MtrE Loop2-specific multiple antigenic peptide vaccine and monoclonal antibody confer complement-dependent protection against Neisseria gonorrhoeae

Neisseria gonorrhoeae imposes a substantial global health burden due to its high incidence and escalating multidrug resistance. This study investigated the immunogenicity and efficacy of a peptide-based vaccine and a monoclonal antibody (mAb) targeting the conserved Loop2 epitope of the outer membrane protein MtrE. Two multiple antigenic peptide (MAP) vaccines, displaying four copies of MtrE Loop2 with or without a Cathepsin S cleavage site, were formulated with CpG1826 adjuvant. Immunization of mice elicited robust Loop2-specific IgM-dominant antibody responses with complement-dependent anti-gonococcal serum bactericidal activity. In a murine vaginal tract infection model, both vaccines demonstrated significant prophylactic and single-dose therapeutic efficacy. Furthermore, a human-mouse chimeric mAb (M01), consisting of mouse variable domains and human IgG1 constant domains, was generated from a dominant B-cell clonotype obtained from MAP vaccine-immunized mice. M01 exhibited high-affinity binding to MtrE and potent complement-dependent bactericidal activity. In a murine infection model, intravaginal administration of M01 significantly enhanced gonococcal clearance. Furthermore, Fc-engineered M01 variants confirmed that this efficacy was critically dependent on complement activity. These findings identify MtrE Loop2 as a promising target for both active and passive immunization strategies against N. gonorrhoeae, and underscore the critical role of complement-mediated activity as a mechanistic correlate of protection.