Evaluation of a Live-Attenuated Foot-and-Mouth Disease Virus as a Vaccine Candidate

Abstract

A variant of foot-and-mouth disease virus (FMDV) lacking the leader (L) coding region (A12-LLV2) was previously constructed and shown to be less virulent in cattle than its wild-type parent (A12-IC). In this study, cattle were tested for their clinical and immunological responses to subcutaneous inoculation with A12-LLV2 or A12-IC or to intramuscular vaccination with chemically inactivated A12-IC. Five weeks postinoculation animals were challenged by intradermal inoculation in the tongue with a virulent cattle-passaged virus. A12-LLV2-inoculated animals showed no clinical signs of disease and developed a neutralizing antibody response by 4 days postinoculation, whereas a companion control bovine did not seroconvert. After challenge, two of three inoculated animals did not develop lesions, but showed mild signs of infection. The third inoculated animal developed some lesions, but these were less severe than in the uninoculated control animal, which showed classical FMD. All animals inoculated with A12-IC developed a fever, two showed typical FMD lesions, and the companion control seroconverted, indicating that it had acquired infection by contact. The A12-IC-inoculated animals and the control were protected from challenge. Animals vaccinated with inactivated virus showed no clinical signs of disease and developed a neutralizing antibody response, and the control did not seroconvert. Upon challenge none of the vaccinated animals developed lesions, one developed a fever, and the control developed FMD. These experiments demonstrate the potential of a rationally designed live-attenuated FMDV vaccine.

Inhibition of L-Deleted Foot-and-Mouth Disease Virus Replication by Alpha/Beta Interferon Involves Double-Stranded RNA-Dependent Protein Kinase

“…As we have previously shown, L-deleted FMDVs are attenuated in their natural hosts, including swine and bovines (1,3,5,14). Their attenuation appears related to the inability to block synthesis of cytokines such as IFN-␣/␤ due to the absence of L proteinase activity.…”

“…L proteinase also cleaves host translation initiation factor eIF-4G resulting in the shutoff of host cap-dependent mRNA translation (7,10,13,15). Consequently, FMDV RNA, which initiates translation in a cap-independent fashion via an internal ribosome entry site (IRES) and does not require intact eIF-4G, can freely use the host protein synthesis machinery for viral protein production (6,10,14,20,22).…”

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

“…New attenuated virus vaccines have been designed by modification of infectious FMDV clones. Chimeric viruses in which the RGD receptor binding site [162] or the L gene [155] were deleted, induced protection in natural hosts without producing clinical symptoms. In spite of these promising results, the wide FMDV host-range and the high potential for variation of the virus make a careful study of the stability and pathogenicity of new recombinant vaccines necessary before they can be considered for field trials.…”

A Safe Foot-and-Mouth Disease Vaccine Platform with Two Negative Markers for Differentiating Infected from Vaccinated Animals

“…L pro has also been shown to induce degradation of nuclear factor B (NF-B) in FMDV-infected cells, leading to inhibition of the host innate immune response (14,15). Numerous studies with genetically engineered serotype A FMDVs lacking L pro have been shown to be infectious but grow more slowly in cell culture (37) and is attenuated in both cattle and swine (5,7,26).…”