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Title: Characterization of cytotoxic T lymphocyte function following foot-and-mouth disease virus infection and vaccination

item Patch, Jared
item Kenney, Mary
item Pacheco Tobin, Juan
item Grubman, Marvin
item Golde, William

Submitted to: Viral Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/15/2013
Publication Date: 7/5/2013
Citation: Patch, J.R., Kenney, M.A., Pacheco Tobin, J., Grubman, M.J., Golde, W.T. 2013. Characterization of cytotoxic T lymphocyte function following foot-and-mouth disease virus infection and vaccination. Viral Immunology. 26(4):239-249 DOI:10.1089/vim.2013.0011.

Interpretive Summary: Infection of livestock species with foot-and-mouth disease virus (FMDV) can be economically devastating as outbreaks in disease free countries can lead to strict quarantine of susceptible species and eventual cull and slaughter of exposed animals. Vaccines have become critical to control of disease following outbreaks as well as eradication of disease. The adaptive immune response to vaccination can be separated into two arms, the humoral or antibody response and the cellular response. Immunity to viral infection is commonly very dependent on the cellular immune response however the response to FMDV has been historically focused on neutralizing (virus blocking) antibody responses. The cellular immune response has been much more difficult to assess. We report vaccination strategies to induce the humoral or cellular response separately so we can determine the contribution of these different responses in protecting animals from infection. The experimental FMDV vaccine, vectored by human replication defective adenovirus 5, induces strong humoral immune responses but no cellular immunity. An altered Ad5-FMDV construct induces cellular immune responses and poor humoral immunity. Now, for the first time, we now show that the cellular response to FMDV, in the absence of significant humoral immunity, reduces clinical disease, most notably blocking virus spread via blood in animals challenged with live virus. This approach reveals the effect of cellular immunity alone and indicates that adding vaccination for cellular immune responses has the potential to improve the performance of the Ad5-FMDV vectored vaccine.

Technical Abstract: Foot-and-mouth disease (FMD) is an economically important disease of cloven-hoofed animals that remains a global threat to livestock species. The induction of neutralizing antibodies against FMD virus (FMDV) has been the central goal of vaccination efforts against this disease. Although these efforts have yielded much success, challenges remain including lack of cross-neutralizing antibodies, poor induction of cellular immune responses, and inadequate duration of immunity. Despite their prominent role in anti-viral defense, the role of cytotoxic T lymphocytes (CTL) in FMDV immunity has not been defined. We previously developed an assay for detection of CTL cytolytic activity and demonstrated that a modified adenovirus-vectored FMDV vaccine could induce CTL activity. In this present study, we now report induction of FMDV specific CTL responses following infection of pigs with virulent FMDV strain A24. Further, we tested whether the induction of CTLs specific for FMDV following targeted vaccination could protect against challenge with FMDV. The CTL response against FMDV in the absence of significant neutralizing antibody failed to protect against clinical disease. However, clinical disease was delayed and viremia was suppressed compared to control animals, suggesting a role for CTLs in the control of virus shedding. This CTL induction was under the artificial condition of limiting T cell help for the CD8+ CTLs, as antigen was targeted to class I MHC by the vaccine strategy, in part to limit induction of an antibody response. These results provide new insights showing induction of CTL responses to FMDV can be achieved by vaccination, creating the potential for improving vaccine performance by targeting cellular immunity.