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

## TL;DR

A new AI-designed mRNA vaccine targeting VZV's gE protein shows strong and lasting immunity in mice and monkeys, outperforming existing vaccines.

## Contribution

An AI-assisted pipeline was used to design a potent mRNA-LNP vaccine against VZV with enhanced and durable immune responses.

## Key findings

- The vaccine VZV-gEmD elicited strong gE-specific IgG and VZV-specific antibodies in rhesus macaques.
- CD4+ T-cell responses were significantly stronger and longer-lasting with VZV-gEmD compared to Shingrix.
- AI-based screening identified optimal antigen sequences with high immunogenicity in preclinical models.

## 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.

This study designs a novel mRNA‐LNP vaccine targeting VZV glycoprotein E (gE) for herpes zoster via an AI‐assisted pipeline. Validated in mice and rhesus macaques, the mRNA‐LNP vaccine shows strong humoral and cellular immune responses, with CD4+ T‐cell responses more effective and durable than Shingrix, offering a promising prophylactic option.