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.
Highlights
Varicella caused by the primary infection of varicella-zoster virus (VZV) exerts a considerable disease burden globally
VZV wild-type parent Oka (pOka) strain was used as the parent virus to construct an infectious bacterial artificial chromosome (BAC; b) clone of a recombinant Oka virus expressing green fluorescent protein (GFP), designated as brOka-GFP, as described previously[36]
The loxP-flanked BAC vector containing the GFP expression cassette was excised from the viral genomes by co-transfecting b7D-GFP with a Cre expression vector into MRC-5 human embryonic lung fibroblasts (Supplementary Fig. 1c, d), reconstituting the ORF7-deficient candidate vaccine virus, v7D
Summary
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. VOka retains full neurovirulence and can establish latency and reactivate to cause herpes zoster in vaccine recipients, raising safety concerns. 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. VOka retains wild-type neurovirulence and can establish latency in some vaccine recipients and reactivate to cause HZ and neurological complications like meningitis[6,7,12–19]. Current advances in molecular virology and the development of reverse genetic systems have led to the identification of many viral genes associated with virulence and tissue tropism of VZV, providing a sound basis for the rational design of novel live-attenuated VZV vaccine candidate[27–35]. The findings from this study have paved the way for a first-in-human clinical trial of v7D vaccine candidate in China (ChiCTR1900022284)
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