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-12296004-B2
Publication Date
2025-05-13
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 that have a diminished ability to establish latency. Specifically, the recombinant herpes virus comprises a latency gene or transcript linked to an altered or heterologous promoter which leads to expression of the gene or transcript during viral replication but not, or poorly, during latency. The modified virus can replicate but has an impaired capacity to establish latency and may be attenuated.
The problem addressed is the risk associated with live herpes virus vaccines, such as the varicella-zoster virus (VZV) vaccine, forming latent infections that can later reactivate and cause disease such as shingles. While live attenuated vaccines like the 'Oka virus' prevent chickenpox, they maintain latency capacity and later cause zoster. Modifications that reduce the probability of establishing or maintaining latency would reduce these safety risks and provide significant public health benefits.
The invention involves altering promoters linked to latency genes or transcripts, replacing native latency promoters with heterologous promoters derived from the same virus, another virus, or nonviral sources. The latency genes targeted include VZV genes ORF4, ORF21, ORF29, ORF62, ORF63, and ORF66 or their homologs in other herpes viruses. Additionally, deletion or relocation of latency genes with modification via heterologous promoters at new genomic locations can reduce latency establishment while allowing viral replication to stimulate immune responses.
Claims Coverage
The claims cover methods for producing attenuated live herpes viruses with impaired ability to establish latency, focusing on modifications to latency gene promoters, genomic locations, and deletions.
Altering latency gene promoter for expression during replication but diminished latency expression
Introducing a recombinant virus into host cells where the promoter for a latency gene or transcript is modified or replaced so that the gene is expressed during viral replication but not or poorly during latency, thereby producing a virus suitable for vaccines.
Replacement of native latency promoter with heterologous promoter
The recombinant virus genome comprises the promoter for a latency gene or transcript replaced by a heterologous promoter enabling altered expression patterns.
Deletion in latency gene at native location and relocation with heterologous promoter
The recombinant virus genome includes a deletion in a latency gene or transcript at its native genome location, with the gene or transcript relocated to a different genome position and expressed from a heterologous promoter.
Utilization of VZV latency genes including ORF4, ORF21, ORF29, ORF62, ORF63, ORF66
Latency genes selected in the recombinant virus are VZV genes ORF4, ORF21, ORF29, ORF62, ORF63, or ORF66, with emphasis on ORF29 encoding a major DNA binding protein.
Deletion in major DNA binding protein gene at native location
The recombinant virus lacks all or a portion of the DNA binding protein encoding gene at its native genomic location, where the gene hybridizes to nucleic acid encoding VZV ORF29 protein.
Deletion of at least 10 amino acids in major DNA binding protein gene
The nucleic acid encoding the major DNA binding protein has a deletion encoding at least 10 amino acids, for example amino acids 22 to 957 of the ORF29 protein.
Relocation of latency gene or transcript to non-native location
Placing latency gene or transcript at a different genomic location relative to native location, such as between ORF65 and ORF66 of VZV, potentially with mutations in nuclear localization sequence impairing ORF29 nuclear translocation.
The claims collectively cover recombinant herpes viruses with altered or replaced latency gene promoters, deletions and relocation of latency genes—particularly VZV ORF29—resulting in live attenuated viruses with diminished latency establishing ability but capable of replication for vaccine use.
Stated Advantages
Reduces the safety risk of live viral vaccines by diminishing the ability to establish or maintain latent infection, thereby lowering the probability of viral reactivation diseases such as shingles.
Preserves viral replication capacity sufficient to induce an immune response, making the recombinant virus useful as a safer live attenuated vaccine candidate.
Allows modulation of viral gene expression through promoter replacement or modification, enabling control over latency gene expression.
Provides flexibility to insert immunomodulatory genes or other components to further enhance immunogenicity or vaccine efficacy.
Documented Applications
Use of recombinant herpes viruses with diminished latency for immunogenic compositions and live attenuated vaccines to prevent, diminish, or control herpes viral infections and reduce latency establishment.
Vaccination of animals including humans, cats, cows, monkeys, mice, chickens, turkeys, horses, and pigs to confer immunity against herpes viruses with reduced risk of latent infection.
Production methods for live attenuated recombinant viruses suitable for vaccine formulation involving propagation in host cells and formulation with carriers, adjuvants, and stabilizers.
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