The G-H loop of VP1 (residues 132 to 159) of foot-and-mouth disease virus (FMDV) is a prominent feature on the virion surface and has an important role in vaccine efficacy, generation of antigenic variants, and cell binding. Using an infectious cDNA of FMDV, we have constructed serotype A viruses in which the G-H loop has been substituted with the homologous sequences from serotype O or C. These chimeric viruses replicated to high titer and displayed plaque morphologies similar to those of wild-type viruses, demonstrating that the functions provided by the loop can be readily exchanged between serotypes. Monoclonal antibody analyses showed that epitopes contained within the loop were transferred to the chimeras and that epitopes encoded by the type A backbone were maintained. Chemically inactivated vaccines prepared from chimeric viruses induced antibodies in guinea pigs that neutralized both type A and either type O or type C viruses. Swine inoculated with the A/C chimera vaccine also produced cross-reactive antibodies, were protected from challenge with the type A virus, and partially protected against challenge with type C. These studies emphasize the importance of epitopes outside of the G-H loop in protective immunity in swine, which is a natural host of FMDV
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