Vaccine options for influenza: thinking small

Vaccines that direct the immune response towards conserved B cell epitopes of influenza viruses can provide broad protection. In many instances, this requires the design of vaccine antigens that stimulate the immune system to levels that far exceed the natural responses towards such antigens. Here we focus on the matrix protein 2 ectodomain (M2e) as a 'universal' influenza A vaccine candidate. Thanks to its small size and high solubility, M2e can be expressed and delivered in almost any format. Protection against experimental influenza A virus challenge by M2e-based vaccines has been demonstrated in natural host of influenza and clinical studies demonstrated that such vaccines are safe and immunogenic. M2e-specific antibodies protect mainly by Fc receptor-mediated antibody-dependent cellular phagocytosis activity, which is reminiscent to how antibodies directed against the hemagglutinin stalk protect in vivo. Fighting influenza with a broadly protective influenza vaccine will likely require a blend of conserved antigens. M2e deserves its place in such a blend.