Induction of a protective human polysaccharide-specific antibody response in hu-PBL SCID mice by idiotypic...

The human Ab repertoire to the Haemophilus influenzae type b (Hib) polysaccharide (PS) is dominated by Abs that use the kappa II-A2 VL region and that express an idiotype (Id) designated Hibld-1. In this study we determined whether a human Hib PS-specific Ab response could be induced by idiotypic manipulation. We prepared a bispecific vaccine consisting of the F(ab')2 fragment of a mAb specific for Hibld-1, coupled to the F(ab')2 fragment of a mAb specific for CD3, a component of the TCR complex. This bispecific idiotypic vaccine stimulated production of human Abs to Hib PS in severe combined immunodeficient mice engrafted with normal human adult PBLs. The induced Abs uniformly expressed Hibld-1 and protected neonatal rats from Hib bacteremia. Experiments using additional conjugates demonstrated that covalent coupling of the CD3-specific moiety to the anti-Id was required for immunogenicity in this model, a result suggesting that engagement of B cell Id and proximate delivery of T cell signals are both necessary for B cell activation and differentiation. These findings demonstrate that human Ids can serve as targets for induction of a protective anti-PS Ab response.