Synergistic effect of ribavirin and vaccine for protection during early infection stage of foot-and-mouth disease

Figures

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  Fig. 1. In vivo evaluation of anti-foot-and-mouth disease virus (FMDV) activity of antiviral agents. Mice (n = 5 per group) were injected through the intraperitoneal (IP) or intramuscular (IM) routes with several antiviral candidates for protection against FMD. Six hours after the mice were injected with the first antiviral agents, 50 LD50 (LD50, 50% lethal dose) of Asia1/Shamir was challenged IP. A 3 mg/dose of ribavirin or 6-azauridine was injected IP twice per day from day 0 to day 3. A 3 mg/dose of T1105 was injected IP at 0, 8, 13, 24, and 30 h. One day before inoculation with FMDV, 5 × 108 TCID50 (50% tissue culture infective dose) of Ad-3siRNA or Ad-IFNαγ was injected IM. The p value is < 0.0001 (repeated measures ANOVA). n.s., no significant difference; IFN, interferon. **p < 0.01, ***p < 0.001.

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  Fig. 2. Comparison of administration routes of antiviral agents in mice. (A) Ribavirin (10 mg/day) was injected intraperitoneally (IP) or intramuscularly (IM) in mice (n = 5 per group) from day 0 to day 3. Six hours after being administered with the first antiviral agent, mice were injected IP with 50 LD50 (LD50, 50% lethal dose) of Asia1/Shamir. Survival rate of mice by IP or IM (p < 0.001 in ANOVA) and average weight for live mice were determined for 10 days. (B) The mice were administered per oral route (PO) (6, 10, and 15 mg/days, mixed form with feed) from day 0 to day 6. Survival rate of mice (p < 0.0001 in ANOVA) and average weight of live mice were determined for 10 days. Six hours after being administered with the first antiviral agent, mice were injected IP with 50 LD50 of Asia1/Shamir.

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  Fig. 3. Responses to repeat viral challenge in mice treated with antiviral agents/vaccine. At day 0, trivalent vaccinations were administered, and 6 mg or 10 mg ribavirin absorbed in feed were provided from day 0 to day 6 (6 mg or 10 mg/day/mouse). Six hours after vaccine administration and provision of feed in which reagents had been absorbed, mice (n = 5 per group) were injected IP with 50 LD50 (LD50, 50% lethal dose) Asia1 Shamir. Then, at day 10, re-challenge (arrows) was undertaken with 50 LD50 Asia1 Shamir. Changes in the weight and survival rates (p < 0.0001 in ANOVA) of the mice were monitored for 15 days. Copy number of viral RNA in serum for viremia assessment was also determined. Negative control animals all died by day 3. *p < 0.05, **p < 0.01, ***p < 0.001.

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  Fig. 4. Anti-foot-and-mouth disease (FMD) virus responses in mice administrated with antiviral agents containing adjuvants and vaccine. Mice (n = 5 per group) were injected intramuscular with vaccine or with 15 mg of antiviral agent on day 0. Six hours after injecting the first antiviral agent or commercial vaccine trivalent vaccine containing O1 Manisa, A 22 Iraq and Asia1 Shamir; Merial), the mice were inoculated intraperitoneal (IP) with 50 LD50 (LD50, 50% lethal dose) of Asia1/Shamir. (A) Survival rate of mice for 10 days (p < 0.001 in ANOVA) and average weight of live mice for 10 days. On six hours and the third day after being inoculated with the first antiviral agent, mice were twice injected IP with 50 LD50 of Asia1/Shamir. The mice were monitored for 10 days. (B) Survival rate of mice for 10 days (p < 0.0001 in ANOVA) and average weight of live mice for 10 days. The arrows indicate the day of the second challenge (3 dpc). (C) Copy number of viral RNA in serum. Negative control animals all died by day 3. The arrows indicate the day of the second challenge. *p < 0.05, **p < 0.01, ***p < 0.001.