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

ABSTRACT 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.