A MURINE MODEL IN WHICH PROTECTION CORRELATES WITH PERTUSSIS-VACCINE EFFICACY IN CHILDREN REVEALS COMPLEMENTARY ROLES FOR HUMORAL AND CELL-MEDIATED-IMMUNITY IN PROTECTION AGAINST BORDETELLA-PERTUSSIS

The results of phase 3 efficacy trials have shown that acellular and w hole-cell pertussis vaccines can confer protection against whooping co ugh, However, despite the advances in vaccine development, clinical tr ials have not provided significant new information on the mechanism of protective immunity against Bordetella pertussis, Classical approache s based on measurement of antibody responses to individual antigens fa iled to define an immunological correlate of protection, A reliable an imal model, predictive of acellular and whole-cell pertussis vaccine p otency in children, would facilitate an elucidation of the mechanism o f immune protection against B. pertussis and would assist in the regul atory control and future development of pertussis vaccines. In this st udy, we have shown that the rate of B. pertussis clearance following r espiratory challenge of immunized mice correlated with vaccine efficac y in children, Using this model together with mice with targeted disru ptions of the gamma interferon (IFN-gamma) receptor, interleukin-4 or immunoglobulin heavy-chain genes, we have demonstrated an absolute req uirement for B cells or their products in bacterial clearance and a ro le for IFN-gamma in immunity generated by previous infection or immuni zation with the whole-cell pertussis vaccine, The results of passive i mmunization experiments suggested that protection early after immuniza tion with acellular pertussis vaccines is mediated by antibody against multiple protective antigens, In contrast, more complete protection c onferred by previous infection or immunization with whole-cell pertuss is vaccines reflected the induction of Th1 cells. Our findings suggest that the mechanism of immunity against B, pertussis involves humoral and cellular immune responses which are not directed against a single protective antigen and thus provide an explanation for previous failur es to define an immunological correlate of protection.