Next-generation intranasal influenza vaccines: mechanisms, platforms, and translational progress

Seasonal influenza vaccination remains the most effective strategy for reducing influenza burden and preventing severe disease. Despite decades of vaccine development, the seasonal influenza vaccine is administered intramuscularly and provides suboptimal and highly variable effectiveness depending on host factors, pre-existing immunity, and antigenic match between vaccine and circulating strains. Recent advances in vaccine development have highlighted the potential of intranasal vaccine delivery as a strategy to increase protection against influenza virus infection by inducing local and systemic immune responses. Across multiple intranasal platforms under development, mucosal immunity, particularly secretory IgA and T- and B-cell immune responses, plays a central role in shaping protection against influenza virus infection. Live-attenuated influenza vaccines (LAIV) elicit protective immune responses, particularly in the pediatric population, and remain the only currently licensed intranasal seasonal influenza vaccine. However, variable performance in adults, strain-dependent viral fitness, and clinical contraindications have limited their broader applicability. These limitations have driven the development of next-generation intranasal influenza vaccine platforms designed to preserve the immunological advantages of mucosal vaccination while improving consistency, safety, and applicability across diverse populations. This review synthesizes current knowledge on licensed and emerging intranasal influenza vaccine platforms, including replicating viral platforms and non-replicating platforms, and discusses key immunological mechanisms, challenges, and translational progress. Together, these advances underscore the growing potential of intranasal vaccination as a next-generation strategy to improve influenza control.