Induction of Foot-and-Mouth Disease Virus-Specific Cytotoxic T Cell Killing by Vaccination

Abstract

Foot-and-mouth disease (FMD) continues to be a significant threat to the health and economic value of livestock species. This acute infection is caused by the highly contagious FMD virus (FMDV), which infects cloven-hoofed animals, including large and small ruminants and swine. Current vaccine strategies are all directed toward the induction of neutralizing antibody responses. However, the role of cytotoxic T lymphocytes (CTLs) has not received a great deal of attention, in part because of the technical difficulties associated with establishing a reliable assay of cell killing for this highly cytopathic virus. Here, we have used recombinant human adenovirus vectors as a means of delivering FMDV antigens in a T cell-directed vaccine in pigs. We tested the hypothesis that impaired processing of the FMDV capsid would enhance cytolytic activity, presumably by targeting all proteins for degradation and effectively increasing the class I major histocompatibility complex (MHC)/FMDV peptide concentration for stimulation of a CTL response. We compared such a T cell-targeting vaccine with the parental vaccine, previously shown to effectively induce a neutralizing antibody response. Our results show induction of FMDV-specific CD8؉ CTL killing of MHC-matched target cells in an antigen-specific manner. Further, we confirm these results by MHC tetramer staining. This work presents the first demonstration of FMDV-specific CTL killing and confirmation by MHC tetramer staining in response to vaccination against FMDV.

Inoculation of Swine with Foot-and-Mouth Disease SAP-Mutant Virus Induces Early Protection against Disease

“…Recently, a cytotoxic T cell lymphocyte (CTL) response during natural FMDV infection has been reported (37). The idea that a good vaccine against FMDV should combine stimulation of both humoral and cellular responses has been considered for a long time (4), and several attempts to include T cell stimulation in FMDV vaccine strategies have been pursued (6,32,38,62). How- ever, none of the vaccine platforms evaluated to date are able to induce the same immune response as the natural infection.…”

Use of recombinant capsid proteins in the development of a vaccine against the foot-and-mouth disease virus

“…However, it has been possible to achieve protection against FMDV challenge in animals using these vectors 60 but high levels of the adenovirus are required which may suggest that the expression of the FMDV proteins is relatively low, albeit detectable. 46 It is noteworthy that adenovirus vectors expressing serotype A (A24) cassettes have proved to be more successful than serotype O (O1 Campos) but the basis for this difference is not defined. 61 The baculovirus expression system also uses transcription from within the nucleus but most baculovirus transcripts are not spliced and it therefore appears that the potential for adverse modification of transcripts derived from FMDV cDNA within recombinant baculoviruses is more limited.…”

“…"Live" attenuated vaccines have the property of producing viral antigens within the infected cells and short peptides derived from such antigens are then displayed on the surface of infected cells in association with host MHC proteins, this is particularly important for the induction of cytotoxic T-cells. However, the role of cytotoxic T-cells in generating protection against FMDV is not clear 46 but induction of other T-cell responses may affect the duration of immunity. 47 Inactivated vaccines are recognized by antigen presenting cells and principally induce a B-cell response but this response is positively influenced by the presence of CD4(+) T-cells, since depletion of these cells reduces the level and nature of the antibody response.…”

“…23,49,50 However, this precursor protein is not very immunogenic and fails to generate a protective immune response. 46,49 Hence, more recently, the focus has been on expressing "empty capsid particles" (see Figure 2) since these non-infectious particles (lacking the viral genome) have the same antigenic and immunogenic properties as whole viruses 19,51 while having the advantage of not constituting a risk of spreading from the production plant. However, achieving the efficient expression of FMDV empty capsid particles has not proved completely straightforward (see below).…”

Advances in swine immunology help move vaccine technology forward

“…Purified protein and antibody reagents are increasingly available to elucidate immune developmental and regulatory pathways in animal species, as are molecular tools and sequence data for characterization of humoral and cellular immune effector functions (Butler, 1998; Butler et al, 2006; Butler et al, 2001; Butler et al, 2009; Butler et al, 2004; Eguchi-Ogawa et al, 2009; Eguchi-Ogawa et al, 2012; Eguchi-Ogawa et al, 2010; Honma et al, 2003; Schwartz et al, 2012a, b; Sinkora et al, 2002; Uenishi et al, 2009). Methods for recombinant antibody expression and tetramers for antigen-specific T-cell responses in swine have been developed (Butler et al, 2013; Patch et al, 2011). These advances significantly enhance vaccine development by providing mechanistic models for interpretation of experimental data, and use of surrogate immunological endpoints that predict in vivo outcomes.…”