Pathogenic epitopes, heterologous immunity and vaccine design

Abstract

Substantial research has been directed towards the development of a new generation of vaccines that are based on the inclusion of immunogenic epitopes in recombinant vectors. Here we examine the evidence that under certain conditions immunogenic epitopes can do more harm than good and might therefore be considered pathogenic. We suggest that the specific removal of such pathogenic epitopes from vaccines might increase their prophylactic potential, while minimizing the risk of side-effects from vaccine use.

Figure 1. Narrowing of a T-cell response by crossreactivity and heterologous immunity.

This figure shows a diverse naive repertoire of T cells. Two different, but crossreactive, viruses stimulate T cells with different specificities to different epitopes. The red and half-red circles indicate crossreactive responses. Infection of a virus immune host with the crossreactive virus (virus 2) causes a change in immunodominance and a focusing of the immune response by expanding crossreactive T cells.

Figure 2. Impact of TCR private specificities on heterologous viral challenge.

This figure shows genetically different naive T-cell repertoires from genetically identical individuals, such as identical twins. Although using different TCRs, the twins' naive immune systems make quantitatively similar responses to a primary virus challenge that stimulates the T cells that have a 'red' TCR. However, they now have expanded clones of memory T cells, which might (red circles, top) or might not (no red circles, bottom) respond to a non-identical but crossreactive heterologous pathogen. These private TCR specificities cause an alteration in memory responses to a second pathogen. TCR, T-cell receptor.

Figure 3. Progression of virus-induced autoimmunity.

This figure shows how infection with a virus (virus 1) that encodes a self-like epitope might initiate an autoimmune process and how infection with a second virus (virus 2) might shift a controlled response into one that causes an autoimmune disease.

Figure 4. Heterotypic immunity with influenza A virus.

This figure illustrates a theoretical T-cell response to various influenza A virus epitopes (influenza virus A strain 1), including the highly conserved and immunodominant M1_58–66 epitope (coloured red). Vaccination with a different influenza A strain (strain 2) should boost the response to the M1_58–66 epitope at the expense of responses to other epitopes. We propose that if the M1_58–66 epitope was deleted (ΔM1) or mutated, a more effective response might be induced to a broader selection of epitopes (right-hand side, lower panel).