For FluMist?/Fluenz live attenuated influenza vaccine (LAIV), efficient virus replication in human nasal epithelial cells (hNEC) is an important factor in vaccine effectiveness (VE). The necessity of antigenic similarity of LAIV viruses to the WHO-recommended strains for VE is less clear. Here, we aimed to describe the relative importance of optimal hNEC replication and antigenic match in protection from wild-type (wt) challenge in vivo. The efficacy of an A/H1N1pdm09 LAIV strain (LAIVH1.opt) with optimised hNEC replication but reduced antigenicity relative to its parent (LAIVH1.par) was assessed. Delivered at a low dose, animals vaccinated with antigenically matched LAIVH1.par shed wt challenge virus and exhibited influenza-like illness post-challenge. Conversely, antigenically divergent LAIVH1.opt provided protection from both endpoints. LAIVH1.opt was also found to be more immunogenic in ferrets than LAIVH1.par, generating superior anti-HA and anti-NA antibody responses. We conclude that efficient virus replication can supersede antigenic match for high LAIV efficacy.