Anti-CD28 has a potent adjuvant effect on the antibody response to soluble antigens mediated through CTLA-4 by-pass

With the surge in potential new vaccines produced as recombinant proteins or synthetic peptides has come a pressing need to identify safe, potent immunological adjuvants to enhance immunogenicity of these antigens. CD28 is an important costimulatory molecule for T cells, and it has been shown that cell surface expression of its ligands, CD80 and CD86, can enhance cellular immune responses against tumor cells, however, these tumor cells do not normally express the ligands. Many new vaccines will be based upon soluble recombinant antigens, and in vaccination with these antigens CD80 and CD86 would normally be expressed on activated antigen-presenting cells and additional stimulation through CD28 would not be predicted to enhance responses further. However, we show here that, surprisingly, CD28 antibody can very strongly enhance immune responses against soluble proteins, but only when directly attached to the antigen. The mode of action of CD28 antibodies appears to be linked to their ability to signal through CD28, but not to bind the negative feedback regulatory antigen, CTLA-4. CD28 stimulants may represent novel, highly effective and safe immunological adjuvants for use with a wide range of prophylactic and therapeutic vaccines.