Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, United States of America.
PLoS Negl Trop Dis. 2019 Jan 4;13(1):e0007037. doi: 10.1371/journal.pntd.0007037. eCollection 2019 Jan.
Enterotoxigenic Escherichia coli (ETEC) encoding heat-stable enterotoxin (ST) alone or with heat-labile enterotoxin (LT) cause moderate-to-severe diarrhea (MSD) in developing country children. The Global Enteric Multicenter Study (GEMS) identified ETEC encoding ST among the top four enteropathogens. Since the GEMS objective was to provide evidence to guide development and implementation of enteric vaccines and other interventions to diminish diarrheal disease morbidity and mortality, we examined colonization factor (CF) prevalence among ETEC isolates from children age <5 years with MSD and from matched controls in four African and three Asian sites. We also assessed strength of association of specific CFs with MSD.
METHODOLOGY/PRINCIPAL FINDINGS: MSD cases enrolled at healthcare facilities over three years and matched controls were tested in a standardized manner for many enteropathogens. To identify ETEC, three E. coli colonies per child were tested by polymerase chain reaction (PCR) to detect genes encoding LT, ST; confirmed ETEC were examined by PCR for major CFs (Colonization Factor Antigen I [CFA/I] or Coli Surface [CS] antigens CS1-CS6) and minor CFs (CS7, CS12, CS13, CS14, CS17, CS18, CS19, CS20, CS21, CS30). ETEC from 806 cases had a single toxin/CF profile in three tested strains per child. Major CFs, components of multiple ETEC vaccine candidates, were detected in 66.0% of LT/ST and ST-only cases and were associated with MSD versus matched controls by conditional logistic regression (p≤0.006); major CFs detected in only 25.0% of LT-only cases weren't associated with MSD. ETEC encoding exclusively CS14, identified among 19.9% of 291 ST-only and 1.5% of 259 LT/ST strains, were associated with MSD (p = 0.0011). No other minor CF exhibited prevalence ≥5% and significant association with MSD.
CONCLUSIONS/SIGNIFICANCE: Major CF-based efficacious ETEC vaccines could potentially prevent up to 66% of pediatric MSD cases due to ST-encoding ETEC in developing countries; adding CS14 extends coverage to ~77%.
单独编码耐热肠毒素（ST）或同时编码热不稳定肠毒素（LT）的肠产毒性大肠杆菌（ETEC）可导致发展中国家儿童发生中度至重度腹泻（MSD）。全球肠道多中心研究（GEMS）确定 ETEC 是引起腹泻的前 4 种病原体之一。由于 GEMS 的目的是提供证据，以指导肠道疫苗和其他干预措施的制定和实施，从而减少腹泻病的发病率和死亡率，因此我们检测了来自非洲四个国家和亚洲三个国家五个年龄<5 岁的 MSD 患儿和匹配对照者 ETEC 分离株中定植因子（CF）的流行率，并评估了特定 CF 与 MSD 之间关联的强度。
方法/主要发现：在三年期间，通过医疗设施招募 MSD 病例，并对其进行了标准化检测，以确定许多肠道病原体。为了鉴定 ETEC，每个患儿的 3 个大肠埃希氏菌菌落通过聚合酶链反应（PCR）检测 LT、ST 编码基因；对确诊的 ETEC 通过 PCR 检测主要 CF（黏附因子抗原 I [CFA/I]或 Coli Surface [CS]抗原 CS1-CS6）和次要 CF（CS7、CS12、CS13、CS14、CS17、CS18、CS19、CS20、CS21、CS30）。806 例 ETEC 患儿中，每个患儿的 3 个检测株中均具有单一的毒素/CF 模式。在 LT/ST 和 ST 单独感染的患儿中，66.0%检测到主要 CF，其为多种 ETEC 候选疫苗的组成部分，与匹配对照相比，通过条件逻辑回归（p≤0.006）与 MSD 相关；在 LT 单独感染的患儿中，仅 25.0%检测到主要 CF，与 MSD 无关。在 291 例 ST 单独感染和 259 例 LT/ST 株中，分别有 19.9%和 1.5%检测到仅编码 CS14 的 ETEC，与 MSD 相关（p = 0.0011）。没有其他次要 CF 的流行率≥5%，且与 MSD 显著相关。
结论/意义：基于主要 CF 的有效 ETEC 疫苗可能有潜力预防发展中国家因 ST 编码 ETEC 引起的 66%的儿童 MSD 病例；加入 CS14 后，覆盖率可扩展到~77%。
