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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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Survival of FA1090wt inoculated into mice actively immunized with MAP1-MPL.Group 1: MAP1-MPL immunized mice (16 immunized, 14 infected) and MAP-control-MPL immunized mice (16 immunized, 15 infected) were challenged with FA1090wt (5.4×105 CFU). Group 2: MAP1 immunized mice (10 immunized, 10 infected) and MAP-control immunized mice (7 immunized, 6 infected were challenged with FA1090wt (4×105 CFU). A. Kaplan-Meier curves indicating time to clearance of challenged N. gonorrhoeae FA1090wt. B. Mean log10 (CFU) isolation trends over time. Isolation of N. gonorrhoeae from MAP1 and MAP-control immunized mice are represented by dashed and solid lines, respectively. C. Mean area under the curve (AUC log10 CFU) vs. time computed for each mouse to consolidate cumulative infection; AUC log10 CFU was compared between groups.
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ppat-1003559-g006: Survival of FA1090wt inoculated into mice actively immunized with MAP1-MPL.Group 1: MAP1-MPL immunized mice (16 immunized, 14 infected) and MAP-control-MPL immunized mice (16 immunized, 15 infected) were challenged with FA1090wt (5.4×105 CFU). Group 2: MAP1 immunized mice (10 immunized, 10 infected) and MAP-control immunized mice (7 immunized, 6 infected were challenged with FA1090wt (4×105 CFU). A. Kaplan-Meier curves indicating time to clearance of challenged N. gonorrhoeae FA1090wt. B. Mean log10 (CFU) isolation trends over time. Isolation of N. gonorrhoeae from MAP1 and MAP-control immunized mice are represented by dashed and solid lines, respectively. C. Mean area under the curve (AUC log10 CFU) vs. time computed for each mouse to consolidate cumulative infection; AUC log10 CFU was compared between groups.

Mentions: In Groups 1 and 2 (Experimental Design shown in Figure 5), MAP1 and MAP-control immunized mice (n = 16 in each group in Group 1 and n = 10 and n = 7 respectively, in Group 2) were selected/pre-treated as described in Materials and Methods and then challenged intravaginally with FA1090wt (5.4×105 CFU in Group 1 and 4×105 CFU in Group 2). Fourteen of 16 mice from the MAP1 group in Group 1, 10/10 mice in Group 2 and 15/16 mice from the MAP-control group in Group 1 and 6/7 mice in Group 2 became infected at the outset (defined by a positive intravaginal culture for N. gonorrhoeae on Day 1 and/or 2). Time to clearance of FA1090wt by Kaplan Meier was decreased in MAP1 vs. MAP-control immunized mice (median time of clearance, 5 vs. 9 days) in each experiment (P = 0.0001 and P = 0.002 in Groups 1 and 2, respectively) (Figure 6A). Mixed model analysis indicated significant differences in colonization trends of FA1090wt over time between the two groups comparing MAP1 vs. MAP-control immunized mice in both Groups 1 (P = 0.0001) and 2 (P<0.0001) (Figure 6B). A significant difference in the Mean Areas Under the Curve (MAUCs) (log10 CFU vs. time) between groups inoculated with FA1090wt was seen in each of the challenge experiments: P = 0.001 in Experiment 1 and P<0.0001 in Experiment 2 (Figure 6C).


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)

Survival of FA1090wt inoculated into mice actively immunized with MAP1-MPL.Group 1: MAP1-MPL immunized mice (16 immunized, 14 infected) and MAP-control-MPL immunized mice (16 immunized, 15 infected) were challenged with FA1090wt (5.4×105 CFU). Group 2: MAP1 immunized mice (10 immunized, 10 infected) and MAP-control immunized mice (7 immunized, 6 infected were challenged with FA1090wt (4×105 CFU). A. Kaplan-Meier curves indicating time to clearance of challenged N. gonorrhoeae FA1090wt. B. Mean log10 (CFU) isolation trends over time. Isolation of N. gonorrhoeae from MAP1 and MAP-control immunized mice are represented by dashed and solid lines, respectively. C. Mean area under the curve (AUC log10 CFU) vs. time computed for each mouse to consolidate cumulative infection; AUC log10 CFU was compared between groups.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3757034&req=5

ppat-1003559-g006: Survival of FA1090wt inoculated into mice actively immunized with MAP1-MPL.Group 1: MAP1-MPL immunized mice (16 immunized, 14 infected) and MAP-control-MPL immunized mice (16 immunized, 15 infected) were challenged with FA1090wt (5.4×105 CFU). Group 2: MAP1 immunized mice (10 immunized, 10 infected) and MAP-control immunized mice (7 immunized, 6 infected were challenged with FA1090wt (4×105 CFU). A. Kaplan-Meier curves indicating time to clearance of challenged N. gonorrhoeae FA1090wt. B. Mean log10 (CFU) isolation trends over time. Isolation of N. gonorrhoeae from MAP1 and MAP-control immunized mice are represented by dashed and solid lines, respectively. C. Mean area under the curve (AUC log10 CFU) vs. time computed for each mouse to consolidate cumulative infection; AUC log10 CFU was compared between groups.
Mentions: In Groups 1 and 2 (Experimental Design shown in Figure 5), MAP1 and MAP-control immunized mice (n = 16 in each group in Group 1 and n = 10 and n = 7 respectively, in Group 2) were selected/pre-treated as described in Materials and Methods and then challenged intravaginally with FA1090wt (5.4×105 CFU in Group 1 and 4×105 CFU in Group 2). Fourteen of 16 mice from the MAP1 group in Group 1, 10/10 mice in Group 2 and 15/16 mice from the MAP-control group in Group 1 and 6/7 mice in Group 2 became infected at the outset (defined by a positive intravaginal culture for N. gonorrhoeae on Day 1 and/or 2). Time to clearance of FA1090wt by Kaplan Meier was decreased in MAP1 vs. MAP-control immunized mice (median time of clearance, 5 vs. 9 days) in each experiment (P = 0.0001 and P = 0.002 in Groups 1 and 2, respectively) (Figure 6A). Mixed model analysis indicated significant differences in colonization trends of FA1090wt over time between the two groups comparing MAP1 vs. MAP-control immunized mice in both Groups 1 (P = 0.0001) and 2 (P<0.0001) (Figure 6B). A significant difference in the Mean Areas Under the Curve (MAUCs) (log10 CFU vs. time) between groups inoculated with FA1090wt was seen in each of the challenge experiments: P = 0.001 in Experiment 1 and P<0.0001 in Experiment 2 (Figure 6C).

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