Antibody-based microbicides are an attractive strategy for preventing gonorrhea in women based on the Isafety, efficacy and the long-standing clinical use of antibodies (Abs) to prevent infection and, or disease. We hypothesize Abs that interfere with the ability of Neisseria gonorrhoeae (GC) to evade host innate defenses will be more effective than those that prevent infection through antibody-mediated clearance mechanisms alone. To facilitate the development of prophylactic agents against GC, we developed a female mouse model of GC lower genital tract infection. Here we propose to test three GC surface molecules (MtrE, sialyl-transferase(Lst), and Opacity (Opa) proteins) that have a detectable impact on GC survival in mice aspotential targets of antibody-based microbicides. We will also test porin-specific Abs based on strong in vitro evidence that porin protects against complement-mediated defenses. Specifically, we will i.) assess the effectiveness of Abs to surface-exposed regions of MtrE, the outer membrane channel of the MtrCDE and FarAB, MtrE efflux systems, in decreasing GC resistance to antimicrobial agents in vitro and in preventing experimental infection in mice, ii.) Define the potential of Abs specific for GC porin loops involved in down-regulation of complement activation to decrease serum resistance in vitro and to prevent experimental murine infection iii.) determine the effectiveness of Abs against alpha-2,3 sialyltransferase (LsO in protecting GC fromCMP-NANA-dependent serum resistance in vitro and in reducing GC infectivity in mice, and iv.) assess the functional activities of Abs against the first semivariable and fourth conserved surface exposed loops of GC Opa proteins and the capacity of these Abs to prevent GC infection in mice. The protective potential of Abs specific for the target in each aim will be assessed by measuring agglutination, bactericidal, and opsono-phagocytic activity; antibody-mediated inhibition of target molecule function will also be tested. Abs withactivity in one or more of these functional assays will be tested for the capacity to passively prevent lexperimental murine GC infection. These studies will allow us to define correlates of protection, which may lead to the development of effective monoclonal antibody-based microbicides and mucosal vaccines.
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