Genetically engineered equine influenza virus and uses thereof
Inventors
Palese, Peter • Garcia-Sastre, Adolfo • Chambers, Thomas
Assignees
University of Kentucky • Icahn School of Medicine at Mount Sinai
Publication Number
US-8137676-B2
Publication Date
2012-03-20
Expiration Date
2025-06-01
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Abstract
The present invention relates, in general, to attenuated equine influenza viruses having an impaired ability to antagonize the cellular interferon (IFN) response, and the use of such attenuated viruses in vaccine and pharmaceutical formulations. In particular, the invention relates to attenuated equine influenza viruses having modifications to an equine NS1 gene that diminish or eliminate the ability of the NS1 gene product to antagonize the cellular IFN response. These viruses replicate in vivo, but demonstrate decreased replication, virulence and increased attenuation, and therefore are well suited for use in live virus vaccines, and pharmaceutical formulations.
Core Innovation
The present invention concerns attenuated equine influenza viruses that possess an impaired ability to antagonize the cellular interferon (IFN) response, primarily achieved by introducing specific mutations or deletions in the equine influenza NS1 gene. These viruses, while capable of in vivo replication, exhibit decreased replication rates and reduced virulence as compared to wild-type equine influenza viruses. This makes them ideal candidates for live virus vaccine and pharmaceutical use, as they can induce immunity without causing illness or only result in milder symptoms.
The invention addresses the problem that current equine influenza vaccines, often based on inactivated viruses, provide inadequate and short-lived protection against infection. In addition, traditional methods for producing attenuated viruses are unpredictable, inefficient, and may not consistently produce effective immune responses. Previous approaches also failed to predictably identify genetic alterations required for attenuation, particularly using recombinant DNA technology for negative-strand RNA viruses like influenza.
By engineering deletions or mutations in the NS1 gene that reduce or eliminate the ability of the NS1 gene product to counteract the host IFN response, these engineered viruses are both attenuated in their ability to replicate and able to generate a robust IFN-mediated immune response. The invention further allows these viruses to be used as backbones for expressing heterologous sequences, such as antigens from foreign pathogens or tumor antigens, enabling broader vaccine or therapeutic applications, including the induction of local IFN responses for infectious disease prophylaxis or cancer treatment.
Claims Coverage
The patent contains two independent claims, each identifying key aspects of inventive features involving a genetically engineered attenuated equine influenza virus for vaccine formulation and methods for inducing an immune response in horses.
Genetically engineered attenuated equine influenza virus with NS1 gene deletion (amino acids 1-126 remaining)
A vaccine formulation comprising a genetically engineered attenuated equine influenza virus is described, wherein the virus has an impaired interferon antagonist phenotype, and comprises an NS1 gene with a mutation resulting in a deletion of all of the amino acid residues of NS1 except amino acid residues 1-126. This inventive feature underpins the attenuation mechanism by targeting a defined truncation in the NS1 protein sequence.
Use of the vaccine formulation to induce an immune response in horses
A method for inducing an immune response in a horse is delineated, comprising administering to the horse an effective amount of the above-described vaccine formulation (with NS1 gene mutation resulting in retention of amino acid residues 1-126 only). This feature establishes the application of the genetically engineered attenuated virus as an immunizing agent for horses.
In summary, the inventive features are focused on a precise genetic alteration in the equine influenza NS1 gene to confer attenuation and impaired interferon antagonism, and the application of this modified virus in a vaccine formulation to induce immune responses in horses.
Stated Advantages
Provides live virus vaccines that are capable of generating an immune response and creating immunity without causing illness or causing only fewer and/or less severe symptoms due to decreased virulence.
Enables induction of robust interferon (IFN) responses that have protective effects against subsequent infectious diseases and can induce antitumor responses.
The viruses can be engineered to serve as vectors for vaccine development or pharmaceutical formulations, including expression of foreign pathogen epitopes or tumor antigens.
Attenuated viruses can stimulate immunity more effectively than inactivated vaccines and are suitable for intranasal administration, leading to mucosal and longer lasting immunity.
Allows consistent and reproducible attenuation through specific genetic engineering approaches, overcoming unpredictability of traditional attenuation methods.
Documented Applications
Use in vaccine formulations for the treatment, management, or prevention of equine influenza virus infections in horses.
Use in immunogenic or pharmaceutical formulations for the prevention or treatment of other infectious diseases or interferon-treatable diseases, including cancer.
As vectors for the expression of heterologous epitopes or tumor antigens in horses and other susceptible species (e.g., donkey, zebra, camel, dog, avian).
For localized induction of interferon responses at targeted tissue sites to minimize systemic side effects.
For vaccine and pharmaceutical production via propagation in cells, cell lines, or embryonated eggs (especially in IFN-deficient systems).
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