Carrier-induced epitope-specific regulation and its bypass in a protein-protein conjugate

Abstract

In the course of clinical trials on a birth control vaccine, it was found that some of the immunized women responded poorly to booster immunizations. This vaccine consists of a dimer of theβ chain of human chorionic gonadotropin (βhCG) and the α chain of ovine luteinizing hormone (αoLH), linked to tetanus toxoid (TT) as a carrier. Changing this carrier to diphtheria toxoid resulted in reversion to high anti-hCG antibody titers, indicating the extent to which the carrier influences anti-ligand responses in this system. The suppression of anti-hCG responses after booster immunizations was reminiscent of the phenomenon of carrier-induced, epitope-specific regulation. In a mouse model designed to test the effects of preimmunization with TT on anti-hCG responses, we found that a single preimmunization with TT causes reduced anti-αhCG antibody responses in two out of four mouse strains, while anti-αoLH antibody responses were not affected by the preimmunization with TT. This is particularly interesting considering that β hCG and αoLH were not presented when linked separately to TT. In an effort to devise a strategy to circumvent this carrier-induced, ligand-specific hyporesponsiveness, we investigated the effectiveness of a synthetic T helper epitope from TT as carrier. We show that preimmunization with TT causes a less profound reduction in anti-hCG titers if the preimmunized mice are subsequently injected with αoLH-β hCG conjugated to a synthetic tetanus toxin peptide recognized by TT-induced and peptide-induced T cells.