Recombinant virus with diminished latency and methods of using same
Inventors
Cohen, Jeffrey I. • Pesnicak, Lesley
Assignees
US Department of Health and Human Services
Publication Number
US-11305009-B2
Publication Date
2022-04-19
Expiration Date
2027-11-09
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Abstract
The disclosure provides recombinant herpes virus with diminished latency. In embodiments, the recombinant herpes virus comprises a latency gene or transcript linked to an altered or heterologous promoter. The disclosure also provides compositions and methods for inducing immunity in animals using the recombinant herpes viruses.
Core Innovation
The invention provides recombinant herpes viruses with diminished latency, comprising a latency gene or transcript linked to an altered or heterologous promoter. The recombinant virus genome has the promoter for a latency gene or transcript modified so that the gene or transcript is expressed during virus replication but poorly expressed or not expressed during latency. The recombinant herpes viruses can replicate but have an impaired ability to establish latency and are attenuated in some embodiments.
The problem being solved is that live virus vaccines, such as the live attenuated varicella-zoster virus (VZV) vaccine based on the Oka virus, can establish latent infections, which may later reactivate and cause shingles. This latent infection phase compromises the safety of live viral vaccines. Thus, there is a need for improved vaccines that present less risk of establishing or maintaining latent infection, thereby enhancing safety while still inducing immunity.
Claims Coverage
The patent includes seven claims focused on methods of inhibiting latent viral infection using recombinant viruses with altered promoters for latency genes, covering various aspects of the recombinant genome and mutations.
Recombinant virus with altered promoter for latency gene or transcript
A recombinant virus comprising all or a portion of a herpes virus genome, wherein the promoter for a latency gene or transcript is altered or modified, allowing the gene or transcript to be expressed during virus replication.
Recombinant virus targeting infection from specific herpes viruses
The recombinant virus can be from herpes simplex virus, varicella-zoster virus, Marek's disease virus, pseudorabies virus, or cytomegalovirus.
Replacement of latency gene promoter by heterologous promoter
The latent gene or transcript promoter is replaced by a heterologous promoter different from the native one.
Recombinant genome with deletion at native location and relocation under heterologous promoter
The recombinant genome includes a deletion in the latency gene or transcript at its native location, with the gene or transcript relocated to a different genome location and expressed from a heterologous promoter.
Latency gene selected from specific VZV ORFs
The latency gene is selected from varicella-zoster virus ORF4, ORF21, ORF29, ORF62, ORF63, or ORF66.
Latency gene relocated with mutation
The latency gene or transcript is relocated in the genome relative to its native location and comprises at least one mutation.
Mutation in nuclear localization sequence of VZV ORF29
For VZV ORF29, the mutation is a deletion or substitution in the nuclear localization sequence that impairs the protein's ability to translocate to the nucleus.
The claims cover recombinant herpes viruses with altered promoters for latency genes, their specific application to various herpes viruses, modifications including deletion and relocation of latency genes, and mutations affecting nuclear localization to impair latency establishment.
Stated Advantages
The recombinant herpes viruses diminish the ability to establish or maintain latent infection, thereby potentially increasing vaccine safety compared to existing live virus vaccines that can establish latency and later reactivate.
The altered viruses can replicate sufficiently to induce an immune response but have reduced latency, providing safer live attenuated vaccines.
Overexpression or deletion of specific latency proteins like ORF29 impairs late gene expression and viral latency, contributing to attenuation with preserved replication capacity.
Documented Applications
Immunogenic compositions and vaccine formulations comprising recombinant herpes viruses with diminished latency, for use in inducing immunity in animals, including humans.
Use in methods for preventing, controlling, or diminishing herpes virus infection and/or establishment or maintenance of latent infection.
Use in preparations of live attenuated virus vaccines with improved safety profiles due to reduced latent infection.
Recombinant viruses can be administered by various routes including intramuscular, subcutaneous, intrapulmonary, intranasal, transdermal, intravenous, and others.
The compositional use includes incorporation of carriers, adjuvants such as cytokines or chemokines, and vaccine stabilizers.
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