New Approaches to in silico Design of Epitope-Based Vaccines

82 CHAPTER 7. APPLICATIONS
7.2.4 Discussion
In 2007, Vider-Shalit et al. proposed to use a genetic algorithm to simultaneously select
and order epitopes for a string-of-beads EV focusing primarily on allele, antigen and
MHC/antigen coverage [24]. The authors applied their algorithm to a set of HCV antigens.
We employed the peptide cocktail corresponding to the resulting EV to evaluate the
epitope selection framework presented in Chapter 5. In addition, we demonstrated the
flexibility of our approach.
Two peptide cocktail vaccines were designed using the framework: one based on our
refined definition of good vaccine, and one based on a combination of our refined definition
and the one proposed in [24]. Both peptide cocktail vaccines outperform the vaccine
proposed in [24] with respect to various quality criteria including MHC/antigen coverage,
a property that was not incorporated in the design of our first vaccine. Furthermore, we
could show that 18 epitopes suffice to provide the same coverage Vider-Shalit et al. provide
with 24 epitopes.
The results of this study are consistent with the results presented in Chapter 5, demonstrating
the utility of our epitope selection framework also for realistic EV design problems.
7.3 Design of String-of-Beads Vaccines
The focus of the second vaccine design study is on highly variable viruses. Traditional
anti-viral vaccines are based on killed or attenuated viruses. These whole-organism vaccines
rely primarily on the induction of a B-cell response and of neutralizing antibodies.
Many widespread viruses, such as HCV, HIV, and IV have highly variable and rapidly
mutating surface proteins, making the development of a potent whole-organism vaccine
challenging. Vaccine trials against such viruses have either demonstrated the induction of
time-limited protection (e.g., IV), failed or induced protection spanning a small part of the
population [129–131]. In this study we aim to design universal string-of-beads vaccines,
i.e., string-of-beads vaccines yielding broad population coverage as well as broad coverage
of viral strains. In addition to taking population coverage, antigen coverage and epitope
conservation into account, we also consider the choice of target antigens.
An important mechanism used by viruses in order to evade immune pressure is to reduce
the number of epitopes in their proteins via mutations [132]. Such mutations typically have
a fitness cost [133–135]. The presence of a high number of escape mutations in a protein
indicates that the evolutionary advantage for the virus of removing epitopes in this protein
outweighs the corresponding fitness cost. This is the case if a T cell-mediated immune
response against the protein reduces the viral survival probability. Hence, proteins with a
low epitope density may be promising, albeit difficult, targets for an EV. A caveat of this
rationale is that the mutation costs may vary among proteins, and a low number of epitopes
may indicate a low fitness cost for mutations instead of a particular importance of the
protein. However, the group of Yoram Louzoun has previously shown for multiple viruses
that a high epitope density correlates well with late expression of a protein or low protein
copy numbers, while low epitope densities are typically observed in early expressed proteins