Thermal inactivation of rotavirus
Inventors
Jiang, Baoming • Glass, Roger I. • Saluzzo, Jean-Francois
Assignees
US Department of Health and Human Services
Publication Number
US-11103572-B2
Publication Date
2021-08-31
Expiration Date
2028-09-04
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Abstract
Methods of thermally inactivating a rotavirus are provided according to the present invention which include exposing the rotavirus to a temperature in the range of about 50° C.-80° C., inclusive, for an incubation time sufficient to render the rotavirus incapable of replication or infection. The thermally inactivated rotavirus is antigenic and retains a substantially intact rotavirus particle structure. Vaccine compositions and methods of vaccinating a subject against rotavirus are provided which include generation and use of thermally inactivated rotavirus.
Core Innovation
The invention provides methods of thermally inactivating rotavirus by exposing the virus to temperatures ranging from about 50° C. to 80° C. for a time sufficient to render the virus incapable of replication or infection. The thermally inactivated rotavirus remains antigenic and retains a substantially intact rotavirus particle structure, including characteristics such as the triple-layered capsid. The invention includes vaccine compositions containing such thermally inactivated rotavirus and methods of vaccinating subjects against rotavirus using these vaccines.
The problem addressed by the invention is the lack of effective methods for inactivating rotavirus for vaccine composition while preserving antigenicity and maintaining substantially intact double-layer and triple-layer rotavirus particle structures. Existing oral live vaccines have continuing safety and efficacy concerns, prompting the need for an alternative parenteral vaccine using inactivated rotavirus. Effective thermal inactivation methods that preserve structural integrity and antigenicity have been difficult to achieve.
The invention solves this problem by identifying temperature and time combinations for heat treatment of isolated rotavirus particles suspended in specific aqueous buffers with defined osmolality, divalent cation salts, and sugar or sugar alcohol concentrations. This approach renders rotavirus incapable of replication or infection while retaining viral particle morphology and antigenicity. The resulting inactivated rotavirus includes substantially intact viral proteins such as VP1, VP2, VP4, VP5, VP6, and VP7 necessary for vaccine efficacy.
Claims Coverage
The patent contains one independent claim describing a vaccine composition with key features defining the preparation and formulation of thermally inactivated rotavirus.
Vaccine composition including thermally inactivated rotavirus with intact particle structure
The vaccine composition comprises antigenic thermally inactivated rotavirus having a substantially intact triple-layer, double-layer, or mixture thereof particle structure. The rotavirus is produced by suspending isolated rotavirus particles in an aqueous buffer with osmolality from about 200-500 mOsm, containing a salt of divalent cations from about 1 mM to 15 mM, and sugars and/or sugar alcohols at about 1-20% w/v, followed by exposure of the preparation to a temperature range of 50° C. to 73° C. for about 30 minutes to 24 hours, rendering the rotavirus incapable of replication or infection while preserving antigenicity and structure.
Inclusion of an adjuvant and pharmaceutically acceptable carrier
The vaccine composition additionally includes an adjuvant selected from aluminum-based compounds such as AlOH, AlPO4, aluminum oxide or aluminum salts, or others like Freund's adjuvant, iron oxide, saponin, DEAE-dextran, mineral oil, or bacterial lipopolysaccharides, combined with a sterile pharmaceutically acceptable carrier to form the vaccine.
Immunogenicity inducing neutralizing antibodies
The antigenic thermally inactivated rotavirus combined with the adjuvant in the vaccine composition induces production of neutralizing antibodies against rotavirus when administered to a subject.
Optional enteric coating with plasticizer
The vaccine composition may further include an enteric coating containing a plasticizer to facilitate delivery, particularly to protect the vaccine until reaching the lower gastrointestinal tract.
The independent claim covers a vaccine composition formulated with thermally inactivated rotavirus particles maintaining specific structural integrity, produced by controlled thermal and buffer conditions, combined with an adjuvant and pharmaceutically acceptable carrier. The vaccine induces neutralizing immune responses and may optionally include enteric coatings for administration.
Stated Advantages
The thermally inactivated rotavirus retains antigenicity and substantially intact particle structure, which is critical for eliciting an effective immune response.
The thermal inactivation method provides a safe alternative to live oral vaccines, avoiding associated safety and efficacy concerns.
The vaccine compositions including adjuvants such as aluminum hydroxide enhance immune responses even with very low doses of antigen.
The heat-inactivated rotavirus vaccine demonstrated protective efficacy in animal models by reducing virus shedding and shortening duration of rotavirus infection.
Documented Applications
Vaccination of humans and non-human mammals and avian subjects against rotavirus infection.
Parenteral administration of vaccine compositions including thermally inactivated rotavirus for inducing protective immunity.
Use of thermally inactivated rotavirus vaccine to prevent or reduce severity of rotavirus-mediated disease such as diarrhea in children and animal models.
Formulation of vaccines for intramuscular, intradermal, mucosal, nasal, subcutaneous or oral routes including solid dosage forms and liquid formulations.
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