Antiviral activity of bovine type III interferon against foot-and-mouth disease virus
Inventors
De Los Santos, Teresa B. • Zhu, James J. • Diaz-San Segundo, Fayna • Grubman, Marvin J. • Koster, Marla J.
Assignees
US Department of Agriculture USDA
Publication Number
US-8906384-B2
Publication Date
2014-12-09
Expiration Date
2030-12-22
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Abstract
A member of the bovine type III IFN family, boIFN-λ3, was identified and characterized. We expressed boIFN-λ3 using a recombinant replication defective human adenovirus type 5 (Ad5) and demonstrated antiviral activity against foot-and-mouth disease virus (FMDV) and vesicular stomatitis virus (VSV) in bovine cells in vitro. Cattle were inoculated with Ad5-boIFN-λ3 followed by intradermolingual or aerosol FMDV challenge. Results demonstrated that the type III IFN family is conserved in bovines and that treatment of cattle with boIFN-λ3 alone or in combination with IFN-α is able to confer delayed and reduced severity of FMD. Furthermore inoculation with Ad5-boIFN-λ3 alone conferred full protection against aerosol challenge for at least 7 days after administration suggesting that type III IFN used in combination with FMD vaccines could fill one of the current gaps in emergency vaccination against FMDV.
Core Innovation
The invention relates to an isolated, recombinant nucleic acid comprising a sequence encoding bovine interferon-λ3 (boIFN-λ3), and antiviral pharmaceutical compositions containing a vector with this nucleic acid. These compositions induce systemic antiviral activity, specifically anti-foot and mouth disease virus (FMDV) activity, and upregulate specific gene expression in vivo to delay and reduce the severity of foot and mouth disease (FMD) in infected animals.
Foot-and-mouth disease virus (FMDV) causes a highly contagious disease in cloven-hoofed livestock with rapid spread and high morbidity. Existing vaccines have limitations, especially in FMD-free countries where differentiating vaccinated from infected animals is problematic, leading to trade restrictions. Treatment with type I and II interferons (IFNs) shows only partial protection in cattle, highlighting the need for new antivirals effective in this species.
Type III IFNs, including IFN-λ3, have been recently identified in several species and are known to induce antiviral activities. No bovine type III IFNs had been characterized prior to this invention. The invention identifies, clones, and characterizes boIFN-λ3, demonstrating its antiviral activity against FMDV and its capacity to regulate interferon-stimulated genes. Delivery of boIFN-λ3 via a recombinant adenovirus vector confers in vivo protection in cattle, including delayed and reduced FMD severity and full protection against aerosol challenge, supporting its use alone or in combination with other IFNs or FMD vaccines to improve emergency vaccination strategies.
Claims Coverage
The patent includes thirteen claims featuring several independent claims covering the isolated boIFN-λ3 nucleic acid, pharmaceutical compositions comprising boIFN-λ3 alone or in combination, and methods of use for treating animals susceptible to FMDV.
Isolated and recombinant nucleic acid encoding bovine interferon-λ3
An isolated or recombinant cDNA comprising a sequence encoding bovine interferon-λ3 (boIFN-λ3), including the specific amino acid (SEQ ID NO:2) and nucleotide (SEQ ID NO:1) sequences.
Antiviral pharmaceutical compositions comprising boIFN-λ3
Pharmaceutical compositions containing an effective amount of isolated or recombinant boIFN-λ3 cDNA or a vector encoding boIFN-λ3, capable of inducing systemic antiviral activity against FMDV.
Combination antiviral compositions with type I interferons or FMD vaccine
Compositions comprising boIFN-λ3 cDNA combined with porcine or bovine type I IFN cDNA, or with an FMD vaccine vector, which induce systemic antiviral activity, up-regulate interferon-stimulated genes, and reduce FMD severity.
Methods of reducing FMDV infection and disease severity
Methods administering effective dosages of compositions comprising boIFN-λ3 with type I IFNs or FMD vaccine in animals to reduce the degree or rate of FMDV infection, delay and reduce disease severity, and induce expression of IFN-stimulated genes correlated with systemic control of viral replication.
The claims comprehensively cover the isolated boIFN-λ3 gene and its use alone or in combination with other interferons or FMD vaccines in pharmaceutical compositions, as well as methods for reducing FMDV infection and enhancing antiviral gene expression in susceptible animals.
Stated Advantages
Treatment with boIFN-λ3 alone or combined with IFN-α delays and reduces the severity of foot and mouth disease in cattle.
BoIFN-λ3 administered via an adenovirus vector provides full protection against aerosol FMDV challenge for at least seven days after administration.
BoIFN-λ3 targets antiviral activity to epithelial tissues such as those in the upper respiratory tract, preventing virus spread and lesion formation.
Use of boIFN-λ3 in combination with FMD vaccines fills gaps in existing emergency vaccination strategies against FMDV.
Documented Applications
Use of recombinant boIFN-λ3 as an antiviral pharmaceutical composition to confer protection against FMDV in cattle, swine, goats, and sheep.
Compositions combining boIFN-λ3 with porcine or bovine type I interferons or FMD vaccines to induce systemic antiviral activity and upregulate interferon-stimulated genes in vivo.
Use of boIFN-λ3 administered by adenovirus vectors as a prophylactic or therapeutic agent to reduce infection rate and severity of FMD upon direct intradermolingual or aerosol FMDV challenge.
Use of boIFN-λ3 to induce expression of IFN-stimulated genes in skin and upper respiratory tract tissues, the primary sites of FMDV replication.
Employing poIFN-α as an adjuvant to enhance immune responses to FMD vaccines in swine, improving long-term protection.
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