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

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.

Comparison of immune responses induced by two or three doses of an alum‐adjuvanted inactivated SARS‐CoV‐2 vaccine in mice

“…The expression of CD62L has also been used to distinguish naïve, effector, and memory T cells. 34 , 35 , 36 Once reactivated by antigens, memory CD4+ cells could assist with the production of antibodies by B cells, and memory CD8+ cells could help increase the production of cytotoxic T lymphocytes. In brief, CD44+/CD62L+ cells were used to gate memory T cells.…”

“…Thus, CD44 has been reported to be a valuable marker for memory cell subsets. The expression of CD62L has also been used to distinguish naïve, effector, and memory T cells 34–36 . Once reactivated by antigens, memory CD4+ cells could assist with the production of antibodies by B cells, and memory CD8+ cells could help increase the production of cytotoxic T lymphocytes.…”

Advances in mRNA vaccines for viral diseases

“…Taking into consideration the possibility that the transport and distribution of gE protein translated by mRNA vaccines may differ from that by the viral genome, researchers created a double mutant mRNA vaccine in the Cterminal of VZV gE, which demonstrated stability in both CMI response and humoral immunity. 32 This means the double mutant mRNA vaccine could be a candidate for herpes zoster.…”

“…This vaccine induced a strong immune response in nonhuman primates (NHP) and probably provided a solid foundation for the creation of a prophylactic vaccine against herpes zoster in humans. Taking into consideration the possibility that the transport and distribution of gE protein translated by mRNA vaccines may differ from that by the viral genome, researchers created a double mutant mRNA vaccine in the C‐terminal of VZV gE, which demonstrated stability in both CMI response and humoral immunity 32 . This means the double mutant mRNA vaccine could be a candidate for herpes zoster.…”

Alphaherpesvirus glycoprotein E: A review of its interactions with other proteins of the virus and its application in vaccinology

“…The intracellular carboxy-terminus of VZV gE affects the transport of gE, which in turn affects the final presentation pathway of gE as an antigen. Following mutations at the carboxy-terminus of gE (mutant Y569A and mutants S593A, S595A, T596A and T598A), the ability to induce the highest gE-specific IgG titers reduced viral transmission( Cao et al, 2021 ). Furthermore, gE deletion mutants are defective in transmission from epithelial cells to axons and from neuronal cell bodies to axon terminals.…”