Immunization against a Saccharide Epitope Accelerates Clearance of Experimental Gonococcal Infection

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.

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

“…Expression of LgtG is important for murine infection (14). Passive administration of mAb 2C7, as well as active immunization with a peptide mimic (mimitope) of the 2C7 epitope that was configured as a ‘multi-antigen peptide’ on a poly-lysine ‘backbone’ significantly shortened the duration and burden of infection in the murine vaginal colonization model of gonorrhea (14).…”

Summary and Recommendations from the National Institute of Allergy and Infectious Diseases (NIAID) Workshop “Gonorrhea Vaccines: the Way Forward”

“…The most successful of such single antigens used as vaccines have been bacterial capsular polysaccharides. While these are not present in N. gonorrhoeae, conserved saccharides are present in gonococcal lipooligosaccharides (LOSs) (18) and should be exploited further as vaccine candidates (19).…”

Animal Models of Immunity to Female Genital Tract Infections and Vaccine Development

“…A female mouse model is now available and has been useful for studying N. gonorrhoeae adaptation to the female genital tract , signaling through innate receptors Packiam et al, 2014), and the relationship between antibiotic resistance and fitness (Kunz et al, 2012;Warner et al, 2008). The mouse model has also been used to identify protective and immunosuppressive pathways Liu et al, , 2013Packiam et al, 2014, Zhu et al, 2012 and to accelerate the development of therapeutic and prophylactic products against gonorrhea (Gulati et al, 2013;Plante et al, 2000;Spencer et al, 2004;Zeitlin et al, 2001;Zhu et al, 2011). Known host restrictions that limit the capacity of female mice to mimic gonorrhea in humans include the absence of human-specific receptors for adherence and invasion pathways, human transferrin and lactoferrin glycoproteins, soluble regulators of the complement cascade (factor H, C4b-binding protein), and IgA1, the substrate of gonococcal IgA1 protease (extensively reviewed in Jerse et al (2011)).…”

“…Antibodies against 2C7-OS (Gulati et al, 1996) or a 2C7-OS peptide mimic (Ngampasutadol et al, 2006) are bactericidal and promote opsonophagocytic killing of N. gonorrhoeae. Intraperitoneal immunization of mice with a multiantigenic form of the 2C7-OS peptide mimic protected mice from subsequent challenge, as did passive delivery of 2C7 monoclonal antibody (Gulati et al, 2013). The transferrin receptor is a promising target on the basis of its surface exposure, limited antigenic variability, and importance for experimental urethritis of male subjects (Cornelissen et al, 1992).…”