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

被引：52

作者：

Heine, Shannon J. ^{[1
,2
]}

Diaz-McNair, Jovita ^{[1
,2
]}

Andar, Abhay U. ^{[3
]}

Drachenberg, Cinthia B. ^{[4
]}

van de Verg, Lillian ^{[5
]}

Walker, Richard ^{[5
]}

Picking, Wendy L. ^{[6
]}

Pasetti, Marcela F. ^{[1
,5
]}

机构：

[1] Univ Maryland, Ctr Vaccine Dev, Sch Med, Baltimore, MD 21201 USA

[2] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA

[3] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA

[4] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA

[5] PATH, Enter Vaccine Initiat, Washington, DC 20001 USA

[6] Oklahoma State Univ, Dept Microbiol & Mol Genet, Stillwater, OK 74078 USA

来源：

JOURNAL OF IMMUNOLOGY | 2014年 / 192卷 / 04期

基金：

美国国家卫生研究院;

关键词：

DEVELOPING-COUNTRIES; INVASION PLASMID; BELLS-PALSY; FLEXNERI; VACCINES; DISEASES; IMMUNOGENICITY; RESPONSES; CHILDREN; ANTIBODY;

D O I：

10.4049/jimmunol.1302743

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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. In this study, we investigated the immunogenicity and protective efficacy of IpaB and IpaD administered intradermally (i.d.) with a double-mutant of the Escherichia 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, and Langerhans cells, and colocalization of vaccine Ag within skin-activated APC were demonstrated through histology and immunofluorescence microscopy. Ag-loaded neutrophils, macrophages, dendritic cells, and Langerhans cells remained in the tissue at least 1 wk. IpaB, IpaD, and dmLT-specific serum IgG- and IgG-secreting cells were produced following i.d. immunization. The protective efficacy was 70% against Shigella flexneri and 50% against Shigella 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; secretory IgA, as well as mucosal and systemic IgA Ab-secreting cells, were seemingly absent. Vaccine-induced T cells produced IFN-gamma, IL-2, TNF-alpha, 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.

引用

页码：1630 / 1640

页数：11