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-10543268-B2
Publication Date
2020-01-28
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 genetically engineered attenuated swine influenza viruses with impaired ability to antagonize the cellular interferon (IFN) response, particularly through modifications of the swine NS1 gene that diminish or eliminate the NS1 gene product's antagonist activity. These attenuated viruses replicate in vivo with reduced replication, virulence, and increased attenuation, making them well suited for use in live virus vaccines and pharmaceutical formulations.
The problem addressed is the need for new and more effective vaccines and immunogenic formulations for preventing swine influenza virus infections. Conventional inactivated vaccines provide limited protection and are less durable, while traditional methods for producing attenuated viruses are unpredictable and involve chance mutation selection. The invention solves this problem by deliberately engineering specific mutations in the NS1 gene of swine influenza viruses that alter their ability to inhibit the cellular IFN response, leading to attenuated yet immunogenic virus strains.
The invention demonstrates that swine influenza viruses with deletions in the NS1 gene are impaired in their ability to inhibit IFN production in vitro and show decreased virulence in vivo, evidenced by fewer lung lesions and reduced viral titers. It unexpectedly shows that shorter deletions in the NS1 gene correlate with greater attenuation, contrary to observations in human influenza virus models, and that such modified viruses can elicit robust IFN responses that can be leveraged for vaccine and pharmaceutical applications beyond influenza itself.
Claims Coverage
The patent contains multiple independent claims focusing on genetically engineered swine influenza viruses with specific NS1 gene mutations and related immunogenic formulations and methods of use.
Attenuated swine influenza virus with NS1 deletion
A genetically engineered attenuated swine influenza virus comprising all eight viral segments of swine influenza virus A/Swine/Texas/4199-2/98, where the NS viral segment contains a mutation resulting in an NS1 protein consisting only of amino acid residues 1 to 126 of the wild-type NS1 protein.
Immunogenic formulation comprising the attenuated virus
An immunogenic formulation comprising the genetically engineered attenuated swine influenza virus having the NS1 deletion as described above.
Swine influenza virus NS1 protein deletions from carboxy-terminus
An attenuated swine influenza virus comprising a NS1 protein having a deletion of 90 to 95 amino acid residues from the carboxy-terminus of the NS1 protein derived from A/Swine/Texas/4199-2/98, including specific deletions of 90, 93 or 95 amino acid residues.
Chimeric and reassortant attenuated viruses
The engineered attenuated viruses may be reassortants or chimeric, comprising heterologous sequences, including epitopes or segments derived from different viruses, without altering the attenuated phenotype.
Methods for preventing swine influenza disease
Methods involving administering an effective amount of the immunogenic formulation comprising the attenuated swine influenza virus with NS1 deletions to pigs to prevent swine influenza virus disease, including intranasal administration as a preferred route.
The independent claims cover genetically engineered swine influenza viruses with specific NS1 deletions that produce attenuated phenotypes, associated immunogenic formulations, chimeric and reassortant variants expressing heterologous sequences, and methods of vaccination for preventing swine influenza disease in pigs.
Stated Advantages
The attenuated viruses replicate in vivo inducing sufficient immunological and cytokine responses with decreased virulence compared to wild-type viruses.
These viruses induce robust interferon responses which can provide protection against infectious diseases and IFN-treatable diseases, including potential antitumor effects.
Attenuated viruses are ideal candidates for live virus vaccines, offering longer lasting immunity and cross-protection compared to inactivated vaccines.
Use of genetically engineered mutations allows predictable attenuation and production of vaccine strains with defined properties.
Vaccination with attenuated NS1 deletion mutants provides protective immunity against homologous and partial protection against heterologous swine influenza virus challenges.
Documented Applications
Use as live virus vaccines to prevent swine influenza virus infection in pigs.
Use in immunogenic formulations for inducing immune responses against swine influenza virus or as vectors expressing epitopes from foreign pathogens or tumor antigens.
Use in pharmaceutical formulations for prophylaxis or treatment of other infections, IFN-treatable diseases such as cancer, and inducing antitumor responses.
Engineering of attenuated swine influenza viruses to express ligands or epitopes to alter tropism to target specific organs, tissues, or tumors for localized IFN induction.
Methods of vaccinating pigs by administering an effective dose of the attenuated virus formulation including intranasal delivery.
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