Peptide-Based Vaccinology: Experimental and Computational Approaches to Target Hypervariable Viruses through the Fine Characterization of Protective Epitopes Recognized by Monoclonal Antibodies and the Identification of T-Cell-Activating Peptides

Hindawi Publishing Corporation Clinical and Developmental Immunology Volume 2013, Article ID 521231, 12 pages http://dx.doi.org/10.1155/2013/521231 Review Article Peptide-Based Vaccinology: Experimental and Computational Approaches to Target Hypervariable Viruses through the Fine Characterization of Protective Epitopes Recognized by Monoclonal Antibodies and the Identification of T-Cell-Activating Peptides Matteo Castelli,1 Francesca Cappelletti,1 Roberta Antonia Diotti,1 Giuseppe Sautto,1 Elena Criscuolo,1 Matteo Dal Peraro,2 and Nicola Clementi1 1 2 Microbiology and Virology Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy Laboratory for Biomolecular Modeling, Institute of Bioingeneering, School of Life Sciences, Ecole Polytechnique Fédérale, 1015 Lausanne, Switzerland Correspondence should be addressed to Nicola Clementi; Received 8 May 2013; Accepted 6 June 2013 Academic Editor: Roberto Burioni Copyright © 2013 Matteo Castelli et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Defining immunogenic domains of viral proteins capable of eliciting a protective immune response is crucial in the development of novel epitope-based prophylactic strategies. This is particularly important for the selective targeting of conserved regions shared among hypervariable viruses. Studying postinfection and postimmunization sera, as well as cloning and characterization of monoclonal antibodies (mAbs), still represents the best approach to identify protective epitopes. In particular, a protective mAb directed against conserved regions can play a key role in immunogen design and in human therapy as well. Experimental approaches aiming to characterize protective mAb epitopes or to identify T-cell-activating peptides are often burdened by technical limitations and can require long time to be correctly addressed. Thus, in the last decade many epitope predictive algorithms have been developed. These algorithms are continually evolving, and their use to address the empirical research is widely increasing. Here, we review several strategies based on experimental techniques alone or addressed by in silico analysis that are frequently used to predict immunogens to be included in novel epitope-based vaccine approaches. We will list the main strategies aiming to design a new vaccine preparation conferring the protection of a neutralizing mAb combined with an effective cell-mediated response. 1. Introduction The development of vaccines directed against clinical relevant viral pathogens is perhaps the most important contribution of immunology to public health. Traditional vaccine preparations are based on attenuated or inactivated whole viruses or partially purified viral proteins. These strategies, although effective against a large number of pathogens, present drawbacks due to viral intrinsic characteristics such as poor or null in vitro replication and antigenic hypervariability [1]. In order to overcome these issues, quite a number of novel approaches have been developed, one of the most promising focusing on epitope-based vaccine preparation. The possibility to use minimal structures such as peptides, or a mixture of them, as the main constituent of a vaccinal preparation, presents many advantages. Firstly, peptides can be easily produced in vitro reducing production costs and simplifying large-scale vaccine production procedures. Moreover, expression of peptides belonging to viral proteins does not necessarily require in vitro pathogens growth, overcoming viral culturing issues. 2 Clinical and Developmental Immunology X-ray co crystallization NMR Epitope excision H/D exchange Random peptide libraries Structure based Direct structural analysis Conformational epitopes Sequence based Mass spectrometrybased methods In silico approaches Experimental approaches Prediction of Ag protective regions Propensity scale Protective mAb-epitopes characterization Linear epitopes Mimotopes Gene fragment libraries Improved scale Machine-learning algorithms Identification of protein structural motifs to be included in epitopebased vaccines targeting hypervariable virus ELISPOT Intracytoplasmatic cytokines staining Experimental approaches Lymphoprolifer. Proteasome cleavage T-cell epitopes identification Cell based In silico approaches TAP interaction Structure based Cell free MHC I/II binders Sequence based Figure 1: The described approaches to characterize protein structural motifs to be included in new vaccines targeting hypervariable viruses. The synergistic use of techniques combining experimental and in silico approaches is also shown. This strategy also presents safety benefits, zeroing problematic related to back mutations for attenuated viruses and reducing side effects due to possible improper immune response against viral antigenic determinants. Perhaps the most important aspect of using well-characterized synthetic peptides as immunogens is related to the specific triggering of both humoral and cell-mediated immune responses against a fundamental domain of a viral protein. Moreover, the possibility to remove antigen (Ag) domains activating suppressor mechanisms may elicit only a protective response targeting conserved functional regions shared among hypervariable viruses [2]. Despite these advantages, to date no epitope-based vaccines have been used in clinical practice. This is mainly due to low immunogenicity and difficulties related to the fine identification of protective epitopes and/or properly folded antigen structural motifs to be included in a vaccinal preparation. The latter is fundamental to properly activate an effective immune response. Furthermore, a main goal for a successful epitope-based vaccine approach is the identification of epitopes capable of eliciting both humoral and cellmediated responses [3, 4]. Different strategies, spanning from antigen presentation techniques to in silico design of structural motifs to be included in vaccinal preparations, have been developed in order to overcome these issues. In this paper we review the most promising approaches in peptide-based vaccine setup applicable to hypervariable viruses. In particular we will focus on the methods at the interface between experimental and computational procedures aiming at the prediction of B and T-cell-activating peptides (Figure 1). 2. Selection of B-Cell-Activating Peptides: Immune Humoral Response as a Probe to Identify Crucial Domains A crucial step in epitope-based vaccine design is the identification of antigens capable of eliciting a protective immune response specific for a pathogen of interest. Depending on the characteristics of the virus to be targeted, humoral and cellular response changes in relevance. As an example, the former plays a crucial role in conferring specific immu (...truncated)