Intradermal or Sublingual Delivery and Heat-Labile Enterotoxin Proteins Shape Immunologic Responses to a CFA/I Fimbria-Derived Subunit Antigen Vaccine against Enterotoxigenic Escherichia coli
Intradermal or Sublingual Delivery and Heat-Labile Enterotoxin Proteins Shape Immunologic Responses to a CFA/I Fimbria-Derived Subunit Antigen Vaccine against Enterotoxigenic Escherichia coli
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DOI：
10.1128/iai.00460-19
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发表时间：
2019-11-01
影响因子：
3.1
通讯作者：
Norton, Elizabeth B.
中科院分区：
文献类型：
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作者：
Maciel, Milton, Jr.;Bauer, David;Norton, Elizabeth B.
产肠毒素大肠杆菌（ETEC）是儿童、旅行者和部署的军事人员感染性腹泻的主要原因。因此，疫苗的开发将有利于公共卫生。一种策略是使用定植因子亚单位与抗原/佐剂类毒素组合作为ETEC疫苗。在这里，我们研究了皮内（i.d.）或舌下（s.l.）CFA/I菌毛抗原的递送，包括与双突变型热不稳定毒素（LT）LT-R192 G/L211 A（dmLT）混合的CfaEB和CfaE-热不稳定毒素B亚基（LTB）嵌合体。此外，我们将dmLT与其他LT蛋白进行了比较，以更好地了解佐剂菌毛和类毒素免疫的产生以及对任何局部皮肤反应原性的影响。我们证明，用与CfaEB混合的dmLT免疫诱导了对CFA/I菌毛和LT的稳健的血清和粪便抗体应答，但i.d.制剂对于S.L.不是最佳的。交付.改善s.l.当将更高剂量的dmLT（1至5 μ g）与CfaEB混合时，或者当使用CfaE-LTB嵌合抗原时，甚至更好，观察到接种结果。基于ETEC对红细胞凝集的抑制，通过酶联免疫吸附试验检测的血清抗CFA/I总抗体是功能性抗体的最佳预测因子。在i.d.期间用其他LT蛋白或具有改变的B亚基结合的制剂免疫免疫（例如，通过添加5%乳糖、LTA 1或LT-G33 D）最小程度地改变了抗体应答和细胞因子回忆应答的发展，但降低了注射部位的皮肤反应原性。这些结果揭示了制剂和递送参数如何影响对抗ETEC的类毒素和菌毛衍生亚单位疫苗的适应性免疫应答。
Enterotoxigenic Escherichia coli (ETEC) is a major cause of infectious diarrhea in children, travelers, and deployed military personnel. As such, development of a vaccine would be advantageous for public health. One strategy is to use subunits of colonization factors combined with antigen/adjuvant toxoids as an ETEC vaccine. Here, we investigated the intradermal (i.d.) or sublingual (s.l.) delivery of CFA/I fimbrial antigens, including CfaEB and a CfaE-heat-labile toxin B subunit (LTB) chimera admixed with double mutant heat-labile toxin (LT) LT-R192G/L211A (dmLT). In addition, we compared dmLT with other LT proteins to better understand the generation of adjuvanted fimbrial and toxoid immunity as well as the influence on any local skin reactogenicity. We demonstrate that immunization with dmLT admixed with CfaEB induces robust serum and fecal antibody responses to CFA/I fimbriae and LT but that i.d. formulations are not optimal for s.l. delivery. Improved s.l. vaccination outcomes were observed when higher doses of dmLT (1 to 5 mu g) were admixed with CfaEB or, even better, when a CfaE-LTB chimera antigen was used instead. Serum anti-CFA/I total antibodies, detected by enzyme-linked immunosorbent assay, were the best predictor of functional antibodies, based on the inhibition of red blood cell agglutination by ETEC. Immunization with other LT proteins or formulations with altered B-subunit binding during i.d. immunization (e.g., by addition of 5% lactose, LTA1, or LT-G33D) minimally altered the development of antibody responses and cytokine recall responses but reduced skin reactogenicity at the injection site. These results reveal how formulations and delivery parameters shape the adaptive immune responses to a toxoid and fimbria-derived subunit vaccine against ETEC.