New Approaches to in silico Design of Epitope-Based Vaccines

2.3. VACCINES 15
the immune system paves the way for a rational approach to vaccine design, limiting the
vaccine to those parts that are relevant for an immune response. Rational vaccine design
uses experimental and computational methods to identify antigens, suited to form the
basis of the vaccine. There are numerous options for constructing a vaccine once a set
of potential antigens is known. The antigens or antigenic peptides can be used, either as
complete AA sequence or as its corresponding RNA or DNA.
Epitope-based vaccines (EVs), using only the smallest immunogenic regions of a protein
antigen, are a fairly new approach. They can be designed - at least in theory - to evoke
an immune response that is very specifically directed at highly immunogenic regions of
antigens. This design process can also take the immune system of the host into consideration:
the tailoring to specific MHC alleles and combinations thereof provides the basis
for a personalized therapy. Moreover, EVs have numerous advantages that make them
particularly interesting for the pharmaceutical industry, for example, safety as well as ease
of production, analytical control, and distribution.
It is not surprising, that EVs have recently been getting more and more attention. They
have proven successful in preclinical trials in mice [38], on which many of the preliminary
studies have been conducted. A large number of clinical studies, both from academia and
industry, have also been successful and have entered and/or completed clinical phase I and
II trials [5–7, 39, 40]. Several commercial products have now entered clinical phase III
trials. The indications for the vaccines in trial are mostly various cancers (e.g., leukemia,
colorectal cancer, gastric cancer, lung cancer) and infectious diseases (predominantly HIV
and hepatitis C virus). Since health agencies such as the FDA require proof of the effectiveness
and safety of every individual component of a vaccine, the number of epitopes
to be included in the EV is typically kept rather small. However, so far there is no EV
approved for use in human on the market. This is mainly attributed to difficulties with
peptide stability and delivery [41].
Delivery
In the search for a practical, safe and potent means to deliver EVs, various delivery strategies
are being explored in clinical studies [25]. Strategies range from (A) peptide cocktails
(Figure 2.3A) to (B) concatenation of the epitopes into a string-of-beads construct (Figure
2.3B) to (C) concatenated epitopes with intervening spacer sequences (Figure 2.3C)
or (D) longer polypeptides assembled by skillfully overlapping the selected epitopes (Figure
2.3D). Taken out of their antigenic context, epitopes display a reduced and possibly
insufficient capability of inducing an immune response, as they are likely to be ignored by
the immune system. This is obviously disadvantageous for vaccine potency. A means to
overcome this problem are adjuvants. Adjuvants enhance the immunogenicity by provoking
inflammatory reactions, i.e., they attract the attention of the immune system. In addition,
some adjuvants protect the epitopes from extracellular proteases [42].
EV delivery strategies can be roughly divided into two classes: strategies delivering
the peptides themselves and strategies delivering the corresponding RNA or DNA. Examples
for the former are lipopeptide vaccines, immunostimulating complexes and cell-based
delivery. Examples for the latter are recombinant-vector vaccines and DNA vaccines.