A single-dose mRNA vaccine induces potent and long-lasting humoral and cellular immunity against the varicella-zoster virus in a murine model.

INTRODUCTION: Herpes zoster is an infectious disease caused by the varicella-zoster virus (VZV). In adults, the reactivation of VZV can lead to severe neuralgia and skin rashes. Although the licensed vaccines are available, their associated adverse reactions and the shortage of required adjuvants necessitate the development of novel VZV vaccines. METHODS: We developed a novel VZV mRNA vaccine candidate (named as KH014) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. Its immunogenicity was evaluated in BALB/c mice receiving single-dose, two-dose, or heterologous prime-boost regimens in comparison with the licensed adjuvanted subunit vaccine Shingrix®. Humoral responses were assessed by ELISA and microneutralization assays; cellular immunity was characterized by ELISpot, intracellular cytokine staining, and memory T-cell phenotyping via flow cytometry. RESULTS: In mice, immunization with either a single-dose or two-dose of KH014 elicited superior VZV-specific humoral and cellular immune responses compared to the licensed vaccine Shingrix(®). Furthermore, the antigen-specific CD4(+) T-cell responses elicited by a single KH014 were significantly higher and persisted for at least 10 weeks, underscoring the capacity of KH014 to induce durable protective immunity against VZV. Heterologous KH014 prime/Shingrix(®) boost further enhanced cellular responses, including polyfunctional CD4⁺ and CD8⁺ T cells, and induced favorable central and effector memory T-cell profiles. CONCLUSION: The KH014 mRNA vaccine candidate induces robust and durable humoral and cellular immunity against VZV in mice, with a single dose sufficient to elicit T-cell responses superior to those of two-dose Shingrix(®). These findings support further development of KH014 as a potential single-dose vaccine and inform heterologous immunization strategies to optimize protective efficacy against herpes zoster.