Immunizing the Immune: Can We Overcome Influenza’s Most Formidable Challenge?

The first human influenza virus was isolated more than 85 years ago, and several vaccine candidates were developed and tested soon after. Yet, controlling infections mediated by this respiratory pathogen continues to present a formidable challenge. Development of an effective influenza vaccine has been undermined by the dynamic nature of influenza viruses: these viruses have the unique capacity to escape pre-existing immunity. In this perspective, I highlight pre-existing immunity as a different, but related, hurdle that may actually lessen the effectiveness of influenza vaccine-induced immune responses. Specifically, I discuss the impact of pre-existing immunity on the generation of de novo B cell responses to influenza vaccination. As the influenza virus changes its major antigenic determinants, it creates new ones in the process. Our immune system adapts by targeting the new determinants. However, pre-existing antibodies and memory B cells interfere with the generation of de novo responses against these newly formed epitopes, rendering vaccines less effective. Overcoming such interference is essential for the development of more effective influenza vaccines.