Maier Nicole, Grahek Shannon L, Halpern Jane, Restrepo Suzanne, Troncoso Felipe, Shimko Janet, Torres Olga, Belkind-Gerson Jaime, Sack David A, Svennerholm Ann-Mari, Gustafsson Björn, Sjöstrand Björn, Carlin Nils, Bourgeois A Louis, Porter Chad K
PATH, Washington, DC 20001, USA.
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Microorganisms. 2023 Sep 27;11(10):2414. doi: 10.3390/microorganisms11102414.
The efficacy of an Oral Whole Cell ETEC Vaccine (OEV) against Travelers' Diarrhea (TD) was reexamined using novel outcome and immunologic measures. More specifically, a recently developed disease severity score and alternative clinical endpoints were evaluated as part of an initial validation effort to access the efficacy of a vaccine intervention for the first time in travelers to an ETEC endemic area. A randomized, double-blind, placebo-controlled trial followed travelers to Guatemala or Mexico up to 28 days after arrival in the country following vaccination (two doses two weeks apart) with an ETEC vaccine. Fecal samples were collected upon arrival, departure, and during TD for pathogen identification. Serum was collected in a subset of subjects to determine IgA cholera toxin B subunit (CTB) antibody titers upon their arrival in the country. The ETEC vaccine's efficacy, utilizing a TD severity score and other alternative endpoints, including the relationship between antibody levels and TD risk, was assessed and compared to the per-protocol primary efficacy endpoint. A total of 1435 subjects completed 7-28 days of follow-up and had available data. Vaccine efficacy was higher against more severe (≥5 unformed stools/24 h) ETEC-attributable TD and when accounting for immunologic take (PE ≥ 50%; < 0.05). The vaccine protected against less severe (3 and 4 unformed stools/24 h) ETEC-attributable TD when accounting for symptom severity or change in activity (PE = 76.3%, = 0.01). Immunologic take of the vaccine was associated with a reduced risk of infection with ETEC and other enteric pathogens, and with lower TD severity. Clear efficacy was observed among vaccinees with a TD score of ≥4 or ≥5, regardless of immunologic take (PE = 72.0% and 79.0%, respectively, ≤ 0.03). The vaccine reduced the incidence and severity of ETEC, and this warrants accelerated evaluation of the improved formulation (designated ETVAX), currently undergoing advanced field testing. Subjects with serum IgA titers to CTB had a lower risk of infection with ETEC and . Furthermore, the TD severity score provided a more robust descriptor of disease severity and should be included as an endpoint in future studies.
采用新的结果指标和免疫学方法，重新审视了口服全细胞产肠毒素大肠杆菌疫苗（OEV）预防旅行者腹泻（TD）的效果。具体而言，作为首次在产肠毒素大肠杆菌流行地区旅行者中评估疫苗干预效果的初始验证工作的一部分，对最近开发的疾病严重程度评分和替代临床终点进行了评估。一项随机、双盲、安慰剂对照试验跟踪了接种产肠毒素大肠杆菌疫苗（两剂，间隔两周）后前往危地马拉或墨西哥的旅行者，直至他们抵达该国后28天。在抵达、离开时以及发生旅行者腹泻期间采集粪便样本以进行病原体鉴定。在一部分受试者中采集血清，以确定他们抵达该国时的IgA霍乱毒素B亚单位（CTB）抗体滴度。利用旅行者腹泻严重程度评分和其他替代终点，包括抗体水平与旅行者腹泻风险之间的关系，评估了产肠毒素大肠杆菌疫苗的效果，并与符合方案的主要疗效终点进行了比较。共有1435名受试者完成了7至28天的随访并提供了可用数据。对于更严重的（≥5次不成形粪便/24小时）产肠毒素大肠杆菌所致旅行者腹泻，以及考虑到免疫应答（血清保护率≥50%；P<0.05）时，疫苗效力更高。当考虑症状严重程度或活动变化时，疫苗对不太严重的（3次和4次不成形粪便/24小时）产肠毒素大肠杆菌所致旅行者腹泻具有保护作用（血清保护率=76.3%，P=0.01）。疫苗的免疫应答与产肠毒素大肠杆菌和其他肠道病原体感染风险降低以及旅行者腹泻严重程度降低相关。在旅行者腹泻评分≥4或≥5的疫苗接种者中观察到了明确的效力，无论免疫应答情况如何（血清保护率分别为72.0%和79.0%，P≤0.03）。该疫苗降低了产肠毒素大肠杆菌的发病率和严重程度，这使得对目前正在进行高级现场试验的改进配方（命名为ETVAX）进行加速评估成为必要。血清CTB IgA滴度较高的受试者感染产肠毒素大肠杆菌和[此处原文缺失一种病原体]的风险较低。此外，旅行者腹泻严重程度评分提供了更有力的疾病严重程度描述，应作为未来研究的一个终点纳入。
