Coronaviruses, vaccines comprising the same, and methods for preventing disease
Inventors
Assignees
Loyola University Chicago • US Department of Agriculture USDA
Publication Number
US-11684667-B2
Publication Date
2023-06-27
Expiration Date
2038-03-02
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Abstract
Coronaviruses, vaccines comprising the same, and methods for preventing disease. One embodiment of such includes a live, attenuated coronavirus comprising a variant replicase gene encoding polyproteins comprising a non-structural protein (nsp)-15, the replicase gene encoding the nsp15 and causes any change, including mutations and/or deletions, that affects the stability or activity of the nsp15.
Core Innovation
The invention provides mutant coronaviruses, vaccines comprising mutant coronaviruses, methods of producing vaccines, and methods of preventing disease in subjects. One embodiment includes a live, attenuated coronavirus comprising a variant replicase gene encoding polyproteins that include non-structural protein 15 (nsp15), where the replicase gene encodes nsp15 and causes changes such as mutations and/or deletions that affect the stability or activity of nsp15.
The problem being solved addresses the limitations of existing coronavirus vaccines, which are based on natural attenuation, virus inactivation, and recombinant viral structural proteins that do not elicit robust or long-term protective immune responses. The lack of long-term protection may be due to inefficient induction of innate immune responses, such as type I interferons, which are critical for promoting adaptive immunity and immune memory. Therefore, there is a desire for a vaccine capable of stimulating strong innate immune responses alongside effective adaptive immune protection.
The invention solves this by providing coronaviruses with mutated nsp15 that either destabilize the protein or inactivate its endoribonuclease activity, leading to activation of type I interferon responses in macrophages. This activation limits viral replication, dissemination, and disease. The mutant coronaviruses can induce apoptosis in infected macrophages and are highly attenuated in vivo but provide protective immunity. The mutant nsp15 disrupts the virus’s ability to evade host dsRNA sensors by affecting the association of dsRNA with viral replication complexes, thus enabling immune detection.
Claims Coverage
The patent includes one independent claim focused on a method for stimulating type I interferon production in porcine alveolar macrophages via administration of a mutated virus.
Method of stimulating type I interferon production in porcine alveolar macrophages
Administering a composition comprising a live, attenuated porcine epidemic diarrhea virus (PEDV) with one or more substitution mutations in the non-structural protein 15 (nsp15). The mutations include substitution of a catalytic histidine amino acid resulting in loss of endoribonuclease enzymatic activity. The PEDV excludes mutations in ExoN.
The claims cover a method of stimulating type I interferon production by administering a mutated live, attenuated PEDV with impaired nsp15 enzymatic activity, specifically via substitution mutations disrupting catalytic histidine residues.
Stated Advantages
Activation of type I interferon in subjects inoculated with the mutant coronavirus limits viral replication, dissemination, and disease.
The mutant virus induces a robust innate immune response including interferon activation and apoptotic cell death in infected macrophages.
Vaccines comprising mutant coronaviruses provide protective immunity while being highly attenuated and safe in in vivo models.
Documented Applications
Vaccines for inoculating subjects against existing and emerging coronaviruses including SARS-CoV, MERS-CoV, human coronaviruses (229E, OC43, HKU1, NL63), feline infectious peritonitis virus, canine coronavirus, infectious bronchitis virus of chickens, bovine coronavirus, and various porcine coronaviruses (TGEV, PDCoV, PEDV, PRCV, PHE-CoV).
Using live, attenuated coronavirus vaccines comprising mutated nsp15 that activate type I interferon to treat or prevent coronavirus diseases in subjects.
Stimulating innate immunity in porcine alveolar macrophages by administration of live, attenuated PEDV with mutations in nsp15 that abrogate endoribonuclease activity.
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