Genetically engineered swine influenza virus and uses thereof
Inventors
Palese, Peter • Garcia-Sastre, Adolfo • Webby, Richard J. • Richt, Juergen A. • Webster, Robert G. • Lager, Kelly M.
Assignees
St Jude Childrens Research Hospital • Icahn School of Medicine at Mount Sinai • US Department of Agriculture USDA
Publication Number
US-10098945-B2
Publication Date
2018-10-16
Expiration Date
2025-06-01
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Abstract
The present invention relates, in general, to attenuated swine 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 swine influenza viruses having modifications to a swine 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 invention relates to attenuated swine influenza viruses having an impaired ability to antagonize the cellular interferon (IFN) response due to modifications in the swine NS1 gene. These modifications diminish or eliminate the ability of the NS1 gene product to counteract the cellular IFN response, resulting in viruses that replicate in vivo with decreased replication, virulence, and increased attenuation. Such viruses are well suited for use in live virus vaccines and pharmaceutical formulations.
The problem solved by the invention is the need for effective vaccines against swine influenza virus infections, given that existing inactivated vaccines provide limited protection and that conventional methods for producing attenuated viruses are inefficient and unpredictable. Swine influenza viruses evolve rapidly, causing significant veterinary and human public health concerns. The invention addresses these issues by providing genetically engineered swine influenza viruses with defined mutations in the NS1 gene to impair IFN antagonism, leading to attenuation and suitability for vaccine use.
The invention is based on the discovery that swine influenza viruses with deletions in the NS1 gene show impaired replication and reduced virulence in pigs compared to wild-type virus. Surprisingly, shorter NS1 proteins confer greater attenuation, contrary to results with human influenza viruses. The attenuated viruses induce robust IFN responses which contribute to their phenotype and provide a basis for live vaccine development and pharmaceutical applications including prevention or treatment of IFN-treatable diseases beyond swine influenza.
Claims Coverage
The patent claims cover methods for preventing swine influenza in pigs using immunogenic compositions comprising genetically engineered attenuated swine influenza viruses with mutations in the NS1 gene resulting in specific deletions. Main inventive features include the precise NS1 gene deletion size, virus strain, and use as vectors expressing heterologous sequences.
Genetic modification of swine influenza virus NS1 gene to impair interferon antagonist phenotype
A method for preventing swine influenza virus disease in pigs by administering an immunogenic composition comprising a genetically engineered attenuated swine influenza virus with a mutation in the swine influenza virus NS1 gene that results in an NS1 protein having a deletion of between 90 and 94 amino acids from the carboxy-terminus.
Use of specific swine influenza virus strains with NS1 deletions
Using swine influenza viruses deriving NS1 genes from strains such as A/Swine/Texas/4199-2/98 or various other listed swine strains that have defined NS1 deletions as vaccine candidates.
Inclusion of reassortant or chimeric virus forms
The attenuated virus can be a reassortant or a chimeric virus comprising a heterologous sequence, including viruses engineered to express epitopes of foreign pathogens or segments from different viruses without altering the attenuated phenotype.
Immunization methods in pigs
Methods of immunizing pigs with compositions comprising genetically engineered attenuated swine influenza viruses with defined NS1 deletions to induce immunity against swine influenza virus infection.
The claims cover the use of genetically engineered attenuated swine influenza viruses with defined deletions in the NS1 gene, particularly deletions of about 90 amino acids from the carboxy-terminus, derived from specific swine strains, for immunization and disease prevention in pigs. The compositions can include reassortants or chimeric viruses expressing heterologous sequences and can be used in methods to prevent swine influenza virus infections.
Stated Advantages
The attenuated swine influenza viruses replicate in vivo yet demonstrate decreased virulence and increased attenuation, making them ideal candidates for live virus vaccines.
These viruses induce robust interferon responses, which may confer protection against subsequent infectious diseases and induce antitumor responses.
The genetic engineering approach allows for deliberate, specific mutations in the NS1 gene, enabling production of more effective vaccines compared to conventional methods that rely on chance mutants.
The attenuated viruses can be propagated in various substrates including pig cells and embryonated eggs, facilitating vaccine production.
Attenuated viruses can serve as vectors for expression of epitopes from other pathogens or tumor antigens, broadening their utility.
Documented Applications
Live virus vaccines for prevention of swine influenza virus infections in pigs.
Pharmaceutical formulations for prophylaxis or treatment of infections and interferon-treatable diseases such as cancer in pigs.
Use as vectors for recombinant vaccines expressing epitopes from heterologous pathogens or tumor antigens.
Immunogenic formulations to induce immune response for treatment, management or prevention of swine influenza virus infections and associated symptoms.
Methods for preventing, managing or treating cancer by administering the attenuated swine influenza viruses or formulations thereof.
Propagation of attenuated swine influenza viruses in various substrates for vaccine or pharmaceutical production.
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