The race toward a universal influenza vaccine: Front runners and the future directions.

Influenza virus is the pathogen of influenza (flu) and millions of people suffer from the infection worldwide, posing a significant health risk. The current influenza vaccines induce neutralizing antibodies against hemagglutinin (HA) to achieve strain-specific neutralization. The effectiveness of seasonal vaccines is usually low and unpredictable because of the antigenic variation and genetic plasticity of viruses, as well as the interference of preexisting immunity. A universal influenza vaccine is urgently needed to prevent a wide variety of influenza viruses. Nevertheless, reaching this difficult optimal goal requires a step-by-step approach. Innovative strategies and vaccine platforms are being developed in order to generate robust cross-protective immunity. In this review, we summarize candidate influenza vaccines that meet two criteria: first, they are designed to provide protection against multiple influenza viruses; second, they had passed regulatory evaluations and have entered various stages of clinical trials. We discuss these vaccine candidates based on the different vaccine-production platforms, with the focus on antigen selection, design, adjuvants, immunomodulators, and routes of vaccine delivery in the development of universal influenza vaccines.