mRNA Vaccines for Influenza: Hope for a Universal Vaccine?

Seasonal influenza epidemics and pandemics remain a persistent public health threat. A universal influenza vaccine is urgently needed. Such a vaccine must accommodate rapid viral evolution, strain diversity-including types A and B and their many subtypes-and the complexities of human immune history and biases. Messenger RNA (mRNA)-formulated lipid-nanoparticles have evolved from an emergency pandemic vaccine experiment into a versatile vaccine platform. This technology has demonstrated potential to address several critical challenges in developing a universal influenza vaccine, including rapid strain updates, the production of high-valent formulations, and the ability to target conserved antigens that may induce broader and longer-lasting protection. This review summarizes recent studies and applications of multivalent antigen selection strategies and self-amplifying and circular RNA vaccine platforms to develop mRNA influenza vaccines to achieve vaccine universality, with an emphasis on immune responses against conserved targets. We also review the latest advances in generating long-term mucosal immunity against influenza through optimized mRNA delivery. Finally, we discuss practical considerations for correlates of protection, manufacturing, and accessibility, pioneering mRNA vaccine candidates heading to clinical trials, and milestones that define vaccine "universality."