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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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Anti-LOS IgG antibody responses induced by MAP1-MPL immunization.32 BALB/c mice were immunized intraperitoneally (ip) with MAP1 emulsified with MPL and boosted four times at 3-week intervals. A. Total anti-LOS IgG antibody levels at wk 5, 8,11 and 14 following immunization. B. Post-immunization (wk 14) anti-LOS IgG subclass, IgM and IgA anti-LOS antibody levels. Results are represented as box plots; the spots represent outliers beyond the 1.5 IQR (intraquartile range). IgG subclass responses indicate a TH1-biased response (see text, [22]).
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ppat-1003559-g003: Anti-LOS IgG antibody responses induced by MAP1-MPL immunization.32 BALB/c mice were immunized intraperitoneally (ip) with MAP1 emulsified with MPL and boosted four times at 3-week intervals. A. Total anti-LOS IgG antibody levels at wk 5, 8,11 and 14 following immunization. B. Post-immunization (wk 14) anti-LOS IgG subclass, IgM and IgA anti-LOS antibody levels. Results are represented as box plots; the spots represent outliers beyond the 1.5 IQR (intraquartile range). IgG subclass responses indicate a TH1-biased response (see text, [22]).

Mentions: Sera from mice actively immunized with MAP1 or MAP-control (a peptide that does not bind 2C7), each administered with a Monophosphoryl Lipid A (MPL) containing adjuvant, were evaluated for total IgG antibody elicited against LOS of FA1090wt. Two weeks following the third booster of MAP1 (given in week 14), the median serum anti-LOS IgG antibody level had risen to 1.018 µg/ml (range 0.353 to 2.204 µg/ml) (Figure 3A). A mixed model analysis of mean anti-LOS antibody levels over time showed significant increases between weeks designated for antibody testing (P<0.001) (Figures 3A and S3). MAP-control immunization did not yield anti-LOS IgG responses (<0.001 µg/ml) but showed IgG antibody responses against MAP-control itself (data not shown). MAP1 immune sera did not contain detectable IgG antibody (<0.001 µg/ml) against LOS prepared from FA1090lgtG−, confirming that the LOS antibody response following MAP1 immunization was 2C7 specific (data not shown). Samples obtained from vaginal swabs showed median anti-LOS IgG levels of 0.008 µg/ml (range 0.005–0.015 µg/ml) from MAP1 immunized mice at 14 weeks (data not shown).


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)

Anti-LOS IgG antibody responses induced by MAP1-MPL immunization.32 BALB/c mice were immunized intraperitoneally (ip) with MAP1 emulsified with MPL and boosted four times at 3-week intervals. A. Total anti-LOS IgG antibody levels at wk 5, 8,11 and 14 following immunization. B. Post-immunization (wk 14) anti-LOS IgG subclass, IgM and IgA anti-LOS antibody levels. Results are represented as box plots; the spots represent outliers beyond the 1.5 IQR (intraquartile range). IgG subclass responses indicate a TH1-biased response (see text, [22]).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3757034&req=5

ppat-1003559-g003: Anti-LOS IgG antibody responses induced by MAP1-MPL immunization.32 BALB/c mice were immunized intraperitoneally (ip) with MAP1 emulsified with MPL and boosted four times at 3-week intervals. A. Total anti-LOS IgG antibody levels at wk 5, 8,11 and 14 following immunization. B. Post-immunization (wk 14) anti-LOS IgG subclass, IgM and IgA anti-LOS antibody levels. Results are represented as box plots; the spots represent outliers beyond the 1.5 IQR (intraquartile range). IgG subclass responses indicate a TH1-biased response (see text, [22]).
Mentions: Sera from mice actively immunized with MAP1 or MAP-control (a peptide that does not bind 2C7), each administered with a Monophosphoryl Lipid A (MPL) containing adjuvant, were evaluated for total IgG antibody elicited against LOS of FA1090wt. Two weeks following the third booster of MAP1 (given in week 14), the median serum anti-LOS IgG antibody level had risen to 1.018 µg/ml (range 0.353 to 2.204 µg/ml) (Figure 3A). A mixed model analysis of mean anti-LOS antibody levels over time showed significant increases between weeks designated for antibody testing (P<0.001) (Figures 3A and S3). MAP-control immunization did not yield anti-LOS IgG responses (<0.001 µg/ml) but showed IgG antibody responses against MAP-control itself (data not shown). MAP1 immune sera did not contain detectable IgG antibody (<0.001 µg/ml) against LOS prepared from FA1090lgtG−, confirming that the LOS antibody response following MAP1 immunization was 2C7 specific (data not shown). Samples obtained from vaginal swabs showed median anti-LOS IgG levels of 0.008 µg/ml (range 0.005–0.015 µg/ml) from MAP1 immunized mice at 14 weeks (data not shown).

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