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Immunization against a saccharide epitope accelerates clearance of experimental gonococcal infection.

Gulati S, Zheng B, Reed GW, Su X, Cox AD, St Michael F, Stupak J, Lewis LA, Ram S, Rice PA - PLoS Pathog. (2013)

Bottom Line: The epitope is expressed by 94% of gonococci that reside in the human genital tract (in vivo) and by 95% of first passaged isolates.To circumvent the limitations of saccharide immunogens in producing long lived immune responses, previously we developed a peptide mimic (called PEP1) as an immunologic surrogate of the 2C7-OS epitope and reconfigured it into a multi-antigenic peptide, (MAP1).The OS epitope defined by mAb 2C7 may represent an effective vaccine target against gonorrhea, which is rapidly becoming incurable with currently available antibiotics.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
The emergence of ceftriaxone-resistant strains of Neisseria gonorrhoeae may herald an era of untreatable gonorrhea. Vaccines against this infection are urgently needed. The 2C7 epitope is a conserved oligosaccharide (OS) structure, a part of lipooligosaccharide (LOS) on N gonorrhoeae. The epitope is expressed by 94% of gonococci that reside in the human genital tract (in vivo) and by 95% of first passaged isolates. Absence of the 2C7 epitope shortens the time of gonococcal carriage in a mouse model of genital infection. To circumvent the limitations of saccharide immunogens in producing long lived immune responses, previously we developed a peptide mimic (called PEP1) as an immunologic surrogate of the 2C7-OS epitope and reconfigured it into a multi-antigenic peptide, (MAP1). To test vaccine efficacy of MAP1, female BALB/c mice were passively immunized with a complement-dependent bactericidal monoclonal antibody specific for the 2C7 epitope or were actively immunized with MAP1. Mice immunized with MAP1 developed a TH1-biased anti-LOS IgG antibody response that was also bactericidal. Length of carriage was shortened in immune mice; clearance occurred in 4 days in mice passively administered 2C7 antibody vs. 6 days in mice administered control IgG3λ mAb in one experiment (p = 0.03) and 6 vs. 9 days in a replicate experiment (p = 0.008). Mice vaccinated with MAP1 cleared infection in 5 days vs. 9 days in mice immunized with control peptide (p = 0.0001 and p = 0.0002, respectively in two replicate experiments). Bacterial burden was lower over the course of infection in passively immunized vs. control mice in both experiments (p = 0.008 and p = 0.0005); burdens were also lower in MAP1 immunized mice vs. controls (p<0.0001) and were inversely related to vaccine antibodies induced in the vagina (p = 0.043). The OS epitope defined by mAb 2C7 may represent an effective vaccine target against gonorrhea, which is rapidly becoming incurable with currently available antibiotics.

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Simplified schematic of the oligosaccharide (OS) structure of gonococcal LOS.Lipooligosaccharide glycosyl transferase (lgt) genes that are involved in LOS biosynthesis and are subject to phase variation are indicated in grey italic font. Each transferase catalyzes the substitution of the next more distal hexose onto the LOS backbone. The grey shaded box represents the minimum OS structure expressed by naturally occurring gonococcal strains that is required for mAb 2C7 binding.
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ppat-1003559-g001: Simplified schematic of the oligosaccharide (OS) structure of gonococcal LOS.Lipooligosaccharide glycosyl transferase (lgt) genes that are involved in LOS biosynthesis and are subject to phase variation are indicated in grey italic font. Each transferase catalyzes the substitution of the next more distal hexose onto the LOS backbone. The grey shaded box represents the minimum OS structure expressed by naturally occurring gonococcal strains that is required for mAb 2C7 binding.

Mentions: Despite antigenic heterogeneity of LOS, we have identified a common oligosaccharide structure within gonococcal LOS that is recognized by a murine monoclonal antibody (mAb), called 2C7 [9], [11]. This structure (Figure 1) requires the substitution of lactose onto HepII and at a minimum, substitution of lactose on HepI [12]. The 2C7 epitope was identified directly in the genital secretions of 94% of 68 culture-positive subjects and on 95% of 101 strains of N. gonorrhoeae isolated from infected subjects [9]. Human antibodies against the 2C7 epitope also mediate complement-dependent bacterial killing and opsonophagocytosis. Compared to purified LOS, the 2C7 epitope selectively elicited a greater antibody response after gonococcal endometritis and disseminated infection [9]. Male volunteers immunized with a gonococcal outer membrane vaccine that contained LOS harboring the 2C7 epitope developed a 10-fold excess of 2C7 antibody compared to a rise in antibody against whole LOS [9], thereby confirming superior immunogenicity of the 2C7 epitope in a human vaccine trial.


Immunization against a saccharide epitope accelerates clearance of experimental gonococcal infection.

Gulati S, Zheng B, Reed GW, Su X, Cox AD, St Michael F, Stupak J, Lewis LA, Ram S, Rice PA - PLoS Pathog. (2013)

Simplified schematic of the oligosaccharide (OS) structure of gonococcal LOS.Lipooligosaccharide glycosyl transferase (lgt) genes that are involved in LOS biosynthesis and are subject to phase variation are indicated in grey italic font. Each transferase catalyzes the substitution of the next more distal hexose onto the LOS backbone. The grey shaded box represents the minimum OS structure expressed by naturally occurring gonococcal strains that is required for mAb 2C7 binding.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3757034&req=5

ppat-1003559-g001: Simplified schematic of the oligosaccharide (OS) structure of gonococcal LOS.Lipooligosaccharide glycosyl transferase (lgt) genes that are involved in LOS biosynthesis and are subject to phase variation are indicated in grey italic font. Each transferase catalyzes the substitution of the next more distal hexose onto the LOS backbone. The grey shaded box represents the minimum OS structure expressed by naturally occurring gonococcal strains that is required for mAb 2C7 binding.
Mentions: Despite antigenic heterogeneity of LOS, we have identified a common oligosaccharide structure within gonococcal LOS that is recognized by a murine monoclonal antibody (mAb), called 2C7 [9], [11]. This structure (Figure 1) requires the substitution of lactose onto HepII and at a minimum, substitution of lactose on HepI [12]. The 2C7 epitope was identified directly in the genital secretions of 94% of 68 culture-positive subjects and on 95% of 101 strains of N. gonorrhoeae isolated from infected subjects [9]. Human antibodies against the 2C7 epitope also mediate complement-dependent bacterial killing and opsonophagocytosis. Compared to purified LOS, the 2C7 epitope selectively elicited a greater antibody response after gonococcal endometritis and disseminated infection [9]. Male volunteers immunized with a gonococcal outer membrane vaccine that contained LOS harboring the 2C7 epitope developed a 10-fold excess of 2C7 antibody compared to a rise in antibody against whole LOS [9], thereby confirming superior immunogenicity of the 2C7 epitope in a human vaccine trial.

Bottom Line: The epitope is expressed by 94% of gonococci that reside in the human genital tract (in vivo) and by 95% of first passaged isolates.To circumvent the limitations of saccharide immunogens in producing long lived immune responses, previously we developed a peptide mimic (called PEP1) as an immunologic surrogate of the 2C7-OS epitope and reconfigured it into a multi-antigenic peptide, (MAP1).The OS epitope defined by mAb 2C7 may represent an effective vaccine target against gonorrhea, which is rapidly becoming incurable with currently available antibiotics.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.

ABSTRACT
The emergence of ceftriaxone-resistant strains of Neisseria gonorrhoeae may herald an era of untreatable gonorrhea. Vaccines against this infection are urgently needed. The 2C7 epitope is a conserved oligosaccharide (OS) structure, a part of lipooligosaccharide (LOS) on N gonorrhoeae. The epitope is expressed by 94% of gonococci that reside in the human genital tract (in vivo) and by 95% of first passaged isolates. Absence of the 2C7 epitope shortens the time of gonococcal carriage in a mouse model of genital infection. To circumvent the limitations of saccharide immunogens in producing long lived immune responses, previously we developed a peptide mimic (called PEP1) as an immunologic surrogate of the 2C7-OS epitope and reconfigured it into a multi-antigenic peptide, (MAP1). To test vaccine efficacy of MAP1, female BALB/c mice were passively immunized with a complement-dependent bactericidal monoclonal antibody specific for the 2C7 epitope or were actively immunized with MAP1. Mice immunized with MAP1 developed a TH1-biased anti-LOS IgG antibody response that was also bactericidal. Length of carriage was shortened in immune mice; clearance occurred in 4 days in mice passively administered 2C7 antibody vs. 6 days in mice administered control IgG3λ mAb in one experiment (p = 0.03) and 6 vs. 9 days in a replicate experiment (p = 0.008). Mice vaccinated with MAP1 cleared infection in 5 days vs. 9 days in mice immunized with control peptide (p = 0.0001 and p = 0.0002, respectively in two replicate experiments). Bacterial burden was lower over the course of infection in passively immunized vs. control mice in both experiments (p = 0.008 and p = 0.0005); burdens were also lower in MAP1 immunized mice vs. controls (p<0.0001) and were inversely related to vaccine antibodies induced in the vagina (p = 0.043). The OS epitope defined by mAb 2C7 may represent an effective vaccine target against gonorrhea, which is rapidly becoming incurable with currently available antibiotics.

Show MeSH
Related in: MedlinePlus