Effects of Varicella-Zoster Virus Glycoprotein E Carboxyl-Terminal Mutation on mRNA Vaccine Efficacy.

Han Cao,Yunfei Wang,Kangyang Lin,Cunbao Liu,Ning Luan

doi:10.3390/vaccines9121440

Han Cao, Yunfei Wang + Show 3 more

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https://doi.org/10.3390/vaccines9121440

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Abstract

Glycoprotein E (gE) is one of the most abundant glycoproteins in varicella-zoster virus and plays pivotal roles in virus replication and transmission between ganglia cells. Its extracellular domain has been successfully used as an antigen in subunit zoster vaccines. The intracellular C-terminal domain was reported to be decisive for gE trafficking between the endoplasmic reticulum, trans-Golgi network and endosomes and could influence virus spread and virus titers. Considering that the trafficking and distribution of mRNA vaccine-translated gE may be different from those of gE translated against the background of the viral genome (e.g., most gE in virus-infected cells exists as heterodimers with another glycoprotein, gI,), which may influence the immunogenicity of gE-based mRNA vaccines, we compared the humoral and cellular immunity induced by LNP-encapsulated mRNA sequences encoding the whole length of gE, the extracellular domain of gE and a C-terminal double mutant of gE (mutant Y569A with original motif AYRV, which targets gE to TGN, and mutants S593A, S595A, T596A and T598A with the original motif SSTT) that were reported to enhance virus spread and elevate virus titers. The results showed that while the humoral and cellular immunity induced by all of the mRNA vaccines was comparable to or better than that induced by the AS01B-adjuvanted subunit vaccines, the C-terminal double mutant of gE showed stable advantages in all of the indicators tested, including gE-specific IgG titers and T cell responses, and could be adopted as a candidate for both safer varicella vaccines and effective zoster vaccines.

Highlights

Ionizable lipid nanoparticle (LNP)-encapsulated mRNA vaccines have been approved by the FDA within one year of their development to prevent coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) [1,2]
In addition to the innate immune mobilization ability of mRNA itself for mRNA vaccines, its outstanding performance is attributed substantially to the unique mechanism of intracellular translation of antigens: the protein translated from the mRNA that enters the cell of the vaccinated person has a high fidelity of posttranslational modifications, such as glycosylation, which is vital for the correct spatial structure of protein antigens; encoded and secreted protein antigens can be processed and presented by major histocompatibility complex (MHC) class II to stimulate CD4+ T helper cells to induce humoral immunity
Cell-mediated immunity (CMI), which is less efficiently induced by subunit or inactivated forms of antigens and is highly dependent on the limited available adjuvants, could be achieved incidentally by the self-adjuvant character of mRNA itself and the mechanism of mRNA vaccine antigen production: the protein antigens translated by mRNA in the cytoplasm could be fully processed into polypeptides and presented to MHC I as heterologous antigens produced by viral infection, which will activate CD8+ cytotoxic T lymphocytes that execute cellular immunity to selectively eliminate cells that express foreign antigens, such as virus-infected host cells [3]

Summary

Introduction

Ionizable lipid nanoparticle (LNP)-encapsulated mRNA vaccines have been approved by the FDA within one year of their development to prevent coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) [1,2]. While pre-existing cellular immune responses upon primary VZV exposure or varicella vaccination could be boosted by the Oka strain at a dose as high as 19,400 plaque-forming units (PFU, compared with 1000–10,000 PFU in varicella vaccines), the attenuated zoster vaccine ZOSTVAXR (developed by Merk in 2005) showed a much lower protection rate than the VZV glycoprotein E (gE) and AS01B adjuvanted subunit vaccine ShingrixTM (developed by GSK in 2017) [15,16,17,18,19,20]. Considering the high price (approximately USD 150–200 per dose and two doses needed) of ShingrixTM, which is attributed mainly to the limited supply of its adjuvant component QS21, more economical zoster vaccines without a production limit are still needed, and mRNA vaccines with the advantages mentioned above are potential candidates [21,22]

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