The Epitope-based Approach
The identification of specific epitopes derived from infectious pathogens and tumors has significantly advanced the development of peptide-based vaccines. Improved understanding of the molecular basis of antigen recognition and HLA binding motifs has resulted in the development of rationally designed vaccines based on algorithms predicting the peptide’s binding to human HLA. This is supported by technological achievements that further encouraged the development of this approach, including the use of transgenic animals that enable a rapid screening of vaccine candidates. Indeed, many studies show the immunological efficacy of peptide-based vaccines against infectious diseases in animal models as well as in clinical studies, which demonstrated the responses to peptide vaccines against infectious diseases including malaria, Hepatitis B and HIV. The use of synthetic peptides in vaccines offers practical advantages such as relative ease of production, chemical stability, and an avoidance of any infectious or oncogenic potential hazard. An additional aspect to be considered is the similarity between the epitope sequence and any sequence of human proteins, in order to avoid autoimmune conditions. This should and can be avoided at the design phase of the new peptide-based vaccine.
Peptides may also allow better manipulation of the immune responses through the use of epitopes designed for stimulating particular subsets of lymphocytes. Most importantly, peptide vaccines appear to be effective in generating immune responses to self-proteins which might be relevant for the development of tumor vaccines. Peptides used in such vaccines are modified, and hence differ from the target self protein. Clinical human trials of single peptides have demonstrated that cancer patients respond to self-tumor antigens, and some studies have shown early positive clinical results. Current efforts in the field are focused on improving the immunogenicity of individual HLA binding peptides as well as developing multiple peptide vaccines for the prevention and treatment of human malignancy. According to analysts, the cancer vaccine market is expected to reach $8 Billion USD by 2012.
Immunological studies in which a single conserved B cell epitope (HA 91-108) was evaluated for its reactivity and efficacy in mice showed partial protection. This epitope, located next to the viral binding site to the host cell’s membrane, is conserved due to its functional role and the non changing nature of the host cell receptor. The partial protection conferred by this single epitope was enhanced by the addition of T cell epitopes from the inner nucleoprotein to the vaccine formulation. The improved efficacy and the cross strain protection observed were obtained by inducing the cellular arm of the immune system.
Special attention should be given to the selection of CTL epitopes within the epitope-based vaccines due to the large degree of MHC polymorphism and the need to know the HLA frequencies in the target population. However, it is now known that HLA Class I molecules can be divided into several families, or supertypes, based on similar peptide-binding repertoires.
A vaccine should include several T cell epitopes that are specific to the prevalent HLA genotypes in order to confer protection to the vast majority of the population.
The epitope based concept, in which a combination of B- and T-cell epitopes are used to confer protection against viral infection, was also utilized in studies on a vaccine against Respiratory Syncytial Virus (RSV). The combination of RSV-specific humoral and cellular immunity induced by the peptide cocktail was more effective at clearing RSV than peptide-induced humoral or cellular immunity alone.
In the case of influenza, different approaches have been considered for the presentation of peptides to the immune system, including the use of protein conjugate or proteosomes, live recombinant salmonella and eventually, the use of the recombinant flagellin, which has been effective. The flagella which comprise polymeric flagellin are highly immunogenic and encompass additional characteristics. The epitope-based vaccine using flagellin as a carrier was successfully tested in several animal models. The results obtained in these experiments illustrate the efficacy of the vaccine against different strains of influenza virus, including the highly pathogenic H5N1 avian strain.
Cumulative results from the literature have shown that peptides directed mainly towards the Hemagglutinin (HA) and nucleoprotein (NP) could be successfully employed in various studies, leading to viral clearance and increased survival. M1 epitope is highly conserved in all Influenza A strains and was also included in BiondVax’s vaccine. This combination has been shown to significantly enhance the protective effect of vaccination against either sub-lethal or lethal challenge with the influenza H3N2 virus. Whereas the B cell epitope alone conferred only a partial protection (<20%), immunization with the B cell epitope together with the CTL epitope resulted in approximately 60% survival. A combination of B cell epitope together with CTL and T helper epitopes protected all the mice (100%) from a lethal challenge.
- Multi-strain protection thus multi-season coverage. One vaccination schedule is expected to confer three to five years protection against the flu.
- Year-round vaccination is possible independent of the flu season and according to patient preferences and health authorities’ multi year vaccination program.
- Short production cycle: Recombinant technology allows year-round production planning, and marketing optimization.