title: Shigella IpaB and IpaD displayed on L. lactis bacterium-like particles induce protective immunity in adult and infant mice.
abstract: Shigella spp. are among the enteric pathogens with the highest attributable incidence of moderate-to-severe diarrhea in children under 5 years of age living in endemic areas. There are no vaccines available to prevent this disease. In this work, we investigated a new Shigella vaccine concept consisting of nonliving, self-adjuvanted, Lactococcus lactis bacterium-like particles (BLP) displaying Shigella invasion plasmid antigen (Ipa) B and IpaD and examined its immunogenicity and protective efficacy in adult and newborn/infant mice immunized via the nasal route. Unique advantages of this approach include the potential for broad protection due to the highly conserved structure of the Ipas and the safety and practicality of a probiotic-based mucosal/adjuvant delivery platform. Immunization of adult mice with BLP-IpaB and BLP-IpaD (BLP-IpaB/D) induced high levels of Ipa-specific serum IgG and stool IgA in a dose-dependent manner. Immune responses and protection were enhanced by BLP delivery. Vaccine-induced serum antibodies exhibited opsonophagocytic and cytotoxic neutralizing activity, and IpaB/D IgG titers correlated with increased survival post-challenge. Ipa-specific antibody secreting cells were detected in nasal tissue and lungs, as well as IgG in bronchoalveolar lavage. Bone marrow cells produced IpaB/D-specific antibodies and contributed to protection after adoptive transfer. The BLP-IpaB/D vaccine conferred 90% and 80% protection against S. flexneri and S. sonnei, respectively. Mice immunized with BLP-IpaB/D as newborns also developed IpaB and IpaD serum antibodies; 90% were protected against S. flexneri and 44% against S. sonnei. The BLP-IpaB/D vaccine is a promising candidate for safe, practical and potentially effective immunization of children against shigellosis.
authors.affiliation: 1] Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA [2] Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Shannon J
authors.initials: SJ
authors.lastname: Heine
authors.affiliation: 1] Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA [2] Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Olga L
authors.initials: OL
authors.lastname: Franco-Mahecha
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
authors.forename: Shyamal
authors.initials: S
authors.lastname: Choudhari
authors.affiliation: Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Blackwelder
authors.affiliation: Mucosis BV, Groningen, The Netherlands.
authors.forename: Maarten L
authors.initials: ML
authors.lastname: van Roosmalen
authors.affiliation: Mucosis BV, Groningen, The Netherlands.
authors.forename: Kees
authors.initials: K
authors.lastname: Leenhouts
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Picking
authors.affiliation: 1] Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, MD, USA [2] Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Pasetti
mesh_terms: D000276:Adjuvants, Immunologic; D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology; D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000276:immunology; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D005260:Female; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D013294:Lactococcus lactis; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000276:immunology; D022281:Shigella Vaccines / Q000008:administration & dosage / Q000276:immunology*; D014611:Vaccination; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C095770:IpaD protein, Shigella flexneri; D022281:Shigella Vaccines; D014614:Vaccines, Synthetic; C087447:ipaB protein, Shigella