Double-blind vaccine-controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults

Cohen, Dani; Ashkenazi, Shai; Green, Manfred S.; Gdalevich, Michael; Robin, Guy; Slepon, Raphael; Yavzori, Miri; Orr, Nadav; Block, Colin; Ashkenazi, Isaac; Shemer, Joshua; Taylor, David N.; Hale, Thomas L.; Sadoff, Jerald C.; Pavliakova, Danka; Schneerson, Rachel; Robbins, John B.

doi:10.1016/s0140-6736(96)06255-1

Cited by 239 publications

(167 citation statements)

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“…A parenteral prototype NICHD vaccine that consists of S. sonnei O polysaccharide conjugated to PsA was shown to be well tolerated and highly immunogenic in stimulating serum IgG O-antigen antibodies in young Israeli soldiers 113,114 . In a randomized, controlled, double-blind Phase III efficacy trial involving several hundred Israeli soldiers, a single dose of the S. sonnei conjugate vaccine conferred 74% protection against S. sonnei diarrhoea during outbreaks on army bases 114 .…”

Section: Shigella Conjugate Vaccinesmentioning

confidence: 99%

“…In a randomized, controlled, double-blind Phase III efficacy trial involving several hundred Israeli soldiers, a single dose of the S. sonnei conjugate vaccine conferred 74% protection against S. sonnei diarrhoea during outbreaks on army bases 114 . The efficacy of the vaccine was related to the level of conjugate-induced IgG anti-O-antigen antibody.…”

Section: Shigella Conjugate Vaccinesmentioning

confidence: 99%

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Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

et al. 2007

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More than 50 years of research has yielded numerous Shigella vaccine candidates that have exemplified both the promise of vaccine-induced prevention of shigellosis and the impediments to developing a safe and effective vaccine for widespread use, a goal that has yet to be attained. This Review discusses the most advanced strategies for Shigella vaccine development, the immune responses that are elicited following disease or vaccination, the factors that have accelerated or impeded Shigella vaccine development and our ideas for the way forward.At the end of the 19th century, as epidemics of bacillary dysentery accompanied by high mortality spread across Japan, the young microbiologist Kiyoshi Shiga examined dysenteric stools and isolated a bacterium that was agglutinated by serum from convalescent patients but not from patients with acute disease [1][2][3] (FIG. 1). That bacterium -known today as Shigella dysenteriae 1 -was the first identified member of the genus Shigella. Four Correspondence to M.L. mlevine@medicine.umaryland.edu. Competing interests statement:The authors declare no competing financial interests. Links NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptShigella species (or groups) are now recognized: S. dysenteriae (group A), which has 15 serotypes; Shigella flexneri (group B), which has 14 classical serotypes and subserotypes; Shigella boydii (group C), which has 20 serotypes; and Shigella sonnei (group D), which has single serotype 4 (TABLE 1).There has been resurgent interest in Shigella as a human pathogen, driven by the availability of more precise data on the disease burden 5-8 , emerging antibiotic resistance 9,10 and the fact that mucosally invasive Shigella, which often cause dysentery (gross blood in diarrhoeal stools), are less amenable to the salutary effects of oral rehydration than non-invasive pathogens that cause watery diarrhoea, such as Vibrio cholerae and enterotoxigenic Escherichia coli. The target populations for the use of Shigella vaccines include infants and young children in developing countries (in which the peak incidence occurs at 12-47 months of age and the S. flexneri serotypes predominate) 5-7 .S. dysenteriae 1, which produces Shiga toxin and typically carries R factors that encode resistance to multiple antibodies, waxes and wanes as a cause of epidemic severe disease in the world's least developed countries [11][12][13][14] Few bacterial pathogens have had their pathogenesis or interactions with mammalian tissues elucidated so precisely at the cellular and subcellular levels as Shigella spp. 20,21 Nevertheless, progress in attaining safe and effective Shigella vaccines has faltered. Herein, we review recent and old clinical trials that have evaluated the safety, immunogenicity and efficacy of candidate Shigella vaccines. We relate the bassis for the most popular strategies (BOX 2), the relevance of the different immune responses measured, the factors that have favoured or impeded vaccine development and, most importantly, the less...

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Section: Shigella Conjugate Vaccinesmentioning

confidence: 99%

Section: Shigella Conjugate Vaccinesmentioning

confidence: 99%

Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

et al. 2007

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“…O-specific polysaccharide (O-SP), the outermost domain of the LPS of shigellae is both an essential virulence factor and a protective antigen based on the following evidence: (i) Shigellae from patients' stool invariably express a complete LPS, whereas LPS-deficient strains are avirulent (8); (ii) the closely related Escherichia coli that express Shigella LPS assume the virulence of this species (9); (iii) convalescence from disease confers LPS-specific immunity, albeit incomplete and of limited duration (1, 10); (iv) preexisting IgG LPS antibodies protected soldiers from shigellosis (11); and (v) immunization of soldiers with a Shigella sonnei conjugate conferred protection against this pathogen related to the level of vaccine-induced IgG antibodies (12). Similar to capsulated pathogens, such as Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis, there is an inverse relation between the level of ''natural'' anti-LPS and the age incidence of shigellosis.…”

mentioning

confidence: 99%

O-Specific polysaccharide conjugate vaccine-induced IgG antibodies prevent invasion of Shigella into Caco-2 cells and may be curative

Chowers

Kirschner²,

Keller³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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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-1β 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.

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“…Shigella sonnei O-SP conjugates were effective in adults [10]. Monoclonal antibodies to the core oligosaccharide of B. pertussis LOS exhibited bactericidal activity and reduced colonization with these bacteria in the lungs and tracheas of mice [13].…”

Section: Discussionmentioning

confidence: 99%

“…Serum IgG anti-LPS has been shown to confer immunity to Gram-negative bacteria [10,11,12]. Monoclonal antibodies to B. pertussis LPS were shown to have complement-dependent bactericidal activity [13].…”

Section: Introductionmentioning

confidence: 99%

Saccharide/protein conjugate vaccines for Bordetella species: Preparation of saccharide, development of new conjugation procedures, and physico-chemical and immunological characterization of the conjugates

Kübler-Kiełb

Vinogradov

Ben-Menachem

et al. 2008

Vaccine

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Bordetellae are Gram-negative bacilli causing respiratory tract infections of mammals and birds. Competitive inhibition assays showed the immunodominance of the non-reducing end of these O-SP. Conjugates of B. bronchiseptica and B. parapertussis O-SP were prepared by two methods: using the Kdo residue exposed by mild acid hydrolysis of the LPS or the core glucosamine residue exposed by deamination of the LPS, for binding to an aminooxylated protein. Both coupling methods were carried out at a neutral pH, room temperature, and in a short time. All conjugates, injected as saline solutions at a fraction of an estimated human dose, induced antibodies in mice to the homologous O-SP. These methodologies can be applied to prepare O-SP-based vaccines against other Gramnegative bacteria.

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Double-blind vaccine-controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults

Cited by 239 publications

References 22 publications

Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

O-Specific polysaccharide conjugate vaccine-induced IgG antibodies prevent invasion of Shigella into Caco-2 cells and may be curative

Saccharide/protein conjugate vaccines for Bordetella species: Preparation of saccharide, development of new conjugation procedures, and physico-chemical and immunological characterization of the conjugates

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