Peptide-Mediated Vaccines. Researchers sought to develop therapeutic vaccines to treat tumors and chronic viral infections, focusing initially on chronic hepatitis B virus (HBV) infection. In such an infection, large amounts of antigen are present in host tissues but are presented by inappropriate cells. Their approach was to introduce antigen in a more efficacious form by using peptides as the source of antigen.
One advantage of this peptide-mediated approach is the ability to target the type of immunity by selecting peptides with either Class I- or Class II-restricted epitopes. It also avoids the confounding effects of producing a lot of antibody, which might have negative effects on cellular immunity. More importantly, it offers the possibility of using peptides that are conserved across various viral isolates, especially in RNA viruses such as hepatitis C and HIV, in which epitope drift is considerable. Finally, it should be possible to select epitopes that might not be tolerized in the host.
The disadvantage of peptides is that they are MHC-restricted, and for this reason a single peptide can only be expected to mount immune responses in a limited number of individuals in the population. As a result, there is a quantitative problem of how many epitopes are required to mount an effective immune response.
The strategy adopted by the researchers—identifying the epitopes that are most capable of inducing CTL responses—required them first to identify the binding motifs responsible for peptide-MHC interaction, then to investigate their immunogenicity, both in vitro and in vivo.
Peptide-MHC Binding Motifs. Researchers began with the most common alleles of human leukocyte antigen group A (HLA-A) and studied their MHC binding motifs. They discovered that some alleles have very similar motifs, such as A3 and A11, which favor hydrophobic residues in position 2 and lysine at the C terminal position. When they examined the binding activity of different peptides, roughly half of the peptides they tested bound significantly to both A3 and A11.
This led to the concept of “super-motifs,” which has been further investigated by several groups. The results show that a combination of peptides that share three of these super-motifs will provide coverage for a very large percentage of all human populations. In this case, the A2 proteins are hydrophobics in the B and F pockets; A3 is hydrophobic and basic; and B7 binds almost any peptide in the F pocket. This finding greatly reduces the number of peptides that must be isolated in order to immunize an outbred population.
The binding motif does not fully define the binding affinity of the peptide, however. Indeed, researchers have observed 10,000-fold differences in binding affinities among peptides that are identical at their anchor positions but differ at