Antigenic variability: Obstacles on the road to vaccines against traditionally difficult targets

Abstract

Despite the impressive impact of vaccines on public health, the success of vaccines targeting many important pathogens and cancers has to date been limited. The burden of infectious diseases today is mainly caused by antigenically variable pathogens (AVPs), which escape immune responses induced by prior infection or vaccination through changes in molecular structures recognized by antibodies or T cells. Extensive genetic and antigenic variability is the major obstacle for the development of new or improved vaccines against "difficult" targets. Alternative, qualitatively new approaches leading to the generation of disease- and patient-specific vaccine immunogens that incorporate complex permanently changing epitope landscapes of intended targets accompanied by appropriate immunomodulators are urgently needed. In this review, we highlight some of the most critical common issues related to the development of vaccines against many pathogens and cancers that escape protective immune responses owing to antigenic variation, and discuss recent efforts to overcome the obstacles by applying alternative approaches for the rational design of new types of immunogens.

Keywords: HIV vaccine; antigenically variable pathogens; cancer vaccine; combinatorial peptide library; variable epitope library.

Figure 1.

Application of VEL-based vaccine immunogens as an alternative approach for the development of vaccines against AVPs and cancer. An intact immune system responds upon infection with AVPs and against cancer by generating a limited pool of T cells. The vaccination with DASIs induces larger repertoire of lymphocytes, however, these cells were shown to fail to provide protection against APVs and cancer. Vaccines based on VELs generate the largest pool of T cells capable of containing AVPs infection and the development of cancer [60, 61]. T_E, T_CM, T_EM, T_RM: effector T cells, central, effector and resident memory T lymphocytes, respectively. DASI: defined antigen sequence immunogen. AVP: antigenically variable pathogen. VEL: variable epitope library.