Safer attenuated varicella-zoster virus vaccines with missing or diminished latency of infection

Inventors

Cohen, Jeffrey I. • Cox, JR., Edward M. • Pesnicak, Lesley M.

Assignees

US Department of Health and Human Services

Abstract

Viruses having weakened ability to establish and/or maintain latency and their use as live vaccines are described. The vaccines have one or more alterations in genes that provide continued virus replication but that inhibit latency. The vaccine materials and methods for their construction are exemplified with the varicella zoster virus. Deletion of a significant portion from both copies of the varicella zoster gene ORF63 was shown to inhibit establishment of a latent infection from a live vaccine form of the virus. Insertion of an additional ORF62 gene which is partially truncated with the ORF63 deletion inhibited establishment of latency and allowed normal growth of the virus. Other desirable viral antigen encoding sequence(s) and/or cytokine genes advantageously may replace deleted genetic material to enhance a desired immunological response. Aspects of the discovery pertain to live vaccines of other viruses, and can provide a variety of vaccines having greater safety.

Core Innovation

The invention describes viruses having a weakened ability to establish and/or maintain latency and their use as live vaccines, particularly exemplified using the varicella-zoster virus (VZV). These vaccines comprise one or more genetic alterations in viral genes that allow continued virus replication but inhibit the establishment or maintenance of latency, thereby reducing the risk of latent infection and subsequent reactivation such as shingles. The vaccine virus may have deletions or mutations in genes homologous to VZV ORF63, which is highly expressed during latency and encodes a phosphorylated protein important for establishing latent infection but not required for replication in vitro.

The background highlights the problem that live attenuated vaccines against varicella-zoster virus can establish latent infection, which may later reactivate and cause shingles, posing a safety concern. Existing live vaccines like the Oka strain prevent chickenpox but do not eliminate the risk of latency and reactivation. Thus, the challenge is to develop live virus vaccines that replicate well but have diminished ability to establish or maintain latency to improve vaccine safety and public health outcomes.

The summary explains that by modifying or deleting one or more copies of a latent phase transcribed gene such as ORF63, live virus vaccines with less latency can be made. Alternatively, truncations of ORF62 or homologous genes may be introduced to maintain viral replication while inhibiting latency. The invention extends to similar genes in other herpesviruses homologous to ORF63 or ORF62 and includes inserting antigen-encoding sequences or cytokine genes to improve immune response. The recombinant viruses replicate to wild-type titers in vitro yet have significantly reduced ability to establish latency, providing safer live vaccines.

Claims Coverage

The patent contains six independent claims focusing on live varicella-zoster virus vaccines with impaired ability to establish latency through genetic modifications involving ORF62 and ORF63 gene alterations.

The claims collectively cover live varicella-zoster virus vaccines genetically engineered to impair establishment of latency by deleting or truncating the ORF63/ORF70 genes and by including an intact ORF62 gene alongside an additional truncated ORF62 gene, resulting in viruses that replicate efficiently yet have diminished latency potential.

Stated Advantages

Documented Applications