Potent and Long‐Lasting Immunogenicity Generated by LNP‐mRNA gE Antigen Against Varicella Zoster Virus via an AI‐Assisted Pipeline

Herpes zoster (HZ), caused by varicella zoster virus (VZV) reactivation commonly in elderly/immuno-compromised individuals, leads to tremendous social burden. Despite approved vaccines, there is an urgent need for longer-lasting and more effective HZ vaccines. This study designs a novel mRNA-LNP vaccine targeting VZV glycoprotein E (gE), with the assistance of AI technology, achieving effective and enduring prevention against VZV infection with favorable safety. From numerous empirically designed antigen sequences, AI-based screening identifies promising candidate variants, which are systematically evaluated based on their humoral and cellular immune responses in BALB/c mice. The study further explores the underlying correlation between the cellular localization and immunogenicity of the vaccine candidates and screens 5'UTR elements affecting mRNA expression. A 4-week administration interval and immunogenicity are subsequently validated via detection of gE-specific IgG antibodies and CD4⁺ T-cell responses in mice. Notably, the vaccine VZV-gEmD elicits strong humoral response, including gE-specific IgG antibodies and VZV-specific antibodies in rhesus macaques. The CD4⁺ T-cell responses, critical for VZV reactivation protection, are significantly stronger and longer lasting with VZV-gEmD than with Shingrix. These findings highlight its potential as an effective prophylactic vaccine for HZ and provide confidence for the utilization of this mRNA platform in VZV vaccine development.