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-9549975-B2
Publication Date
2017-01-24
Expiration Date
2025-06-01
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 provides attenuated swine influenza viruses having an impaired ability to antagonize the cellular interferon (IFN) response, specifically through modifications to the swine NS1 gene which reduce or eliminate the NS1 gene product's capacity to counteract the cellular IFN response. These viruses replicate in vivo but exhibit decreased replication, virulence, and increased attenuation, making them suitable for use in live virus vaccines and pharmaceutical formulations.
The problem being solved concerns the need for new and more effective vaccines and immunogenic formulations for preventing swine influenza virus infections. Conventional methods for producing attenuated viruses often rely on chance isolation of host range mutants and can result in viruses that are difficult to propagate or insufficiently immunogenic. The invention addresses the unpredictability of genetic alterations needed for attenuation and the limitations of inactivated vaccines, offering genetically engineered viruses with defined mutations in the NS1 gene to achieve attenuation.
Claims Coverage
The patent contains independent claims focusing on genetically engineered attenuated swine influenza viruses with specific NS1 gene mutations that impair interferon antagonist activity.
Genetically engineered attenuated swine influenza virus with NS1 carboxy-terminus deletion
A swine influenza virus genetically engineered to have an NS1 gene mutation resulting in a deletion of between 90 and 94 amino acid residues from the NS1 protein's carboxy-terminus, impairing its interferon antagonist phenotype. The NS1 gene originates from A/Swine/Texas/4199-2/98.
Subtypes and reassortants of attenuated virus
The genetically engineered attenuated swine influenza virus can be from several subtypes including H1N1, H1N2, H3N2, H3N1, H9N2, or H5N1, and may be a reassortant strain.
Chimeric viruses expressing heterologous sequences
The attenuated virus can be chimeric, expressing heterologous sequences such as epitopes of foreign pathogens or tumor antigens, or engineered to express epitopes or at least one segment from different viruses, including various known swine influenza virus strains listed by Genbank accession.
Formulations and propagation systems
Immunogenic and pharmaceutical formulations containing the genetically engineered attenuated virus and physiologically acceptable excipients are claimed, as well as cultured cells (preferably pig cells or pig cell lines) and embryonated chicken eggs containing the virus.
The independent claims cover genetically engineered swine influenza viruses with defined NS1 gene deletions leading to impaired interferon antagonism, encompassing various influenza A subtypes, reassortants, chimeric variants expressing foreign epitopes, related formulations, and propagation systems in cell cultures and embryonated eggs.
Stated Advantages
The attenuated swine influenza viruses demonstrate decreased virulence and increased attenuation while retaining the ability to replicate in vivo and induce robust immune and interferon responses.
Live virus vaccines based on these attenuated viruses have advantages such as improved cross-reactive cell-mediated immunity, longer-lasting immunity, induction of mucosal immunity, intranasal administration, and cost-effectiveness compared to inactivated vaccines.
The attenuated viruses can be used pharmaceutically beyond vaccination to induce protection against other infectious diseases and IFN-treatable diseases, including the potential for antitumor responses.
The deliberate genetic engineering approach provides predictable and reproducible attenuation, overcoming the unpredictability of traditional attenuation or inactivation methods.
Documented Applications
Use as live virus vaccines and immunogenic formulations for prevention, management, or treatment of swine influenza virus infections in pigs and other susceptible animals.
Use as vectors in vaccine formulations to express heterologous epitopes from foreign pathogens or tumor antigens, enabling immunization against other infectious agents or cancers.
Use in pharmaceutical formulations to prevent, manage, or treat infections beyond swine influenza, as well as IFN-treatable diseases including cancers by induction of localized interferon responses.
Propagation of attenuated viruses in substrates such as pig cells, cell lines, and embryonated chicken eggs including IFN-deficient systems for vaccine and pharmaceutical production.
Interested in licensing this patent?