The continuous emergence of foot-and-mouth disease virus (FMDV) serotype A variants in South East Asia is of concern for international FMDV antigen banks, especially when in vitro tests predict a low antigenic match. A vaccination-challenge study was performed by using two emergency FMDV vaccines with A22 Iraq 64 (A22 IRQ) and A Malaysia 97 (A MAY 97) strains, against challenge with a variant strain of FMDV A/Asia/G-IX/SEA-97 lineage at 7- and 21-day post-vaccination (dpv). At 7 dpv, three of five female calves vaccinated with A MAY 97 and four of five vaccinated with A22 IRQ did not show lesions on the feet and were considered protected, while at 21 dpv all five calves were protected with each vaccine, indicating equal efficacy of both vaccine strains. Calves were protected despite relatively low heterologous neutralizing antibody titers to the challenge virus at the time of challenge. All the calves developed antibodies to the non-structural proteins, most likely due to the direct intradermolingual (IDL) inoculation. Only one calf from the A MAY 97-7 group had infectious virus in the serum 1–3-day post-challenge (dpc), while no virus could be isolated from the serum of cattle challenged on 21 dpv. The virus could be isolated from the oral swabs of all calves, 1–7 dpc with viral RNA detected 1–10 dpc. Nasal swabs were positive for virus 1–6 dpc in a small number of calves. The time between vaccination and infection did not have an impact on the number of animals with persistent infection, with almost all the animals showing viral RNA in their oro-pharyngeal fluid (probang) samples up to 35 dpc. Despite the poor in vitro matching data and field reports of vaccine failures, this study suggests that these vaccine strains should be effective against this new A/Asia/G/SEA-97 variant, provided they are formulated with a high antigen dose.