Enteric Diseases Department, Naval Medical Research Center, United States.
Enteric Diseases Department, Naval Medical Research Center, United States; Henry M. Jackson Foundation, United States.
Vaccine. 2021 Sep 15;39(39):5548-5556. doi: 10.1016/j.vaccine.2021.08.032. Epub 2021 Aug 18.
Enterotoxigenic Escherichia coli (ETEC) is a common cause of infectious diarrhoea and a leading cause of morbidity and mortality in children living in resource-limited settings. It is also the leading cause of travellers' diarrhoea among civilian and military travellers. Its dual importance in global public health and travel medicine highlights the need for an effective vaccine. ETEC express colonization factors (CFs) that mediate adherence to the small intestine. An epidemiologically prevalent CF is coli surface antigen 6 (CS6). We assessed the safety and immunogenicity of a CS6-targeted candidate vaccine, CssBA, co-administered intramuscularly with the double-mutant heat-labile enterotoxin, dmLT [LT(R192G/L211A)].
This was an open-label trial. Fifty subjects received three intramuscular injections (Days 1, 22 and 43) of CssBA alone (5 µg), dmLT alone (0.1 µg) or CssBA (5, 15, 45 µg) + dmLT (0.1 and 0.5 µg). Subjects were actively monitored for adverse events for 28 days following the third vaccination. Antibody responses (IgG and IgA) were characterized in the serum and from lymphocyte supernatants (ALS) to CS6 and the native ETEC heat labile enterotoxin, LT.
Across all dose cohorts, the vaccine was safe and well-tolerated with no vaccine-related severe or serious adverse events. Among vaccine-related adverse events, a majority (98%) were mild with 79% being short-lived vaccine site reactions. Robust antibody responses were induced in a dose-dependent manner with a clear dmLT adjuvant effect. Response rates in subjects receiving 45 µg CssBA and 0.5 µg dmLT ranged from 50 to 100% across assays.
This is the first study to demonstrate the safety and immunogenicity of CssBA and/or dmLT administered intramuscularly. Co-administration of the two components induced robust immune responses to CS6 and LT, paving the way for future studies to evaluate the efficacy of this vaccine target and development of a multivalent, subunit ETEC vaccine.
肠产毒性大肠杆菌（ETEC）是感染性腹泻的常见病因，也是资源有限环境中儿童发病率和死亡率的主要原因。它也是平民和军事旅行者旅行者腹泻的主要原因。它在全球公共卫生和旅行医学中的双重重要性突出了对有效疫苗的需求。ETEC 表达定植因子（CFs），介导对小肠的粘附。一种流行的 CF 是大肠菌素表面抗原 6（CS6）。我们评估了 CS6 靶向候选疫苗 CssBA 与双突变不耐热肠毒素（dmLT）[LT（R192G/L211A）]联合肌内给药的安全性和免疫原性。
这是一项开放性试验。五十名受试者分别在第 1 天、第 22 天和第 43 天接受三次肌内注射（5μg）单独 CssBA、单独 dmLT（0.1μg）或 CssBA（5、15、45μg）+dmLT（0.1 和 0.5μg）。在第三次接种后 28 天内主动监测受试者的不良事件。从血清和淋巴细胞上清液（ALS）中对 CS6 和天然 ETEC 不耐热肠毒素 LT 进行抗体反应（IgG 和 IgA）的特征描述。
在所有剂量组中，疫苗均安全且耐受良好，无疫苗相关严重或严重不良事件。在与疫苗相关的不良事件中，大多数（98%）为轻度，79%为短暂的疫苗部位反应。抗体反应呈剂量依赖性诱导，dmLT 具有明显的佐剂作用。接受 45μg CssBA 和 0.5μg dmLT 的受试者的反应率在各种检测中从 50%到 100%不等。
这是第一项研究表明 CssBA 和/或 dmLT 肌内给药的安全性和免疫原性。两种成分的联合给药可诱导针对 CS6 和 LT 的强烈免疫反应，为评估该疫苗靶标的疗效和开发多价、亚单位 ETEC 疫苗铺平了道路。
