Harro Clayton, Louis Bourgeois A, Sack David, Walker Richard, DeNearing Barbara, Brubaker Jessica, Maier Nicole, Fix Alan, Dally Len, Chakraborty Subhra, Clements John D, Saunders Ingelise, Darsley Michael J
Center for Immunization Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
PATH, Washington, DC, USA.
Vaccine. 2019 Mar 28;37(14):1978-1986. doi: 10.1016/j.vaccine.2019.02.025. Epub 2019 Feb 21.
There is no licensed vaccine against enterotoxigenic Escherichia coli (ETEC), a major cause of diarrhea-associated morbidity and mortality among infants and children in low-income countries and travelers. The results of this vaccination/challenge study demonstrate strong protection by an attenuated ETEC vaccine candidate, ACE527, when co-administered with a mucosal adjuvant, the double-mutant heat-labile toxin (dmLT) of ETEC.
Sixty healthy adults participated in a randomized, placebo-controlled, double-blind study with three doses of lyophilized ACE527 (∼3 × 10 of each strain per dose) administered orally with or without dmLT adjuvant (25 µg/dose). Six months later, 36 of these volunteers and a control group of 21 unvaccinated volunteers were challenged with virulent ETEC strain H10407. The primary outcome was severe diarrhea, defined as passing >800 g of unformed stools during the inpatient period following challenge.
The vaccine was well tolerated and induced robust immune responses to key antigens. The protective efficacy (PE) against the primary outcome of severe diarrhea was 65.9% (95% confidence interval [CI] 5.4-87.7, p = 0.003). Among subjects receiving the adjuvanted vaccine, the attack rate of severe diarrhea was 23.1, while in unimmunized controls it was 67.7%. The PE against diarrhea of any severity was 58.5% (95% CI 3.8- 82.1, p = 0.016). There was a strong inverse correlation between shedding of the vaccine strain after either of the first two doses and absence of severe diarrhea upon challenge (RR = 0.29, 95% CI 0.08-1.05, p = 0.041). Challenge strain shedding was 10-fold lower in those receiving the adjuvant than in those receiving vaccine alone. The unadjuvanted vaccine was not protective (PE = 23.1%).
The results of this study support further development of ACE527 + dmLT as a vaccine for children in endemic countries and travelers. This is the first clinical demonstration that dmLT can contribute significantly to vaccine efficacy and may warrant testing with other oral vaccines. (ClinicalTrials.gov registration: NCT01739231).
产肠毒素大肠杆菌（ETEC）是低收入国家婴幼儿及旅行者腹泻相关发病和死亡的主要原因，目前尚无针对ETEC的许可疫苗。这项疫苗接种/攻毒研究结果表明，减毒ETEC候选疫苗ACE527与黏膜佐剂ETEC双突变不耐热毒素（dmLT）联合使用时具有强大的保护作用。
60名健康成年人参与了一项随机、安慰剂对照、双盲研究，口服三剂冻干的ACE527（每剂每种菌株约3×10），有或无dmLT佐剂（25μg/剂）。6个月后，这些志愿者中的36人以及21名未接种疫苗的志愿者组成的对照组接受强毒ETEC菌株H10407攻毒。主要结局为严重腹泻，定义为攻毒后住院期间排出>800g不成形粪便。
该疫苗耐受性良好，可诱导对关键抗原的强烈免疫反应。针对严重腹泻这一主要结局的保护效力（PE）为65.9%（95%置信区间[CI]5.4 - 87.7，p = 0.003）。在接受佐剂疫苗的受试者中，严重腹泻的发病率为23.1%，而未免疫对照组为67.7%。针对任何严重程度腹泻的PE为58.5%（95%CI 3.8 - 82.1，p = 0.016）。在前两剂疫苗接种后任一剂次疫苗菌株排出与攻毒后无严重腹泻之间存在强负相关（RR = 0.29，95%CI 0.08 - 1.05，p = 0.041）。接受佐剂的受试者中攻毒株排出量比仅接受疫苗的受试者低10倍。未加佐剂的疫苗无保护作用（PE = 23.1%）。
本研究结果支持进一步研发ACE527 + dmLT作为流行国家儿童及旅行者的疫苗。这是首次临床证明dmLT可显著提高疫苗效力，可能值得与其他口服疫苗进行联合测试。（ClinicalTrials.gov注册号：NCT01739231）
