Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, United States.
Vaccine. 2019 Jan 21;37(4):602-611. doi: 10.1016/j.vaccine.2018.12.011. Epub 2018 Dec 15.
The public health burden of Enterotoxigenic Escherichia coli (ETEC) is high but no vaccine is specifically approved to prevent ETEC infections.
We performed a Phase 1, dose escalation study (1-50 µg) evaluating the sublingual (SL) delivery of the double mutant heat-labile toxin LTR192G/L211A (dmLT) in 80 healthy adult volunteers. The primary objective was safety and the secondary was the immunogenicity of the dmLT. Subjects received 3 doses of dmLT at days 1, 15, and 29. Subjects receiving the first dose at each dosage level were observed overnight in a research facility. The second and third doses were administered on an outpatient basis. Data from cohorts 1-4 were used to select the cohort 5 dose (25 µg), comparing SL and oral routes.
The vaccine appeared safe and well tolerated with only rare development of vomiting or diarrhea. The serum anti-dmLT IgA and IgG and neutralizing antibody responses were modest after any of the SL immunizations. Serum IgA and IgG titers were increased at the higher antigen doses (25 or 50 µg) but the percent with 4-fold increases was at best 38% for both IgA and IgG. The 4-fold increase among subjects receiving all 3 doses was 43% for both IgA and IgG. Antibody titers following oral administration were, in general, significantly higher than after SL. The frequency of IgA- or IgG-ASCs in circulation were somewhat vaccine dose dependent and were detected at a moderate level. However, antibodies in saliva or stool were rarely detected. Post-vaccination increases in T cells or cytokine production were also infrequent.
The dmLT vaccine formulation evaluated here was safe but only moderately immunogenic at doses up to 50 µg when administered by the SL or oral route. Studies at higher doses with better formulations appear warranted.
肠产毒性大肠杆菌（ETEC）对公共卫生的危害很大，但目前尚无专门用于预防 ETEC 感染的疫苗。
我们进行了一项 1 期、剂量递增研究（1-50μg），评估了双突变不耐热肠毒素 LTR192G/L211A（dmLT）经舌下（SL）给药在 80 名健康成年志愿者中的安全性和免疫原性。主要目的是安全性，次要目的是 dmLT 的免疫原性。受试者在第 1、15 和 29 天接受 3 次 dmLT 剂量。每个剂量水平接受第 1 次剂量的受试者在研究机构中过夜观察。第 2 次和第 3 次剂量在门诊进行。来自队列 1-4 的数据用于选择队列 5 剂量（25μg），比较 SL 和口服途径。
疫苗似乎是安全且耐受良好的，只有少数出现呕吐或腹泻。任何 SL 免疫接种后，血清抗 dmLT IgA 和 IgG 以及中和抗体反应都很温和。在较高的抗原剂量（25 或 50μg）下，血清 IgA 和 IgG 滴度增加，但 IgA 和 IgG 的 4 倍增加率最好为 38%。接受所有 3 次剂量的受试者中，IgA 和 IgG 的 4 倍增加率分别为 43%。口服给药后的抗体滴度通常明显高于 SL。循环中 IgA 或 IgG-ASC 的频率在一定程度上与疫苗剂量有关，并且检测到中等水平。然而，唾液或粪便中很少检测到抗体。疫苗接种后 T 细胞或细胞因子产生的增加也很少见。
在此评估的 dmLT 疫苗制剂在 SL 或口服途径给药时，剂量高达 50μg 是安全的，但仅具有中等免疫原性。需要更高剂量和更好制剂的研究。
