A large fraction of the world’s most widespread and problematic pathogens, such as the influenza virus, seem to persist in nature by evading host immune responses by inducing immunity to genetically and phenotypically plastic epitopes (aka antigenic variation). The more recent re-emergence of pandemic influenza A/H1N1 and avian H5N1 viruses has called attention to the urgent need for more effective influenza vaccines. Developing such vaccines will require more than just moving from an egg-based to a tissue-culture–based manufacturing process. It will also require a new conceptual understanding of pathogen–host interactions, as well as new approaches and technologies to circumvent immune evasion by pathogens capable of more genetic variation. This paper discusses these challenges, focusing on some potentially fruitful directions for future research.
Vaccines often take between 16 and 20 years to develop, and the challenge now is to understand deceptive imprinting better and to systematically identify and characterize deceptive epitopes and low-efficiency, interfering epitopes in influenza and other viruses. Progress would enable targeting of both immunodominant deceptive epitopes and low-efficiency epitopes for genetic modification. In addition, more studies are needed to determine whether such genetic modifications can actually lead to significantly greater vaccine efficacy, but there is great promise in these understanding-driven approaches.