Development of universal influenza vaccines: strategies for broadly cross-reactive influenza vaccine responses

Abstract Influenza virus remains a significant global health threat because of its ability to evolve rapidly and cause both seasonal epidemics and global pandemics. Although seasonal influenza vaccines provide some protection, their effectiveness depends on accurate prediction and annual reformulation to antigenically match circulating strains. Mismatches between vaccine strains and circulating viruses can significantly reduce protective efficacy. Universal influenza vaccines aim to overcome these limitations by eliciting broad and long-lasting immunity against conserved viral components. Recent strategies have focused on targeting conserved antigens shared across diverse strains, such as the HA stem, M2e, NP, and M1, and on employing platforms, including chimeric constructs, peptide ensembles, DNA/RNA-based approaches, and virus-like particles. In parallel, mucosal delivery, particularly via the intranasal route, has gained attention for its ability to induce secretory IgA and tissue-resident memory T (TRM) cells, which provide cross-protective immunity at the respiratory barrier. This review highlights key advances and persistent challenges in the development of broadly cross-reactive influenza vaccines, with emphasis on conserved antigen design, mucosal immunity, delivery strategies, and future directions toward achieving universal protection against both seasonal and pandemic influenza strains.