New Approaches to in silico Design of Epitope-Based Vaccines

90 CHAPTER 7. APPLICATIONS
based on an in silico cleavage of every polypeptide. In the optimal configuration, all HCV
epitopes included in the vaccine were contained in the resulting list of cleaved nonameric
peptides while two epitopes from HIV and one from IV were missing. We introduced
spacers next to these epitopes in the HIV and IV polypeptides resulting in full epitope
recovery. Besides full recovery, vaccine epitopes should be more likely to result from proteasomal
cleavage than other unwanted MHC binding peptides. In order to evaluate the
polypeptides in this regard, we considered the ratio between the average cleavage scores
of vaccine epitopes and of unwanted epitopes. If vaccine epitopes are more likely to be
cleaved than other epitopes the ratio is greater than 1.0. The higher the ratio, the more
favorable the cleavage pattern. The cleavage score ratios range from 1.4 for HIV to 2.0
for IV and 2.2 for HCV. Although the ratio of the HIV polypeptide is comparably low, all
string-of-beads constructs yield favorable cleavage patterns.
7.3.4 Discussion
Traditional approaches to vaccine design had limited success in protecting against chronic
infection with viruses such as HIV and HCV. While the resulting vaccines have been shown
to be effective against IV, their efficacy is usually limited to a certain strain as defined by
the hemagglutinin (HA) and neuraminidase (NA) groups. Furthermore, the time needed
to manufacture such an IV vaccine is an issue: in a best case scenario, it takes five to six
months for a vaccine against a new IV strain to become available [150]. EVs represent a
promising alternative.
The main goal of this work is to analyze whether it is feasible to simultaneously optimize
the protein targeting and the epitope quality in EVs against highly variable viruses. Such
vaccines should be applicable to a large fraction of the target population and aim at
highly conserved epitopes from various antigens. As has been shown for several viruses,
proteins with low epitope density are probably good targets. Another important factor
when designing an EV targeted at a particular geographic area is strain prevalence. Since
our focus is on viruses in the world population, we do not consider it here. However, strain
prevalence can easily be incorporated into the proposed epitope selection approach.
Our first analysis examined the availability of conserved epitopes in the viral proteins.
In the second analysis, we investigated the possibility of including primarily epitopes from
low-SIR antigens. Subsequently, having selected an optimal set of epitopes, we addressed
the question whether a polypeptide with a favorable cleavage pattern can be produced
from these epitopes. For three highly variable viruses, we have shown that it is indeed
possible to select epitope sets that will yield potent vaccines. However, in general, such
sets cannot cover all viral antigens. Specifically, this concerns highly mutable antigens,
such as the envelope proteins of HCV and IV, or proteins subject to high evolutionary
pressure, such as the HIV regulatory proteins. In the case of HIV, the majority of the
optimal epitopes are derived from POL. However, since POL is expressed late and at low
copy numbers, it may be a very poor target. In order to obtain better targets, it may
therefore be advantageous to limit the number of POL-derived epitopes at the cost of a
decrease in predicted immunogenicity.