Vaccine options for influenza: thinking small

•The M2 ectodomain adopts multiple conformations.•M2e vaccines are highly immunogenic in humans.•Anti-M2e antibodies can most likely control influenza infection in humans.•In mice, anti-M2e antibodies control viral replication via alveolar macrophages that can mediate ADCP.•M2e vaccine designs should aim at inducing IgG1 or IgG3 isotype antibodies in humans.