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Intranasal immunization of BALB/c strain mice was carried out using baculovirus-derived human chorionic gonadotrophin (hCG) beta-chain, together with Escherichia coli heat-labile enterotoxin. Gonadotrophin-reactive immunoglobulin A (IgA) was induced in a remote mucosal site, the lung, in addition to a systemic IgG response. The extensive sequence homology with luteinizing hormone (LH) results in the production of LH cross-reactive antibodies when holo-hCG is used as an immunogen. In contrast to wild-type hCGbeta, a mutated hCGbeta-chain containing an arginine to glutamic acid substitution at position 68 did not induce the production of antibodies which cross-react with LH. Furthermore, the epitopes utilized in the B-cell response to the mutated hCGbeta shifted away from the immunodominant region of the parent wild-type molecule towards epitopes within the normally weakly immunogenic C terminus. This shift in epitope usage was also seen following intramuscular immunization of rabbits. Thus, a single amino acid change, which does not disrupt the overall structure of the molecule, refocuses the immune response away from a disadvantageous cross-reactive epitope region and towards a normally weakly immunogenic but antigen-unique area. Similar mutational strategies for epitope-refocusing may be applicable to other vaccine candidate molecules.

Type

Journal article

Journal

Immunology

Publication Date

06/2001

Volume

103

Pages

172 - 178

Keywords

Administration, Intranasal, Animals, Antigens, B-Lymphocytes, Baculoviridae, Chorionic Gonadotropin, beta Subunit, Human, Cross Reactions, Epitopes, B-Lymphocyte, Female, Immunity, Mucosal, Immunization, Immunoglobulin A, Secretory, Immunoglobulin G, Lung, Mice, Mice, Inbred BALB C, Plasmids, Point Mutation, Rabbits, Recombinant Proteins