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Curr Opin Immunol. 2003 Aug;15(4):461-70. Related
Epitope-based vaccines: an update on epitope identification, vaccine design and delivery.
Sette A, Fikes J.
La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA. alex@liai.org
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Immunodominance and it’s relevance for epitope-based vaccines
Naturally occurring immune responses do not recognize all possible epitopes, but are instead commonly focused on relatively few (or in some cases a singular) epitopes. This immunodominance can be very profound, resulting in only one or few specificities dominating the response to a given pathogen, and a large fraction of activated T-cells specific for a single epitope–MHC combination. This rather absolute type of immunodominant immune response is actually frequently observed in various murine and human pathogens and experimental systems. However, it has been shown in several different cases that human responses are often multi-specific (directed against multiple proteins derived from a given pathogen) and broad (directed against multiple epitopes within a given protein). It is unclear at this point how commonplace it is for a large fraction of cellular immunity to be directed against one or few protein antigens, or even against one or few epitopes contained within those proteins, especially when human responses against large complex pathogens are considered. It is possible, however, that the response might be directed against a large number of protein antigens, and against a large number of epitopes contained within those proteins.
Major variables influencing immunodominance are:
1. The capacity of the prospective epitope to be bound by appropriate MHC molecules.
2. The existence of a T-cell repertoire capable of recognizing the epitope–MHC complexes when presented on the surface of antigen-presenting cells (APCs) or infected/cancer cells.
3. The efficiency with which the prospective epitope is generated by cellular processing and presented on the surface of the relevant cells [3., 4., 5. and 6.].
Beyond these three variables additional potential mechanisms can contribute to immunodominance, including quality of co-stimulation, potential killing of APCs by dominant T-cell clonotypes, intrinsic structural constraints at the TCR level, and competition amongst T cells The exact role of these mechanisms is currently the subject of considerable debate, and recent data relating to these variables are discussed in more detail below.
Mechanisms of immunodominance
Several studies have documented a relationship between chemical abundance of the various epitopes and immunodominance. Balanced processing (the production of various epitopes in equal amounts as a result of cellular processing) appears to be important for the induction of simultaneous responses. In the context of epitope-based vaccines, a study by Livingston and co-workers [7.] demonstrates that responses against multiple MHC class-I-restricted epitopes can be obtained as a result of balancing the processing yield of the epitopes themselves. Le et al. [8.] similarly report the use of polytopes to achieve the induction of multiple protective responses. Peter, Corradin and co-workers [9.] report the induction of multiple responses by the use of equimolar pools of peptides in incomplete Freund’s adjuvant [IFA], although the effects were weaker in response to the peptide pool in comparison to the isolated peptides. Finally, multiple responses were obtained in a clinical setting utilizing a mixture of four immunogenic peptides loaded onto dendritic cells (DCs; [10.]). Whether these findings on immunodominance are transferable to the MHC class II system is still the object of debate. In fact, Unanue and co-workers [11.] have clearly shown that, in the lysozyme system, the hierarchy of MHC class II-restricted immunodominant epitopes is not directly related to chemical abundance.
Chen, Yewdell and co-workers [12.••] reported that mice lacking CD4, perforin or CD28 maintain immunodominance. Although these results don’t provide a definitive identification of the mechanisms involved in shaping immunodominance, they do represent an important advance. These results seem to indicate that intrinsic features at the T-cell level are crucial in the establishment of immunodominance, and seem to eliminate APC killing and CD4-mediated help as the main determinants of immunodominance [13.]. Consistent with these studies are the results from Whitton and co-authors [14.••], which show that the establishment of immunodominance is IFN-γ mediated; they also indicate that co-expression of the various determinants involved by the same APC is important in establishing immunodominance. The same study clearly pointed out the relevance of immunodominance not only in the context of natural responses, but also for the immune responses induced by vaccines.
Seminal papers by Cerundolo and co-workers [15.], and by Whitton and co-workers [14.••], demonstrated that competition amongst cytotoxic T lymphocytes (CTLs) narrows the breadth of immune responses in prime boost protocols. Interestingly, the competition appears to takes place at the level of expansion of the various CTL specificities, and not at the level of priming, as different CTL subsets can be expanded by the use of constructs separately encoding the various epitopes. Singh and co-workers [16.••] reported that simultaneous immunization with vaccines containing various epitope mutants can induce a variety of different responses, thus suggesting that immune interference can be avoided by simultaneous delivery. Indeed, several independent studies state the importance of T-cell repertoire composition and previous antigenic encounters in shaping immunodominance [16.•• and 17.••]. Brehm and co-workers [18.] pointed out that immunodominance can result from previous exposure to cross-reactive viruses. Slifka et al. [19.] showed that differential selection in the thymus can alter immunodominance. A recent excellent study by Kjer-Nielsen et al. [20.••] also brings into focus the structural constraints that operate at the level of TCR molecules.
An issue that is the topic of considerable debate is the natural evolution of immunodominance. Specifically, it is unclear whether, during the course of naturally evolving immune responses, the breadth of responses narrows or expands, further increasing or decreasing immunodominance. A general consensus has not yet emerged. Gray, Alexander-Miller and co-workers [21.] report, using the simian virus 5 (SV5) infection model, that the immunodominance profile is not established at day 3 post-infection, but by day 5 a clear immunodominance pattern arises and is permanently maintained. A paper by Yu et al. [22.] reports that up to 27 different epitopes can be simultaneously detected in a given individual chronically infected with HIV. The same study reports the appearance and maintenance of discrete epitope patterns consistently observed in different individuals, which appear to broaden with infection progression. In contrast to this, Hollesberg [23.] has reported wide variations in the expressed repertoire of T-cell specificities, which are apparently influenced by the co-expression of other MHC molecules in a given individual. Beltz et al. [24.] also report the influence of other MHC types on the qualitative composition of T-cell responses, and also the possible effects of prior selective expansion of certain specificities. Beltz [25.] reports, in a separate study, the narrowing of response breadth as the immune responses progress. Finally, Smith [26.] shows that stimulations narrow the repertoire in the case of vaccination with a tumor–antigen polytope.
Immunodominance could clearly represent a major issue for epitope-based vaccines. On one hand, it can be argued that, if immunodominance occurs in response to multi-epitope vaccines, then this may negate many of the potential advantages of epitope-based vaccines, which are predicated on the induction of rationally designed, multispecific responses. On the other hand, proponents of the epitope-based vaccines point out that the rational design and modification of the molecular structure of antigens and vaccines is the best way to significantly expand the breadth of responses and overcome the limitations of immunodominance.