Xenoepitope Substitution Avoids Deceptive Imprinting and Broadens the Immune Response to Foot-and-Mouth Disease Virus

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>Many RNA viruses encode error-prone polymerases which introduce mutations into B and T cell epitopes, providing a mechanism for immunological escape. When regions of hypervariability are found within immunodominant epitopes with no known function, they are referred to as “decoy epitopes,” which often deceptively imprint the host's immune response. In this work, a decoy epitope was identified in the foot-and-mouth disease virus (FMDV) serotype O VP1 G-H loop after multiple sequence alignment of 118 isolates. A series of chimeric cyclic peptides resembling the type O G-H loop were prepared, each bearing a defined “B cell xenoepitope” from another virus in place of the native decoy epitope. These sequences were derived from porcine respiratory and reproductive syndrome virus (PRRSV), from HIV, or from a presumptively tolerogenic sequence from murine albumin and were subsequently used as immunogens in BALB/c mice. Cross-reactive antibody responses against all peptides were compared to a wild-type peptide and ovalbumin (OVA). A broadened antibody response was generated in animals inoculated with the PRRSV chimeric peptide, in which virus binding of serum antibodies was also observed. A B cell epitope mapping experiment did not reveal recognition of any contiguous linear epitopes, raising the possibility that the refocused response was directed to a conformational epitope. Taken together, these results indicate that xenoepitope substitution is a novel method for immune refocusing against decoy epitopes of RNA viruses such as FMDV as part of the rational design of next-generation vaccines.</jats:p>

Efficacy of a Novel Multiepitope Vaccine Candidate against Foot-and-Mouth Disease Virus Serotype O and A

“…The FMDV VP1 G-H loop is structurally disordered and comprises a highly conserved arginineglycine-aspartate triplet (Arg-Gly-Asp, RGD) motif sequence. This motif primarily serves as a receptor binding site, while other exposed amino acids in the G-H loop are highly variable and act as immune decoys [40]. Theoretically, the RGD motif can mediate the initiation of viral infection by interacting with at least 8, and possibly 12, of the 24 currently known integrin receptors [41,42].…”

Foot-and-mouth disease vaccines: recent updates and future perspectives

“…At first, the peptides used corresponded to the C-terminal half of VP1 (residues 200-213) or to the G-H loop, which contains a B-cell epitope (residues 141-160), but these were not sufficiently protective in animal challenge experiments and induced only a limited T-cell response. A possible explanation of the limited protection and immune response is the hypervariability of the G-H loop domain [115]. Optimization of B and T sites via addition of an artificial T helper site and extensive flanking sequences resulted in some protection in pigs.…”

The level of decoy epitope in PCV2 vaccine affects the neutralizing activity of sera in the immunized animals

“…One such tactic is to divert the host immune response with a decoy. Decoy epitopes have been reported in a wide variety of viruses, including human immunodeficiency virus (HIV) [2], feline immunodeficiency virus (FIV) [3], hepatitis C [4], foot and mouth disease [5], middleeast respiratory syndrome coronavirus [6], severe fever with thrombocytopenia syndrome virus [7], porcine reproductive and respiratory syndrome virus (PRRSV) [8], murine gammaherpesvirus-68 (MHV-68) [9], and porcine circovirus type 2 (PCV2) [10]. Because a recombinant mutant capsid protein (CP) with a deleted decoy epitope induced a higher level of virusneutralizing antibody than wild type proteins [11], it was expected that higher levels of decoy epitope in a prepared batch of subunit vaccine would decrease its efficacy.…”