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.
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-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.
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD 21201;
Shannon J
SJ
Heine
Jovita
J
Diaz-McNair
Abhay U
AU
Andar
Cinthia B
CB
Drachenberg
Lillian
L
van de Verg
Richard
R
Walker
Wendy L
WL
Picking
Marcela F
MF
Pasetti
D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage* / Q000276:immunology; D001426:Bacterial Proteins / Q000008:administration & dosage* / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D056738:Cross Protection / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D016503:Drug Delivery Systems; D004405:Dysentery, Bacillary / Q000276:immunology* / Q000517:prevention & control; D004768:Enterotoxins / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D029968:Escherichia coli Proteins / Q000276:immunology; D005260:Female; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D007801:Langerhans Cells / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D022281:Shigella Vaccines / Q000008:administration & dosage / Q000276:immunology*; D012763:Shigella flexneri / Q000276:immunology; D012764:Shigella sonnei / Q000276:immunology; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000276:immunology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D016207:Cytokines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C095770:IpaD protein, Shigella flexneri; D022281:Shigella Vaccines; D022223:Vaccines, Subunit; C087447:ipaB protein, Shigella; C027538:heat-labile enterotoxin, E coli