Vaccines prepared from chimeras of foot-and-mouth disease virus (FMDV) induce neutralizing antibodies and protective immunity to multiple serotypes of FMDV

Abstract

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 0 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 0 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.

Plasmid DNA encoding replicating foot-and-mouth disease virus genomes induces antiviral immune responses in swine

“…390 and 395 exhibited mild signs of disease (based on the criteria shown in footnote b of Table 3). Although there was not a complete correlation between prechallenge neutralizing antibody titer and protection from disease (Table 3), the antibody titers detected in all DNA-vaccinated animals were in the range that produced only partial protection in our earlier studies (18,30).…”

“…Some swine were inoculated in the same muscle with 2 g of binary ethylenimine (BEI)-inactivated (1) type A12 virus emulsified in mineral oil (18). Swine were challenged by the same protocol utilized by Rieder et al (30), except that the challenge virus consisted of approximately 10 5 PFU (equivalent to 10 5 bovine i.d. lingual infectious doses) of the challenge virus described above.…”

“…Radioimmunoprecipitation assays confirmed that sera from swine inoculated with DNA or BEI-inactivated virus immunoprecipitated virus capsid proteins (results not shown). In addition, the sera collected at week 10 were also able to neutralize a genetically engineered virus (A/O chimera [30]) that contains the major immunogenic site of serotype O1 substituted for the equivalent site of type A ( Table 3). Comparison of the abilities of the sera from the BEI virion-vaccinated and DNA-vaccinated swine showed that the ratios of neutralization titers for the A12 and A/O viruses were similar (Table 3).…”

“…Although these peptides induce antibodies that efficiently neutralize the virus in vitro, protection of livestock from virus challenge has been disappointing and has not correlated with prechallenge neutralization titers detected in the sera from these animals (7,(22)(23)(24)35). Although it is unclear where this disparity arises, the importance of antibodies to epitopes present on other portions of the capsid in conferring protection to livestock (20,30) and the intrinsic variability of the virus (8) could explain why peptide vaccines do not protect as well as whole capsid-based vaccines (35). To produce a new generation of safer FMD vaccines, we have used genetic engineering to develop attenuated FMD virions (21,26).…”

Insertion site of FLAG on foot-and-mouth disease virus VP1 G-H loop affects immunogenicity of FLAG

“…Among them, the G-H loop between VP1 residues 140 and 160, linking βG and βH, has a highly conserved arginine-glycine-aspartic acid (RGD) peptide motif, which recognizes an integrin ligand and is the most variable region and one of the most significant antigenic epitopes of FMDV (Bittle et al 1982;Jackson et al 1997;Neff et al 1998;Mahapatra et al 2012). The RGD motif plays a critical role in eliciting host protective immune responses (Rieder et al 1994;Mateu et al 1995;Fischer et al 2003).…”