An mRNA vaccine against monkeypox virus inhibits infection by co-activation of humoral and cellular immune responses

Wanbo Tai (), Chongyu Tian, Huicheng Shi, Benjie Chai, Xinyang Yu, Xinyu Zhuang, Pengyuan Dong, Min Li, Qi Yin, Shengyong Feng, Weixiao Wang, Oujia Zhang, Shibo Liang, Yang Liu, Jianying Liu, Longchao Zhu, Guangyu Zhao (), Mingyao Tian (), Guocan Yu () and Gong Cheng ()
Additional contact information
Wanbo Tai: Shenzhen Bay Laboratory
Chongyu Tian: Shenzhen Bay Laboratory
Huicheng Shi: Tsinghua University
Benjie Chai: Tsinghua University
Xinyang Yu: Tsinghua University
Xinyu Zhuang: Chinese Academy of Agricultural Sciences
Pengyuan Dong: Shenzhen Bay Laboratory
Min Li: Academy of Military Medical Sciences
Qi Yin: Academy of Military Medical Sciences
Shengyong Feng: Tsinghua University
Weixiao Wang: Shenzhen Bay Laboratory
Oujia Zhang: Tsinghua University
Shibo Liang: Shenzhen Bay Laboratory
Yang Liu: Shenzhen Bay Laboratory
Jianying Liu: Shenzhen Bay Laboratory
Longchao Zhu: Shenzhen Bay Laboratory
Guangyu Zhao: Academy of Military Medical Sciences
Mingyao Tian: Chinese Academy of Agricultural Sciences
Guocan Yu: Tsinghua University
Gong Cheng: Tsinghua University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The persistent monkeypox outbreaks intensify the demand for monkeypox vaccines. Based on the mRNA vaccine platform, we conduct a systematic screening of monkeypox virus (MPXV) surface proteins from two types of viral particles, extracellular enveloped viruses (EVs) and intracellular mature viruses (MVs). This screening unveils 12 important antigens with diverse levels of neutralizing immunogenicity. Further assessment reveals that the combinations of 4, 8, and 12 of these antigens, namely Mix-4, Mix-8, and Mix-12, induce varying degrees of immune protection, with Mix-12 being the most potent. This finding demonstrates the significance of not only the level but also the diversity of the neutralizing antibodies in providing potent immune protection. Additionally, we utilize a T cell-epitope enrichment strategy, analyzing the complete proteome sequence of the MPXV to predict antigenic epitope-rich regions. Integration of these epitope-rich regions into a cellular immune-targeting antigen, named MPX-EPs, showcases that a cellular immune-targeting mRNA vaccine can independently confer immune protection. Furthermore, co-immunization with Mix-12 and MPX-EPs achieves complete protection against MPXV challenge. Overall, these results suggest an effective approach to enhance the immune protection of mRNA vaccines through the specific coordination of humoral and cellular immune responses.

Date: 2025
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DOI: 10.1038/s41467-025-58328-x

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