Intradermal delivery of Shigella IpaB and IpaD type III secretion proteins: kinetics of cell recruitment and antigen uptake, mucosal and systemic immunity, and protection across serotypes.
Intradermal delivery of Shigella IpaB and IpaD type III secretion proteins: kinetics of cell recruitment and antigen uptake, mucosal and systemic immunity, and protection across serotypes.
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DOI：
10.4049/jimmunol.1302743
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发表时间：
2014-02-15
期刊：
影响因子：
--
通讯作者：
Pasetti MF
中科院分区：
文献类型：
--
作者：
Heine SJ;Diaz-McNair J;Andar AU;Drachenberg CB;van de Verg L;Walker R;Picking WL;Pasetti MF
志贺氏菌是低收入国家造成巨大儿科腹泻疾病负担的主要病原体之一。目前还没有获得许可的疫苗，现有的候选疫苗仅部分有效且具有血清型特异性。志贺氏菌 III 型分泌系统蛋白 IpaB 和 IpaD 在志贺氏菌属中保守，是基于亚单位的广泛保护性疫苗的候选者。在此，我们研究了使用微针皮内 (i.d.) 与大肠杆菌不耐热肠毒素 (dmLT) 佐剂双突变体施用 IpaB 和 IpaD 的免疫原性和保护功效。在小鼠中测试了不同剂量水平的 IpaB 和 IpaD（有或没有 dmLT）。通过组织学和免疫荧光显微镜证明了疫苗递送至真皮、中性粒细胞、巨噬细胞、树突状细胞（DC）和朗格汉斯细胞（LC）的募集以及疫苗抗原在皮肤激活抗原呈递细胞（APC）内的共定位。负载Ag的中性粒细胞、巨噬细胞、DC和LC在组织中保留至少一周。 IpaB、IpaD 和 dmLT 特异性血清 IgG 和 IgG 分泌细胞在 i.d. 后产生。免疫接种。对福氏链球菌的保护效力为70%，对宋内链球菌的保护效力为50%。当疫苗经鼻内注射时获得了类似的结果。路线需要低 25-40 倍的剂量。值得注意的是，在粘膜分泌物中检测到了 IgG； sIgA 以及粘膜和全身 IgA 抗体分泌细胞 (ASC) 似乎不存在。疫苗诱导的 T 细胞产生 IFN-γ、IL-2、TNF-α、IL-17、IL-4、IL-5 和 IL-10。这些结果证明了 i.d. 的潜力。接种 IpaB 和 IpaD 疫苗可预防志贺氏菌感染并支持进一步的人体研究。
Shigella is one of the leading pathogens contributing to the vast pediatric diarrheal disease burden in low-income countries. No licensed vaccine is available and the existing candidates are only partially effective and serotype-specific. Shigella type III secretion system proteins IpaB and IpaD, which are conserved across Shigella spp., are candidates for a broadly protective, subunit-based vaccine. Herein, we investigated the immunogenicity and protective efficacy of IpaB and IpaD administered intradermally (i.d.) with a double-mutant of the E. coli heat-labile enterotoxin (dmLT) adjuvant using microneedles. Different dosage levels of IpaB and IpaD with or without dmLT were tested in mice. Vaccine delivery into the dermis, recruitment of neutrophils, macrophages, dendritic cells (DC) and Langerhans cells (LC), and colocalization of vaccine antigens within skin-activated antigen presenting cells (APC) was demonstrated through histology and immunofluorescence microscopy. Ag-loaded neutrophils, macrophages, DC and LC remained in the tissue at least one week. IpaB, IpaD and dmLT-specific serum IgG and IgG secreting cells were produced following i.d. immunization. The protective efficacy was 70% against S. flexneri and 50% against S. sonnei. Similar results were obtained when the vaccine was administered intranasally, with the i.d. route requiring 25-40 times lower doses. Distinctively, IgG was detected in mucosal secretions; sIgA as well as mucosal and systemic IgA antibody secreting cells (ASC) were seemingly absent. Vaccine-induced T cells produced IFN-γ, IL-2, TNF-α, IL-17, IL-4, IL-5 and IL-10. These results demonstrate the potential of i.d. vaccination with IpaB and IpaD to prevent Shigella infection and support further studies in humans.
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DOI：
10.2471/blt.10.079426
发表时间：
2011-03-01
期刊：
Bulletin of the World Health Organization: International Journal of Public Health
影响因子：
--
作者：
Hickling, JK;Jones, KR;Kristensen, D
通讯作者：
Kristensen, D
影响因子：
168.9
作者：
Lozano, Rafael;Naghavi, Mohsen;Murray, Christopher J. L.
通讯作者：
Murray, Christopher J. L.
影响因子：
6.5
作者：
Liard, Christelle;Munier, Severine;Combadiere, Behazine
通讯作者：
Combadiere, Behazine
影响因子：
5.5
作者：
Heine, Shannon J.;Diaz-McNair, Jovita;Pasetti, Marcela F.
通讯作者：
Pasetti, Marcela F.
影响因子：
168.9
作者：
Kotloff, Karen L.;Nataro, James P.;Levine, Myron M.
通讯作者：
Levine, Myron M.