Rational design of M2e-based nanoparticle vaccines for universal influenza a protection

Influenza A virus poses ongoing global health and economic challenges due to its antigenic variability and pandemic potential. Current seasonal vaccines targeting the variable hemagglutinin (HA) provide limited and strain-specific protection. The conserved Matrix 2 Ectodomain (M2e) offers a promising universal vaccine target, eliciting protection by targeting infected cells rather than neutralizing virions. However, the mechanism underlying protection mediated by this simple antigen is complex, and no M2e-based vaccine has been licensed yet.

Precise M2e-vaccine optimization is needed. This review provides in-depth description of M2e established knowledge, as well as comparative studies using M2e-based vaccines. From this, the 'ideal archetype' of a universal vaccine including M2e will be defined. Finally, a review of the current preclinical nanoparticle based M2e vaccine will be provided, described, and analyzed.

Optimizing antigen presentation, evaluating Fc-mediated effector functions with standardized assays, and integrating M2e into multivalent nanoparticle platforms targeting complementary conserved antigens are likely to be key steps toward achieving broad, durable, and clinically translatable protection.