circulation of Salmonella Typhi and Paratyphi A. Collectively, these data are consistent with surveillance and modelling studies that indicate multiple infections can occur in high transmission settings, supporting the need for vaccines to reduce the burden of disease in childhood and achieve disease control. Trial registration NCT02192008; clinicaltrials.gov. In this study, we assessed whether previous infection with the bacteria Salmonella Typhi and Salmonella Paratyphi protected against second infections. Healthy volunteers who had been previously infected with these bacteria in earlier human challenge studies were challenged for a second time. We compared the rate of infection in the re-challenge group with healthy volunteers who were challenged for the first time. We found that previous infection was associated with a lower rate of second infections and longer time to disease but was not associated with complete protection from disease. Some individuals appeared to be more resistant to developing infection on both occasions. Previous infection with Salmonella Typhi did not appear to protect against later infection with Salmonella Paratyphi and vice-versa. Antibody responses and clinical symptoms were similar in between first and second infections. These results and future studies could help us to better understand immunity to these bacteria and help the development of new vaccines for Salmonella Typhi and Paratyphi.
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DOI：
10.1093/cid/ciy670
发表时间：
2019-04-08
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Gibani MM;Voysey M;Jin C;Jones C;Thomaides-Brears H;Jones E;Baker P;Morgan M;Simmons A;Gordon MA;Cerundolo V;Pitzer VE;Angus B;Levine MM;Darton TC;Pollard AJ
通讯作者：
Pollard AJ
影响因子：
11.8
作者：
Dobinson, Hazel C.;Gibani, Malick M.;Pollard, Andrew J.
通讯作者：
Pollard, Andrew J.
影响因子：
82.9
作者：
Gibani, Malick M.;Jones, Elizabeth;Pollard, Andrew J.
通讯作者：
Pollard, Andrew J.
影响因子：
--
作者：
Harro, Clayton;Chakraborty, Subhra;Sack, David A.
通讯作者：
Sack, David A.
影响因子：
11.8
作者：
Kirkpatrick, Beth D.;Lyon, Caroline E.;Tribble, David R.
通讯作者：
Tribble, David R.