Article

O-specific [corrected] polysaccharide conjugate vaccine-induced [corrected] antibodies prevent invasion of Shigella into Caco-2 cells and may be curative.

Department of Gastroenterology, Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2007; 104(7):2396-401. DOI: 10.1073/pnas.0610833104
Source: PubMed

ABSTRACT The O-specific polysaccharide (O-SP) domain of Shigella LPS is both an essential virulence factor and a protective antigen for this genus. A critical level of serum IgG anti-O-SP was shown to confer immunity to shigellosis, likely by complement-mediated bacteriolysis of the inoculum. Conjugate Shigella O-SP vaccines were shown to be safe and immunogenic in children, and, in a preliminary study, Shigella sonnei vaccine was protective in young adults. Characteristic of shigellosis is bacterial invasion of intestinal cells. Incubation of shigellae with postimmunization but not preimmunization sera of children vaccinated with S. sonnei or Shigella flexneri 2a O-SP conjugate vaccines inhibited in a type-specific and dose-dependent manner in vitro invasion of intestinal epithelial cells (Caco-2) and the infection-associated increases in IL-1beta and IL-8 mRNA and extracellular cytokine levels. Pretreatment of these sera or of Caco-2 cells with O-SP abrogated these effects also in a type-specific and dose-dependent manner. Confocal microscopy demonstrated antibody-specific inhibition of bacterial adhesion to HeLa cells. These protective effects were duplicated by IgG purified from these sera. These results suggest a dual role for IgG anti-O-SP. In addition to lysis of the inoculum in immune individuals, the newly synthesized IgG anti-O-SP in patients may terminate an established infection by inhibiting shigellae released from epithelial cells from invading new ones. A critical level of IgG anti-O-SP could, therefore, have a protective as well as a curative role in shigellosis.

Full-text

Available from: Nathan Keller, Apr 23, 2015
0 Followers
 · 
158 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Shigella causes diarrhea and dysentery through contaminated food and water. Shigella sonnei live vaccine candidates WRSs2 and WRSs3 are attenuated principally by the loss of VirG(IcsA) that prevents bacterial spread within the colonic epithelium. In this respect they are similar to the clinically tested vaccine candidate WRSS1. However, WRSs2 and WRSs3 are further attenuated by loss of senA, senB and WRSs3 also lacks msbB2. As previously shown in cell culture assays and in small animal models, these additional gene deletions reduced the levels of enterotoxicity and endotoxicity of WRSs2 and WRSs3, potentially making them safer than WRSS1. However the behavior of these second-generation VirG(IcsA)-based vaccine candidates in eliciting an immune response in a gastrointestinal model of infection has not been evaluated. In this study, WRSs2 and WRSs3 were nasogastrically administered to rhesus monkeys that were evaluated for colonization, as well as for systemic and mucosal immune responses. Both vaccine candidates were safe in rhesus monkeys and behaved comparably to WRSS1 in bacterial excretion rates that demonstrated robust intestinal colonization. Furthermore, humoral and mucosal immune responses elicited against bacterial antigens appeared similar in all categories across all three strains indicating that the additional gene deletions did not compromise the immunogenicity of these vaccine candidates. Based on data from previous clinical trials with WRSS1, it is likely that, WRSs2 and WRSs3 will not only be safer in human volunteers but will generate comparable levels of systemic and mucosal immune responses that were achieved with WRSS1.
    Vaccine 05/2011; 29(37):6371-8. DOI:10.1016/j.vaccine.2011.04.115 · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Shigellosis remains a formidable disease globally, with children of the developing world bearing the greatest number of infections. The need for an affordable, safe and efficacious vaccine has persisted for decades. Vaccines to prevent shigellosis can be divided into living and nonliving approaches. Several nonliving Shigella vaccines are currently at different stages of development and show substantial promise. Outlined here is an overview of multiple nonliving vaccine technologies, highlighting their current status and recent advances in testing. In addition, gaps in the knowledge base regarding immune mechanisms of protection are explored.
    Expert Review of Vaccines 12/2009; 8(12):1693-704. DOI:10.1586/erv.09.127 · 4.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In our earlier studies, we constructed a hybrid strain of Shigella dysenteriae type 1 by introducing a plasmid vector pPR 1347. After introduction of a lipopolysaccharide (LPS) biosynthesis gene, virulent Shigella dysenteriae type 1 strain became avirulent. In our present study, we have evaluated the immune response and protective efficacy of avirulent live transconjugant Shigella hybrid (LTSH) strain against wild type Shigella dysenteriae type 1, after four doses of oral (rabbit) and intranasal (mouse) immunizations. Serum IgG titers showed exponential increase during immunization and peaking on the 28th day and remained at that level till the 35th day in both the rabbit and the mouse models. When tested, serum IgG titers persisted for 63days in mice and relatively high for 150days in case of rabbits. Protection studies showed 100% protection against the challenge with wild type Shigella dysenteriae type 1 strain in rabbits and 80% protection in mice. Our results suggested that the LTSH strain could be a useful vaccine candidate strain in the future.
    World Journal of Microbiology and Biotechnology 01/2009; 25(4):679-686. DOI:10.1007/s11274-008-9937-6 · 1.35 Impact Factor