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-10166285-B2
Publication Date
2019-01-01
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 by altering or modifying the promoter of a latency gene or transcript to cause expression during virus replication but not or poorly during latency. These recombinant viruses can replicate but have an impaired ability to establish latency, and may be attenuated. The alteration includes linking the latency gene or transcript to a heterologous promoter, modifying the native promoter, or relocating the latency gene or transcript to a different location in the viral genome under control of an altered or heterologous promoter.
The problem being addressed arises from infections such as chickenpox caused by varicella-zoster virus (VZV), which establishes latent infection in nerve ganglia and can reactivate as shingles. Current live virus vaccines, such as the Oka virus strain for chickenpox, can enter latency and later cause shingles, raising safety concerns. Therefore, there is a need for improved vaccines that have a reduced risk of establishing or maintaining latent infection and are less likely to reactivate, enhancing public health safety.
Claims Coverage
The patent includes one independent claim focusing on a recombinant herpes virus with an altered latency gene or promoter affecting expression and latency. The inventive features cover modifications to the latency gene corresponding to VZV ORF29, changes of promoter type and gene location, and their impact on viral characteristics.
Altered latency gene or promoter for impaired latency establishment
A recombinant herpes virus genome is modified so that a latency gene corresponding to VZV ORF29 and encoding a major DNA binding protein is overexpressed or has reduced expression, resulting in impaired ability to establish latency.
Use of heterologous promoter linked to latency gene
The virus carries a latency gene under control of a promoter different from the native one, such as CMV IE promoter, HSV ICP4 promoter, or SV40 early promoter, to alter expression during viral replication and latency.
Relocation of latency gene within viral genome
The latency gene is positioned at a different, non-native location in the viral genome, for example between ORF65 and ORF66 in VZV, optionally with mutations or deletions, affecting viral replication and latency establishment.
Deletion or mutation of latency gene sequences affecting nuclear localization
The latency gene includes deletions or substitutions in the nuclear localization sequence that impair the encoded major DNA binding protein's ability to translocate to the nucleus, impacting viral latency.
Attenuation of recombinant virus versus wild type or reference virus
The recombinant herpes virus is attenuated compared to the corresponding wild type herpes virus or reference virus, while having diminished ability to establish latency.
Immunogenic compositions comprising recombinant virus
Immunogenic compositions include the recombinant herpes virus and a carrier, optionally further comprising an adjuvant or live vaccine stabilizer, for inducing protective immunity with reduced latent infection risk.
These inventive features collectively provide recombinant herpes viruses with modified expression of a key latency gene, VZV ORF29, by promoter alteration, gene relocation, or deletion, leading to attenuated viruses with impaired latency establishment suitable for safer vaccine compositions.
Stated Advantages
Reduced probability of establishing or maintaining latent infection enhances safety of live viral vaccines.
Ability of recombinant virus to replicate sufficiently to induce immune response while being attenuated and less likely to reactivate.
Overexpression or altered expression of latency gene can impair late gene expression, diminishing latency but allowing acute infection and immunogenicity.
Recombinant viruses provide safer vaccine candidates with decreased risk of shingles or other herpes virus reactivation.
Documented Applications
Use as live attenuated vaccines for preventing or diminishing herpesvirus infections and establishment or maintenance of latency in humans and animals.
Immunization of animals including humans, cats, cows, monkeys, mice, chickens, turkeys, horses, and pigs with immunogenic compositions containing recombinant herpes viruses.
Preparation of vaccine formulations with suitable carriers, adjuvants, and stabilizers for administration via multiple routes including intramuscular, subcutaneous, intrapulmonary, oral, intranasal, and others.
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