Towards influenza vaccine universality: Smart vaccine regimens and adjuvant-driven germinal center responses

Seasonal influenza vaccines are reformulated annually to match circulating strains of influenza A/H1N1, A/H3N2, and B, yet their efficacy remains fundamentally limited to neutralizing antibody responses against the strain-specific but highly variable hemagglutinin (HA) head domain. This limitation is compounded by pre-existing immunity, which preferentially recalls memory B cells targeting the predominant immune determinants, mainly the HA head domain, rather than the relatively conserved components. By contrast, conserved viral regions, including the HA stalk, neuraminidase (NA), the M2 ectodomain (M2e), and internal proteins such as nucleoprotein (NP) and matrix protein 1 (M1), are far less variable and represent attractive targets for broadly protective immunity. Developing an effective and affordable universal influenza vaccine hinges on solving two interconnected problems: redirecting germinal center (GC) selection toward conserved epitopes and programming immune responses for durable systemic and mucosal protection. This brief review highlights recent advances in antigen design, vaccination strategies, and adjuvant use. Together, these advances form a coordinated framework for developing a universal influenza vaccine.