Advances in the Development of a Universal Influenza Vaccine

Influenza remains a persistent global health threat, accounting for an estimated one billion infections and 350,000–600,000 deaths worldwide annually. Beyond substantial mortality and morbidity, influenza imposes major socio-economic costs through healthcare utilisation and productivity losses, amounting to tens of billions of dollars each year. Current seasonal vaccination strategies are constrained by rapid antigenic evolution, which necessitates frequent vaccine reformulation and contributes to suboptimal vaccine efficacy across seasons. These drawbacks highlight the need for a universal influenza vaccine (UIV) that protects against all seasonal and potential pandemic influenza strains via a single dose. This review evaluates the feasibility of a UIV as an alternative to a seasonal influenza vaccine (SIV) by consolidating evidence from current UIV candidates in preclinical and clinical development across a diverse range of platforms and target epitopes. Preclinical studies and clinical trials have demonstrated the safety and tolerability of multiple candidates, as well as their ability to elicit broadly cross-reactive immune responses. However, several challenges remain regarding the long-term efficacy of these vaccines. In particular, pre-existing host immunity can shape subsequent vaccine responses, with immune imprinting introducing biases toward previously encountered influenza strains, potentially reducing vaccine effectiveness. In addition, the genetic plasticity of influenza viruses, driven by ongoing mutations and genetic reassortment, raises concerns about the ability of a single vaccine formulation to maintain broad and durable protection. Overall, several UIV candidates have shown promising early results. Although ecological and immunological barriers remain, a UIV could become a viable alternative to, or eventual replacement, for SIVs.