Call for a paradigm shift in the design of universal influenza vaccines by harnessing multiple correlates of protection

Introduction: The genetic variability and diversity of influenza viruses, and the expansion of their hosts, present a significant threat to human health. The development of a universal influenza vaccine is urgently needed to tackle seasonal epidemics, pandemics, vaccine mismatch, and zoonotic transmissions to humans. Areas covered: Despite the identification of broadly neutralizing antibodies against influenza viruses, designing a universal influenza vaccine that induces such broadly neutralizing antibodies at protective levels in humans has remained challenging. Besides neutralizing antibodies, multiple correlates of protection have recently emerged as crucially important for eliciting broad protection against diverse influenza viruses. This review discusses the immune responses required for broad protection against influenza viruses, and suggests a paradigm shift from an HA stalk-based approach to other approaches that can induce multiple immunological correlates of protection for the development of a universal influenza vaccine. Expert opinion: To develop a truly universal influenza vaccine, multiple correlates of protection should be considered, including antibody responses and T cell immunity. Balanced induction of neutralizing antibodies, antibody effector functions, and T cell immunity will contribute to the most effective vaccination strategy. Live-attenuated influenza vaccines provide an attractive platform to improve the breadth and potency of vaccines for broader protection.