Modifications increasing the efficacy of recombinant vaccines; marked increase in antibody titers with moderately repetitive variants of a therapeutic allergy vaccine.
Development of vaccines targeting important self-molecules like tumor antigens, IgE, cytokines or other regulatory molecules, brings about challenges that are not met in classical vaccine development. Tolerance inducing mechanisms reduce the levels of therapeutic antibodies in the vaccinated subject, and anti-self antibody titers are frequently more than 50-fold lower than the anti-non-self response to the carrier. In order to overcome this limitation in efficacy we have explored various methods to enhance the immunogenicity of the vaccine antigen. Vaccination with a molecule containing two IgE Cepsilon3 domains and thereby a low level of repetitiveness markedly increased the efficacy. The anti-IgE antibody titers in the animals treated with the dimeric vaccine antigen were 4.5, 5 and 8 times higher than in the animals treated with the monomer, in three independent experiments. In addition, this increase in efficacy was not masked by the use of potent adjuvants. The effect persisted even in the presence of Freunds or Montanide ISA 51, two mineral oil based adjuvants. This in contrast to most Toll-like receptor (TLR) agonists, which appear to enhance the immune response only when administrated together with weak adjuvants. This clearly shows that the introduction of a moderately repetitive structure is enough to substantially increase the efficacy of a therapeutic vaccine.
Johansson
Jeannette
J
Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, 75124 Uppsala, Sweden.
Hellman
Lars
L
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D019281:Dimerization; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000628:therapy*; D007073:Immunoglobulin E / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D008353:Mannitol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D009829:Oleic Acids / Q000008:administration & dosage / Q000276:immunology; D009893:Opossums; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D009829:Oleic Acids; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C477385:montanide ISA 51; D007073:Immunoglobulin E; D008353:Mannitol; D005620:Freund's Adjuvant