Development of a skin- and neuro-attenuated live vaccine for varicella

Abstract

Varicella caused by the primary infection of varicella-zoster virus (VZV) exerts a considerable disease burden globally. Current varicella vaccines consisting of the live-attenuated vOka strain of VZV are generally safe and effective. However, vOka retains full neurovirulence and can establish latency and reactivate to cause herpes zoster in vaccine recipients, raising safety concerns. Here, we rationally design a live-attenuated varicella vaccine candidate, v7D. This virus replicates like wild-type virus in MRC-5 fibroblasts and human PBMCs, the carrier for VZV dissemination, but is severely impaired for infection of human skin and neuronal cells. Meanwhile, v7D shows immunogenicity comparable to vOka both in vitro and in multiple small animal species. Finally, v7D is proven well-tolerated and immunogenic in nonhuman primates. Our preclinical data suggest that v7D is a promising candidate as a safer live varicella vaccine with reduced risk of vaccine-related complications, and could inform the design of other herpes virus vaccines.

Studies of Infection and Experimental Reactivation by Recombinant VZV with Mutations in Virally-Encoded Small Non-Coding RNA

“…However, our findings that deletion of 12 nt that are not required for viral replication and establishment of an immune response, but which can apparently abrogate reactivation, suggest the deletions generated could form the basis of a safer vaccine strain virus that is able to replicate in order to generate an immune response but unable to reactivate. The strategy of developing a VZV vaccine by making mutations modulating neuronal infection was recently published [ 31 ], utilizing a VZV mutant for ORF7, previously shown to impact VZV replication in skin and neurons [ 32 ]. This recent study demonstrates the interest and importance of developing safer vaccines for HZ and varicella disease.…”

Rational Design of a Skin- and Neuro-Attenuated Live Varicella Vaccine: A Review and Future Perspectives

“…To construct the ORF7 -deficient VZV vaccine virus, we employed a stop-codon mutation strategy to minimize changes to the original genome sequence of the wild-type virus [ 39 ]. Firstly, the 11 bp region downstream of the ATG start codon of ORF7 was replaced with a three-frame stop-codon cassette in the BAC clone of the VZV wild-type pOka strain, for the abrogation of ORF7 expression.…”

“…To thoroughly confirm the skin- and neuro-attenuation phenotype of v7D, a variety of cell and animal models currently available for evaluation of VZV infection and tissue tropism were used [ 39 ]. Similar to the reported ORF7 deletion mutant [ 32 , 33 ], the lack of ORF7 expression prevents the replication and cell-to-cell spread of v7D in human skin and neuronal cells, both in vitro and in SCID-hu mice in vivo.…”

“…Despite the attenuation phenotype, v7D exhibited wild-type growth in MRC-5 human fetal lung fibroblasts, allowing for the production of v7D as a live vaccine [ 39 ]. Furthermore, similar to vOka, v7D retains full lymphotropism, which may help the replication and dissemination of vaccine viruses in vivo, and can functionally activate human dendritic cells (DCs) to process and present viral antigens to T cells in vitro [ 39 ]. These properties indicate that v7D has the ability to function as a live vaccine and stimulate human adaptive immunities against VZV infection.…”

“…VZV only infects humans, and thus VZV vaccine studies are limited to the use of common experimental animal models, which lack virus–host interactions under natural infection scenarios, to obtain immunogenicity data as indirect clues to VZV vaccine efficacy in humans. For preclinical immunogenicity evaluation of v7D, small animal models, including mice, rats, guinea pigs and rabbits, as well as non-human primate models, were used [ 39 ]. Three subcutaneous immunizations with the same doses of v7D and vOka induced similar and long-lasting VZV-specific antibody and T-cell responses, suggesting that the immunogenicity of v7D was non-inferior to that of vOka in small animals.…”