Foot-and-mouth disease (FMD) is an acute, highly contagious viral disease of domestic and wild cloven-hoofed animals, caused by FMD virus (FMDV). An FMD outbreak can cause major production losses and have significant implications for trade. Vaccination can assist in controlling the disease, and emergency vaccination using high antigen payload vaccines (>6 PD50/dose) is considered an important control approach in the event of an outbreak. In recent years there has been a divergence of serotype A viruses in South East Asia (SEA) into several distinct genetic and antigenic clusters. Numerous variants were found to poorly match serotype A vaccines commonly included in international antigen banks. This study examined the ability of single vaccination with high-potency monovalent A22 IRQ vaccine to protect sheep following challenge with the A/VIT/15/2012 strain, just four days following vaccination. The vaccine proved effective at limiting clinical disease but did not prevent infection.