Novel antibody binding determinants on the capsid surface of serotype O foot-and-mouth disease virus

Abstract

Five neutralizing antigenic sites have been described for serotype O foot-and-mouth disease viruses (FMDV) based on monoclonal antibody (mAb) escape mutant studies. However, a mutant virus selected to escape neutralization of mAb binding at all five sites was previously shown to confer complete cross-protection with the parental virus in guinea pig challenge studies, suggesting that amino acid residues outside the mAb binding sites contribute to antibody-mediated in vivo neutralization of FMDV. Comparison of the ability of bovine antisera to neutralize a panel of serotype O FMDV identified three novel putative sites at VP2-74, VP2-191 and VP3-85, where amino acid substitutions correlated with changes in sero-reactivity. The impact of these positions was tested using site-directed mutagenesis to effect substitutions at critical amino acid residues within an infectious copy of FMDV O1 Kaufbeuren (O1K). Recovered viruses containing additional mutations at VP2-74 and VP2-191 exhibited greater resistance to neutralization with both O1K guinea pig and O BFS bovine antisera than a virus that was engineered to include only mutations at the five known antigenic sites. The changes at VP2-74 and VP3-85 are adjacent to critical amino acids that define antigenic sites 2 and 4, respectively. However VP2-191 (17 Å away from VP2-72), located at the threefold axis and more distant from previously identified antigenic sites, exhibited the most profound effect. These findings extend our knowledge of the surface features of the FMDV capsid known to elicit neutralizing antibodies, and will improve our strategies for vaccine strain selection and rational vaccine design.

Antigenic and genetic comparison of foot-and-mouth disease virus serotype O Indian vaccine strain, O/IND/R2/75 against currently circulating viruses

“…However there was no linear correlation between the number of aa substitutions and the loss of serological cross-reactivity (data not shown) as the isolates displaying an equal no. of aa differences exhibited significantly different serological cross-reactivity indicating a large proportion of the substitutions are neutral and only a few located at particular position of the capsid have an impact on the antigenic phenotype of the virus [37–39] .…”

“…VP2-134 has also been reported to strongly influence the binding of neutralising antigenic site 2 mAbs in serotype O FMDV [19] . In addition VP2-74 and 191 have been recently shown to be linked to antigenic site 2 using a reverse genetics approach [39] . The S–P substitution at position 74 of VP2 could be significant as proline is known to be a helix-breaker.…”

Genetic and antigenic characterisation of serotype A FMD viruses from East Africa to select new vaccine strains

“…Recently, residues VP1-197 and VP2-191 were predicted as epitopes for serotype A FMD viruses using various epitope prediction software [12] . VP2-191 has also been shown to be of antigenic significance in case of serotype O viruses [38] . VP2-134 is located adjacent to VP2-132, a known neutralising epitope in serotype A10 [6] .…”

Prediction and characterization of novel epitopes of serotype A foot-and-mouth disease viruses circulating in East Africa using site-directed mutagenesis

“…The importance of predicted residues for antibody binding can be tested by introducing specific mutations into a cDNA clone of the virus of interest. This approach is widely applied in emerging virus investigations including those into influenza ( Yang et al , 2013 ), FMDV ( Blignaut et al , 2011 ; Asfor et al , 2014 ; Opperman et al , 2014 ) and human immunodeficiency virus type 1 (HIV-1) ( Evans et al , 2014 ).…”