Mucosal vaccines based on the use of cholera toxin B subunit as immunogen and antigen carrier

Abstract

Stimulation of strong mucosal IgA immune responses as a basis for vaccine-induced protection against various pathogens has proved difficult. Most soluble protein antigens administered either parenterally or oral-mucosally have given disappointing results. A notable exception in this regard are cholera toxin (CT) and, particularly in humans, its non-toxic B subunit pentamer moiety (CTB) both of which stimulate a strong intestinal IgA antibody response and long-lasting immunological memory. Based on this, CTB has become an important component in recently developed oral vaccines against cholera and diarrhea caused by enterotoxigenic E. coli. The strong immunogenicity of CT and CTB can to a large extent be explained by their ability to bind to receptors on the intestinal mucosal surface. This has promoted much recent interest in the use of CTB as an oral delivery carrier for other vaccine-relevant antigens. Oral administration of antigens coupled to CTB either chemically or genetically has in several systems been found to markedly potentiate both intestinal and extra-intestinal IgA immune responses against the CTB-coupled antigens and to elicit substantial circulating antibody responses. In contrast to CTB, CT also has strong adjuvant properties for stimulating mucosal IgA immune responses to unrelated, non-coupled antigens after oral co-immunization. This adjuvant activity appears to be closely linked to the A subunit-catalyzed ADP-ribosylating action of CT leading to enhanced cyclic AMP formation in the affected cells.