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.

A recently reported parallel preclinical study between a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine and an inactivated SARS-CoV-2 vaccine adjuvanted with alum showed pulmonary immunopathology typical of eosinophil accumulation in a mouse pneumonia model for the latter, which implied a potential role of cellular immunity in the difference in the protection rate between these two forms of vaccines. For those who have been vaccinated with alum-adjuvanted subunit or inactivated SARS-CoV-2 vaccines, whether the Th2 responses that have been established and the absence of induced cellular immunity could be changed is an open question. Using two heterologous boosts with Th1-oriented CpG ODN-adjuvanted S1-based SARS-CoV-2 subunit vaccines for mice that were primed with two doses of Th2-oriented alum-adjuvanted S1-based SARS-CoV-2 subunit vaccines, we demonstrated that established Th2 orientation could not be reversed to Th1 orientation and that no cellular immunity was induced, which should have been induced if the boosting vaccines were used as the prime vaccines. These results remind us that if widely administered alum-adjuvanted SARS-CoV-2 vaccines cannot overcome the challenge of coronavirus disease 2019 (COVID-19) and that if cellular immunity is important for the efficacy of SARS-CoV-2 vaccines in the future, the choice of more powerful heterologous boosting vaccine forms that can induce cellular immunity should be considered very carefully before application.

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Waning antibodies and rapidly emerging variants are challenges for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine development. Adjusting existing immunization schedules and further boosting strategies are under consideration. Here, the immune responses induced by an alum-adjuvanted inactivated SARS-CoV-2 vaccine in mice were compared among immunization schedules with two or three doses. For the two-dose schedule, a 0-28-day schedule induced 5-fold stronger spike-specific IgG responses than a 0-14-day schedule, with only a slight elevation of spike-specific cellular immunity 14 days after the last immunization. A third homologous boost 2 or 5 months after the second dose for the 0-28-day schedule slightly strengthened humoral responses (1.3-fold for the 0-1-3-month schedule, and 1.8-fold for the 0-1-6-month schedule) 14 days after the last immunization. Additionally, a third homologous boost (especially with the 0-1-3-month schedule) induced significantly stronger cell-mediated immunity than both two-dose immunization schedules for all indexes tested, with a response similar to that induced by a one-dose heterologous boost with BNT162b2 in clinical trials, according to cellular immunity analysis (1.5-fold). These T cell responses were Th2 oriented, with good CD4+ and CD8+ memory. These results may offer clues for applying a homologous boosting strategy for alum-adjuvanted inactivated SARS-CoV-2 vaccines.

Varicella zoster virus (VZV) causes two diseases: varicella upon primary infection and herpes zoster when latent viruses in the sensory ganglia reactivate. While varicella vaccines depend on humoral immunity to prevent VZV infection, cell-mediated immunity (CMI), which plays a therapeutic role in the control or elimination of reactivated VZV in infected cells, is decisive for zoster vaccine efficacy. As one of the most abundant glycoproteins of VZV, conserved glycoprotein E (gE) is essential for viral replication and transmission between ganglion cells, thus making it an ideal target subunit vaccine antigen; gE has been successfully used in the herpes zoster vaccine ShingrixTM on the market. In this report, we found that ionizable lipid nanoparticles (LNPs) approved by the Food and Drug Administration (FDA) as vectors for coronavirus disease 2019 (COVID-19) mRNA vaccines could enhance the synergistic adjuvant effect of CpG oligodeoxynucleotides (CpG ODNs) and QS21 on VZV-gE, affecting both humoral immunity and CMI. Vaccines made with these LNPs showed promise as varicella vaccines without a potential risk of herpes zoster, which identifies them as a novel type of herpes zoster vaccine similar to ShingrixTM. All of the components in this LNP-CpG-QS21 adjuvant system were proven to be safe after mass vaccination, and the high proportion of cholesterol contained in the LNPs was helpful for limiting the cytotoxicity induced by QS21, which may lead to the development of a novel herpes zoster subunit vaccine for clinical application.