The possibility to identify and synthesize amino acid sequences from viral proteins, which are able to generate a protective immune response in animals, has stimulated the development of synthetic vaccines. Although it has already been shown that synthetic peptides in some cases can induce a good immune response, it has turned out that in general they were weak immunogens unless coupled to strongly immunogenic carrier molecules. They were frequently unable to induce protective immunity in vaccinated animals. Attempts to increase the immunogenicity of these antigens for use as vaccine have lead to the development of a series of antigen presentation systems. Many of these are designed to present the antigen as a polyvalent, particulate structure. The development of particulate vector systems for immunogenic epitopes provides a powerful approach for the presentation of antigens. Various systems were used to present foreign epitopes: the core antigen of Hepatitis B virus (HBV) (HBcAg) 1! and the surface antigen of Hepatitis B virus (HBsAg) 2!, the capside protein from Polio virus 3!, the yeast Ty protein 4!, the particles obtained after insertion of HIV 1-gag in Baculovirus 5!, rotavirus VP-6 protein 6!, core particles of the Bluetongue virus (BTV) 7!, and filamentous as well as icosahedral bacteriophages 8,9!.
It has been demonstrated that the immunogenicity of a peptide depends on its sequence as well as on the way it is presented to the immune system. By using a human rhino virus capsid sequence as a heterologous peptide and the particles of HBcAg as a carrier, it was shown that the internal location of the foreign sequence increases the immunogenicity of the epitope by 10 to 50 fold when compared to the amino terminus location 10!. Also the antigenicity (measured as reactivity to a monoclonal antibody (mAb)) was greatly enhanced by placing the foreign peptide in that position in the carrier. Furthermore, both constructs presented the epitopes considerably more efficiently to the mAbs than the free peptides. This was also the case when specific HIV-1 epitopes (the V3 loop) were introduced into different domains of the HBcAg 11!. Since the properties of a given epitope can be influenced by its conformation it was of great interest to have a carrier system with multiple entry sites conferring many possible conformations. This would increase the possibility of finding a conformation closer to the native one for a given sequence. In spite of the fact that, as mentioned above, various particulate systems have been developed for the presentation of epitopes, they were all based on the foreign epitope being inserted mainly in one position. This was partly due to lack of knowledge about the 3-D structure of the carrier particle.
USPTO Backgrounds
USPTO Backgrounds