FMDV is a single-stranded, positive-sense RNA virus (Genus Aphthovirus, family Picornaviridae). The viral genome is about 8.3 kb long, enclosed within a protein capsid. The capsid is composed of 60 copies each of four different structural proteins (VP1-4); VP1-3 are surface exposed while Regorafenib clinical trial VP4 is entirely internal. Crystallographic studies have identified the structure of the FMDV capsid  and 
and immunological epitopes have been mostly found on surface-oriented interconnecting loops between structural elements. Studies employing monoclonal antibodies (mAb) have identified antigenic sites by sequencing mAb neutralisation resistant (mar) mutants , , , , ,  and . Of the five antigenic sites reported so far for the most extensively studied serotype O, site-1 (G-H loop) is
linear and trypsin-sensitive whereas the others are conformational and trypsin-resistant. Equivalent check details neutralising antigenic sites (except site 3) have also been identified for serotype A, with critical residues present in equivalent positions , , ,  and . Serotype A viruses are present on all continents where FMD is reported, and is antigenically diverse  often exhibiting poor cross-protection . In the Middle East (ME), a new variant, A-Iran-05, was identified in samples collected from Iran in 2003 and subsequently spread to neighbouring countries  and North Africa . This genotype replaced the A-Iran-96 and A-Iran-99 genotypes that were previously circulating in the region; did not cross-react with A/Iran/96 vaccine antisera and shared
a closer antigenic relationship with the older A22/Iraq vaccine strain (v/s) . However, many samples isolated after 2006 did not even match with A22/Iraq v/s and so a new v/s, A/TUR/2006 was introduced. From sequence data, Jamal and colleagues indicated candidate amino acid (aa) substitutions in the capsid that might have contributed to these antigenic changes Fossariinae . More recently, there is evidence that viruses from the region now exhibit lower cross-reactivity with the A/TUR/2006 antisera. The aim of this study was to investigate the molecular basis of the antigenic variation in these viruses using capsid sequences and their corresponding antigenic relationship (r1) values. Fifty-seven serotype A viruses from the ME submitted to the Food and Agriculture Organisation’s World Reference Laboratory for FMD (WRLFMD) at the Pirbright Institute were used in this study (Supplementary table). Two are the v/s A22/IRQ/24/64 (A22/Iraq) and A/TUR/2006 that were originally isolated in Iraq and Turkey, in 1964 and 2006 respectively; the 55 other viruses were isolated over a fifteen year period (1996–2011).