Influenza pandemics arise from novel influenza A viruses. Recent emergence of a new clade (2.3.4.4.b) of the highly pathogenic H5N1 in animals and humans highlighted its pandemic potential. We evaluated the immunogenicity and safety of GSK’s AS03-adjuvanted H5N8 vaccine in adults. In this phase 1/2, observer-blinded, age-stratified, randomized trial, healthy US adults (age, ≥18?y) received two intramuscular doses of hemagglutinin antigen (3.75 or 7.50?μg) with AS03A or AS03B, administered 21?d apart. Immunogenicity – seroprotection rates (SPRs), seropositivity, geometric mean titers (GMTs), geometric mean fold rise (GMFR), and seroconversion rates (SCRs) – was evaluated on day 43 using hemagglutination inhibition (HI) and microneutralization (MN) assays. Safety was monitored throughout the study. Of 520 enrolled participants, 518 were vaccinated. On day 43, the US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research criteria for influenza vaccines were met. HI SPRs, seropositivity rates, SCRs, GMTs, and GMFR appeared to be higher in the AS03A vs AS03B group. Immune responses were generally higher in younger (aged 18–64?y) vs older (aged ≥65?y) adults. Immune responses were also detected in MN assays, with a correlation between HI and MN responses on day 43 across age groups and vaccine formulations. Safety was acceptable, with no increase in adverse events post-dose 2. Reactogenicity appeared more common in younger adults. The antigen-sparing potential of AS03 was demonstrated, with an acceptable safety profile. The benefit/risk profile was favorable for all formulations tested, including 3.75?μg AS03A (licensed in the US).