Systemic immunization with antigen coupled to monoclonal antibody (mAb) has been used by several investigators to increase the number of mAb-producing hybrids against an antigen and to elicit antibodies specific for poorly immunogenic epitopes. This strategy has implications for vaccine design in that protective immunity is not necessarily directed at immunodominant epitopes of pathogens and could well be improved by shifting a humoral response toward subdominant epitopes. To date, no studies have addressed the potential for immunomodulatory activity mediated by mucosally applied mAbs bound to antigen. To test whether mucosal administration of an exogenous antibody directed against a streptococcal surface protein could influence the humoral immune response, BALB/c mice were immunized orally or intranasally with Streptococcus mutans alone or S. mutans complexed with a mAb directed against the major surface protein P1. S. mutans is a major etiologic against of dental canes and P1 is a promising vaccine antigen. A passively applied anti-P1 mAb has also been reported to prevent recolonization by S. mutans in human subjects, months to years after the exogenous mAb is no longer detectable. Results described in this proposal indicated that binding of an anti-P1 mAb to the surface of S. mutans prior to mucosal immunization causes significant changes in the subclass distribution and specificity of elicited antibodies. Either of these changes has the potential to alter the protective capacity of a humoral immune response. This information is important from the perspective of identifying anti-P1 mAbs which could be used to shift immunodominance toward a more protective response, in addition to providing a plausible explanation for the extremely long clinical effect reported after """"""""passive"""""""" immunization of human subjects with an anti-P1 mAb. In that case, exogenous mAb may have complexed with recolonizing S. mutans to modify the adaptive immune response toward one of increased protection. This proposal is designed to screen a panel of twelve well characterized anti-P1 mAbs for immunomodulatory activity in BALB/c mice and to characterize changes in their immune response; to assess the effect of altered murine responses mediated by anti-P1 mAbs on protection against S. mutans using in vitro and in vivo model systems; to directly test serum from mAb-treated human clinical trial patients for changes in their anti-S. mutans response; and lastly to elucidate the mechanism by which anti-P1 mAbs may modulate the immune response against S. mutans. Such information would be directly relevant to the study of any active or passive mucosal immunization strategy.
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