Characterization of a peptide vaccine candidate mimicking an oligosaccharide epitope of Neisseria gonorrhoeae and resultant immune responses and function

Ngampasutadol, Jutamas; Rice, Peter A.; Walsh, Mary T.; Gulati, Sunita

doi:10.1016/j.vaccine.2005.07.065

Cited by 34 publications

(61 citation statements)

References 45 publications

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“…Despite its phase-variable nature (7), gonococcal LOS has been considered as a potential vaccine antigen (8, 9). Men who were experimentally infected with N. gonorrhoeae were less likely to become infected upon rechallenge if they elicited an anti-LOS IgG response following the initial infection (10).…”

Section: Introductionmentioning

confidence: 99%

Phase-Variable Heptose I Glycan Extensions Modulate Efficacy of 2C7 Vaccine Antibody Directed against Neisseria gonorrhoeae Lipooligosaccharide

Chakraborti

Lewis

Cox

et al. 2016

The Journal of Immunology

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Neisseria gonorrhoeae , the causative agent of the sexually transmitted infection, gonorrhea, has developed resistance to most conventional antibiotics. Safe and effective vaccines against gonorrhea are needed urgently. A candidate vaccine that targets a lipooligosaccharide (LOS) epitope recognized by monoclonal (mAb) 2C7 attenuates gonococcal burden in the mouse vaginal colonization model. Glycan extensions from the LOS core heptoses (HepI and HepII) are controlled by phase-variable LOS glycosyltransferase (lgt) genes; we sought to define how HepI glycan extensions affect mAb 2C7 function. Isogenic gonococcal mutants in which the lgt required for mAb 2C7 reactivity (lgtG) was genetically locked ‘ON’ and the lgt loci required for HepI variation (lgtA, lgtC and lgtD) were genetically locked ‘ON’ or ‘OFF’ in different combinations were created. We observed 100% complement-dependent killing by mAb 2C7 of a mutant that expressed lactose (Gal-Glc) from HepI, while a mutant that expressed Gal-Gal-Glc-HepI fully resisted killing (>100% survival). Mutants that elaborated 4- (Gal-GlcNAc-Gal-Glc-HepI) and 5-glycan (GalNAc-Gal-GlcNAc-Gal-Glc-HepI) structures displayed ‘intermediate’ phenotypes (<50% killing with 2 μg/ml and >95% killing with 4 μg/ml of mAb 2C7). The contrasting phenotypes of the lactose-HepI and the Gal-Gal-Glc-HepI LOS structures were recapitulated with phase-variants of a recently isolated clinical strain. Despite lack of killing of the Gal-Gal-Glc-HepI mutants, mAb 2C7 deposited sufficient C3 on these bacteria for opsonophagocytic killing by human neutrophils. In conclusion, mAb 2C7 showed functional activity against all gonococcal HepI LOS structures defined by various lgtA/C/D ‘ON/OFF’ combinations, thereby providing further impetus for use of the 2C7 epitope in a gonococcal vaccine.

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Section: Introductionmentioning

confidence: 99%

Phase-Variable Heptose I Glycan Extensions Modulate Efficacy of 2C7 Vaccine Antibody Directed against Neisseria gonorrhoeae Lipooligosaccharide

Chakraborti

Lewis

Cox

et al. 2016

The Journal of Immunology

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“…Antibodies against LOS may protect against re-infection with the homologous strain as suggested in the male urethral experimental gonococcal infection model; those males who showed a 4-fold or greater rise in anti-LOS IgG were more resistant to re-infection with the homologous strain than volunteers who did not mount an anti-LOS response (28). Prior work in our laboratory has identified an LOS epitope that is recognized by a bactericidal monoclonal antibody (mAb) called 2C7 (29) as a potential vaccine candidate and have prompted efforts to develop a mimitopes of the 2C7 LOS epitope as an approach to circumvent the potential toxicity of the LOS molecule (30–31). …”

Section: Introductionmentioning

confidence: 99%

Properdin Is Critical for Antibody-Dependent Bactericidal Activity against Neisseria gonorrhoeae That Recruit C4b-Binding Protein

Gulati

Agarwal

Vasudhev

et al. 2012

The Journal of Immunology

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Gonorrhea, a sexually transmitted disease caused by Neisseria gonorrhoeae, is an important cause of morbidity worldwide. A safe and effective vaccine against gonorrhea is needed because of emerging resistance of gonococci to almost every class of antibiotic. A gonococcal lipooligosaccharide epitope defined by the mAb 2C7 is being evaluated as a candidate for development of an Ab-based vaccine. Immune Abs against N. gonorrhoeae need to overcome several subversive mechanisms whereby gonococcus evades complement, including binding to C4b-binding protein (C4BP; classical pathway inhibitor) and factor H (alternative pathway [AP] inhibitor). The role of AP recruitment and, in particular, properdin in assisting killing of gonococci by specific Abs is the subject of this study. We show that only those gonococcal strains that bind C4BP require properdin for killing by 2C7, whereas strains that do not bind C4BP are efficiently killed by 2C7 even when AP function is blocked. C3 deposition on bacteria mirrored killing. Recruitment of the AP by mAb 2C7, as measured by factor B binding, occurred in a properdin-dependent manner. These findings were confirmed using isogenic mutant strains that differed in their ability to bind to C4BP. Immune human serum that contained bactericidal Abs directed against the 2C7 lipooligosaccharide epitope as well as murine antigonococcal antiserum required functional properdin to kill C4BP-binding strains, but not C4BP-nonbinding strains. Collectively, these data point to an important role for properdin in facilitating immune Ab-mediated complement-dependent killing of gonococcal strains that inhibit the classical pathway by recruiting C4BP.

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“…Samples were plated onto GC chocolate agar (three to five plates for the pooled sera from each group) and incubated for approximately 24 h, and then viable gonococcus colonies were enumerated. Greater than 50% killing compared to negative controls was defined as significant killing (33,39,48).…”

Section: Methodsmentioning

confidence: 99%

Neisseria gonorrhoeae NspA Induces Specific Bactericidal and Opsonic Antibodies in Mice

Jiao

Jiang

et al. 2011

Clin Vaccine Immunol

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Characterization of a peptide vaccine candidate mimicking an oligosaccharide epitope of Neisseria gonorrhoeae and resultant immune responses and function

Cited by 34 publications

References 45 publications

Phase-Variable Heptose I Glycan Extensions Modulate Efficacy of 2C7 Vaccine Antibody Directed against Neisseria gonorrhoeae Lipooligosaccharide

Phase-Variable Heptose I Glycan Extensions Modulate Efficacy of 2C7 Vaccine Antibody Directed against Neisseria gonorrhoeae Lipooligosaccharide

Properdin Is Critical for Antibody-Dependent Bactericidal Activity against Neisseria gonorrhoeae That Recruit C4b-Binding Protein

Neisseria gonorrhoeae NspA Induces Specific Bactericidal and Opsonic Antibodies in Mice

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