Non-responsiveness to a foot-and-mouth disease virus peptide overcome by addition of foreign helper T-cell determinants

Abstract

Study of the immune response to synthetic antigens has shown that uncoupled peptides can realize their potential as vaccines only if they contain domains that react with helper T-cell receptors and Ia antigens in addition to antibody binding sites. Here we consider whether genetically restricted non-responsiveness to an uncoupled peptide could be overcome by synthesizing a peptide with an additional helper T-cell epitope from a different protein. We demonstrate that H-2d mice, which are non-responders to the 141-160 VP1 peptide of foot-and-mouth disease virus (FMDV), can be converted into responders by immunization with peptides containing the FMDV sequence with defined 'foreign' helper T-cell determinants from ovalbumin or sperm whale myoglobin. Furthermore, the virus-neutralizing activity of the antibody raised against peptide was dependent on the determinant used. Thus, FMDV peptides with the added sequences 323-339 from ovalbumin and 132-148 from sperm-whale myoglobin elicited a high degree of neutralizing activity in B10.D2 mice. The sera from mice which received the peptide with the added sequence 105-121 from sperm whale myoglobin did not neutralize the virus, although they had high levels of anti-141-160 FMDV peptide activity. Our data indicate that the T-cell help given by the 'foreign' epitopes is B-cell clone specific. These results are likely to have important implications for the design of peptide vaccines.

Processing and Assembly of Foot-and-Mouth Disease Virus Proteins Using Subgenomic RNA

“…Many approaches towards subunit vaccines for FMDV have been made (e.g. Kleid et al, 1981 ;Bittle et al, 1982;Winther et al, 1986;Clarke et al, 1987;Francis et al, 1987) and, although significant progress has been made, the most immunogenic particle apart from the virus itself is the 'empty' viral capsid (Rowlands et al, 1975). A major problem associated with FMDV vaccines has been outbreaks occurring as a result of improperly inactivated vaccines.…”

Foot-and-mouth disease virus: a long known virus, but a current threat

“…The intraperitoneal inoculation of FMDV produces death in suckling mice, and this has been extensively exploited to titrate virus infectivity. Likewise, FMDV can be adapted, by serial passages, to produce clinical symptoms in guinea-pigs, an animal model that has been used mostly for immunological analyses [98].…”

“…However, the immunogenicity of these peptide constructs in a number of host species was substantially lower than that of conventional vaccines (reviewed in [55,79]). In the following years, the concept that immunogenic peptides should also include viral T cell epitopes to provide an adequate co-operation with immune B lymphocytes to induce an effective neutralising antibody response, became generally accepted [39,55,58,79,98,194,227]. Such T cell peptides should ideally be recognised by T lymphocytes in the context of alleles of MHC class II frequently represented in the populations of the natural hosts [194].…”

Heterotypic recognition of foot-and-mouth disease virus by cattle lymphocytes

“…T. Collen and T. R. Doel Conjugation of B and T cell epitopes (Cox et al, 1988) and collinear synthesis of the same (Borras-Cuesta et al, 1987 have been shown to influence the immunogenicity of peptide antigens. Furthermore, the addition of T cell epitopes to peptides with known B cell activity (Good et al, 1987;Francis et al, 1987b) has been shown to overcome major histocompatibility complex restriction, a known problem with peptide vaccines. Thus, for the development of an effective synthetic FMD vaccine there is a clear need to demonstrate T cell epitopes within the proteins of FMDV that are recognized by a natural host.…”