Antivirals as major weapon for the effective control of Foot-and-Mouth disease in field outbreaks
Sagar M Patel1, Monalisa Sahoo2, Nihar Ranjan Sahoo2, Akash Balasaheb Mote3, Prakash S. Dhamannapatil1
1Livestock Development Officer, Animal Husbandry Department, Maharashtra, India
2Senior Scientist, ICAR-International Center for Foot and Mouth Disease, Arugul, Jatani, Bhubaneswar, Odisha, India
3Ph.D Scholar, Division of Veterinary Public Health, ICAR-IVRI, Izatnagar, U.P, India
Abstract: Foot and mouth disease (FMD) is a severe, highly contagious viral disease of livestock that has a significant economic impact. It is a transboundary animal disease (TAD) that deeply affect the production of livestock and disrupting regional and international trade in animals and animal products. The disease is clinically characterized by severe emaciation, high fever, lameness, and vesicular lesions on the mouth, tongue, feet, snout, and teats of infected animals. The use of antivirals against FMD along with the routine vaccination is the need of hour for the effective control and prevention of its transmission. Various broad‑spectrum replication inhibitors and mutagenic nucleotide analogs including fluorouracil, 5‑azacytidine, 6‑azauridine, ribavirin, favipiravir (T‑705) and its derivative (T‑1105) have been explored for their antiviral potential against FMDV. The use of antiviral agents will pave the way for the effective control of the disease along with its further transmission to other naïve animals.
Key words: Transboundary Animal Disease, Antiviral agents, Prevention and Control.
Foot-and-mouth disease (FMD) is a highly contagious Transboundary Animal Disease (TAD), caused by RNA virus of the genus Aphthovirus (Family- Picornaviridae) with devastating economic consequences to the livestock population globally. The FMD is endemic in India and causes severe economic losses to the tune of approximately Rs. 21,000 crores per annum. The recent report documented total farm-level economic loss to be USD 2768 million (INR 221,110 million), USD 237 million (INR 18,910 million), and USD 133 million (INR 10,610 million) during severe, moderate, and mild disease outbreaks respectively (Govindaraj et al., 2021). Of its 7 serotypes, serotype “O” is widely prevalent in India (80–92%), followed by Asia1 (3–10%) and serotype A (3–8%). The disease is clinically characterized by severe emaciation, high fever, lameness, and vesicular lesions on the mouth, tongue, feet, snout, and teats of infected animals. The mortality rates in adult animals are usually low-to-negligible. In contrast, high mortality rate is observed in suckling and young animals with few or no vesicular lesions. In these cases, death results from myocarditis in young calves up to 3- months old and is age-dependent (Aktas et al., 2015). Earlier investigations suggested that mortality in young suckling ruminants and pigs varied from 20–75% in the most extreme cases. Multiple studies conducted on specimens obtained during field outbreaks and experimental settings (Gulbahar et al., 2011) have confirmed a relationship between acute Foot-and-mouth disease virus (FMDV) infections and fatal myocarditis in young ruminants and pigs. Being a multi-host pathogen with large numbers of serotypes (7) and genotypes (>80), high virulence and contagious nature, high viral load shedding in secretions, and multiple transmission routes, its control and eradication is a herculean task. India has adopted vaccination strategy with trivalent FMDV inactivated virus (serotypes O, A, and Asia 1) vaccines to control and manage the disease through programs like Livestock Health Disease Control Program (LHDCP). However, the emergence of multiple genetically and antigenically divergent lineages within the serotype, carrier status, prolonged convalescence, along with various problems related to vaccine including low immunogenicity, instability of the antigen, insufficient maintenance of the antibody, and little or no cross-protection across serotypes and subtypes makes it difficult to control via routine vaccination (Li et al., 2022). Therefore, the use of antivirals against FMD along with the routine vaccination is the need of hour for the effective control and prevention of its transmission. Antivirals can potentially cover the early period of susceptibility due to their ability for inhibition of rapid virus multiplication. Antivirals can either be designed to specifically inhibit the function of one or more viral proteins or a more generic antiviral approach can be attempted utilizing components of the host innate immune response (Sakudo et al., 2023).
Various broad‑spectrum replication inhibitors and mutagenic nucleotide analogs including fluorouracil, 5‑azacytidine, 6‑azauridine, ribavirin, favipiravir (T‑705) and its derivative (T‑1105) have been explored for their antiviral potential against FMDV. Among them, T‑1105 showed highest promising result in both in-vitro and in-vivo. The published report showed its efficacy for significant suppression of symptoms and clinical signs, such as fever, in pigs and guinea pigs at higher doses(200‑400 mg/kg/day) (8). The National Institute of Animal Health in Japan has highlighted the use of T‑1105 and T‑705 as anti‑FMDV chemical compound for their use for the control of FMD in field outbreaks. Moreover, newly developed antiviral agents such as brequinar (BQR), mizoribine, merimepodib and vesatolimod showed their efficacy against FMDV. The following antiviral agents are showing promising results for the treatment and prevention of FMD in livestock.
Favipiravir: (T‑705,6‑fluoro‑3‑hydroxypyrazine‑2‑carboxamide) inhibits the activity of ribonucleic acid (RNA) dependent RNA polymerase. The efficacy was earlier tested in influenza virus (Lefebvre et al., 2014). The administration of oral dose of T‑1105 (400 mg/kg/day) twice daily for five days showed the potential to reduce FMDV load in guinea pigs and pigs (Nishi et al., 2022).
Ribavirin: Ribavirin is a promising antiviral agent (synthetic purine nucleoside analog) against various serotypes of FMDV interfering with viral polymerase and RNA capping. Its efficacy has been in suckling mice model (Nikunjkumar et al., 2021). In addition, the administration of ribavarin with vaccines synergistically enhanced antiviral activity by enhancing the survival rate and body weight in the experimental animals. Therefore, ribavirin could be used in the early phase of infection or before infection with vaccine treatment.
Brequinar (BQR): the antiviral potential of BQR against FMDV has been studied in-vitro and in-vivo approaches (Li et al., 2019). Treatment with BQR significantly reduced the severity of myocarditis lesions in FMDV‑infected mice which suggest its use as a vaccine before infection.
Mizoribine: Mizoribine is an imidazole nucleoside originally developed as animmunosuppressant for transplantation immunity. The administration of mizoribine solution (50 μg/0.1 ml) by subcutaneous injection to suckling mice inhibited FMDV replication showing significant reduction in the mortality of inoculated mice, which raises the possibility of its use to complement vaccine treatment in the future (li et al., 2019).
GS‑9620 (vesatolimod): GS‑9620, agonist of Toll‑like receptor 7 (TLR7), is an inducer of type 1 interferon, induces an antiviral state in host cells via TLR7. The adjuvant potential of the TLR7 agonist, GS‑9620, in the early phase of FMD has been documented in recent report (Li et al., 2022).
Ivermectin: Recent report showed the efficacy of ivermectin at 2.5 μM and 5 μM concentrations to inhibit the major serotypes of FMDV (O, A and Asia-1) by reducing the viral load of two to three log (Naeem et al., 2023). The reduction of virus titer was more evident at the replication stage as compared to attachment and entry stages.
The treatment of FMDV infected animals with antiviral agents will help to reduce the amount and duration of virus shedding. Recently, there is a growing interest for the identification of promising antiviral agents to complement vaccination for the effective control of FMD. This strategy can be implemented in the final phase of FMD eradication campaigns in countries where the disease is enzootic. The use of antiviral agents will pave the way for the effective control of the disease along with its further transmission to other naïve animals.
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