Foot-and-Mouth Disease and Its Antigens

Abstract

Many factors combine to make foot-and-mouth disease (FMD) one of the most damaging and intractable disease of animals. These include its extreme contagion, wide geographic distribution, great multiplicity of both susceptible animal hosts and viral serotypes, a relatively short duration of immunity to a given serotype and a post-recovery carrier state of the virus in many animal species (e.g., cattle, sheep and goats). Nevertheless, import restrictions and other actions of the U.S. Government have kept the United States free of FMD since 1929, even during outbreaks of the disease in Mexico and Canada in the early 1950’s. Beginning in the late 1940’s, the systematic vaccination of cattle has been practiced in several areas of the world with varying degrees of success. While this procedure has succeeded in Western Europe in greatly reducing the incidence of FMD, the presence of live virus in some batches of vaccine and the escape of virus from vaccine from manufacturing facilities are now responsible for a large proportion of the outbreaks that still occur there. A vaccine is needed that has no possibility of producing the disease. During the last few years, it has been demonstrated that capsid protein VP₁, isolated from type A and C virions or biosynthesized in E. coli transformed with the gene for VP₁, can be used to immunize livestock against FMD. Immunization of livestock has also been achieved with a 13 kd fragment (amino acid residues 55 through 179) cleaved with CNBr from the 213 amino acid long VP₁ chain of type A virions. Immunogenic sites on intact virions, 12 S subunit particles and isolated VP₁ chains have been studied by a combination of methods, including: 1) assessment of the immunogenicity of VP₁-specific fragments and synthetic peptides and 2) mapping monoclonal antibodies (Mabs) generated with virus, VP₁ and the 13 kd fragment to virus, 12 S subunits, VP₁, VP₁-specific fragments and a biosynthetic 32mer. Correlation of these results with sites having variant and serotype sequence variability indicates that the 136–179 region of type A_l2 VP₁ possesses four putative neutralization-specific epitopes (ca. 137–143, 146–151, 152–157 and 170–175). Of three neutralization-specific epitopes on type A_l2 virus, two are also present on 12 S subunits and isolated VP₁ chains. Mabs to the three epitopes appear to neutralize virus by different mechanisms: by viral aggregation, by blocking the site on viral VP₁ that binds to cell receptors or by interfering with a postreceptor attachment step, possibly penetration or uncoating.

Although a peptide synthesized chemically to correspond to amino acid residues 141–160 of type O₁ VP₁ has been shown to produce protective immunity in guinea pigs (Bittle et al., 1982), it has so far been ineffective in cattle. An epitope (residues 146–152) on type O₁ virus and VP₁, co-sequential with the type A_l2 146–151 epitope, has been detected by the binding of antibody to 208 overlapping hexapeptides covering the entire length of VP₁ (Geysen et al., 1984). Using residue replacement synthetic peptides, the epitope was shown to have an absolute requirement for leucyl residues 148 and 151. The coincidence on VP₁ of this type O₁ epitope and a type A_l2 putative epitope strengthens the evidence that variant and serotype changes in FMD virus can both stem from a common precursor epitope sequence.