Frontier Advances in Mucosal Delivery of Broadly Protective Influenza Vaccines

Influenza viruses undergo continuous antigenic variation, posing a serious threat to public health. Current seasonal influenza vaccines are updated annually based on World Health Organization predictions of circulating strains. However, they still face several limitations, including limited prediction accuracy, narrow breadth of protection, weak mucosal immune responses, and insufficient cross-protection against different viral subtypes and variant strains. The development of broadly protective influenza vaccines delivered via mucosal routes provides a promising strategy to enhance local immunity in the respiratory tract, broaden vaccine protection, and reduce the risk of viral infection. This review systematically summarizes current strategies for the development of broadly protective influenza vaccines and advances in their clinical research, with a particular focus on recent progress in antigen design, vaccine platforms, and delivery systems for mucosally delivered broadly protective influenza vaccines. We further summarize emerging immunization strategies for enhancing vaccine efficacy and broadening the breadth of protection, and analyze the challenges and future perspectives associated with clinical translation. This review aims to provide insights for the design, development, and translational application of these vaccines.