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Multi-valent mRNA vaccines against monkeypox enveloped or mature viron surface antigens demonstrate robust immune response and neutralizing activity

查看全文 作　　者：Niubing [1,6,7]Zhang;Xiang [1,8]Cheng;Yilong [2,5]Zhu;Ouyang [3,8]Mo;Huiqing [3]Yu;Liqi [3,8]Zhu;Juan [3,8]Zhang;Linlin [3]Kuang;Ying [3,8]Gao;Ruiyuan [4]Cao;Xiaozhen [3,8]Liang;Haikun [3,8]Wang;Honglin [6,7]Li;Song [4]Li;Wu [4]Zhong;Xuan [1,8]Li;Xiao [2]Li;Pei [3,8]Hao 高影响力作者 机构地区：[1]Key Laboratory of Synthetic Biology,CAS Center for Excellence in Molecular Plant Sciences,Institute of Plant Physiology and Ecology,Chinese Academy of Sciences,Shanghai 200032,China;[2]Changchun Veterinary Research Institute,Chinese Academy of Agricultural Sciences,Changchun 130122,China;[3]Key Laboratory of Molecular Virology and Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,Shanghai 200031,China;[4]National Engineering Research Center for the Emergency Drug,Beijing Institute of Pharmacology and Toxicology,Beijing 100850,China;[5]Academicians Workstation of Jilin Province,Changchun University of Chinese Medicine,Changchun 130117,China;[6]East China University of Science and Technology,Shanghai 200237,China;[7]Lingang Laboratory,Shanghai 200031,China;[8]University of Chinese Academy of Sciences,Beijing 100049,China高影响力机构 出　　处：《Science China(Life Sciences)》索引2023年第66卷第10期,共13页高影响力期刊 基　　金：the National Science and Technology Major Projects(2021YFC2300704);the National Key Research and Development Program of China(2021YFA1301402,2018YFA0903700);the Strategic Priority Research Program of Chinese Academy of Sciences(XDA24010400);Shanghai Municipal Science and Technology Major Project(ZD2021CY001);the National Natural Science Foundation of China(32270695,31972881);support from Lingang Laboratory(Shanghai,China)。 摘　　要：Monkeypox was declared a global health emergency by the World Health Organization,and as of March 2023,86,000 confirmed cases and 111 deaths across 110 countries have been reported.Its causal agent,monkeypox virus(MPV)belongs to a large family of double-stranded DNA viruses,Orthopoxviridae,that also includes vaccinia virus(VACV)and others.MPV produces two distinct forms of viral particles during its replication cycles:the enveloped viron(EV)that is released via exocytosis,and the mature viron(MV)that is discharged through lysis of host cells.This study was designed to develop multi-valent m RNA vaccines against monkeypox EV and MV surface proteins,and examine their efficacy and mechanism of action.Four m RNA vaccines were produced with different combinations of surface proteins from EV(A35R and B6R),MV(A29L,E8L,H3L and M1R),or EV and MV,and were administered in Balb/c mice to assess their immunogenicity potentials.A dynamic immune response was observed as soon as seven days after initial immunization,while a strong Ig G response to all immunogens was detected with ELISA after two vaccinations.The higher number of immunogens contributed to a more robust total Ig G response and correlating neutralizing activity against VACV,indicating the additive potential of each immunogen in generating immune response and nullifying VACV infection.Further,the m RNA vaccines elicited an antigen-specific CD4^(+)T cell response that is biased towards Th1.The m RNA vaccines with different combinations of EVand MV surface antigens protected a mouse model from a lethal dose VACV challenge,with the EV and MV antigens-combined vaccine offering the strongest protection.These findings provide insight into the protective mechanism of multi-valent m RNAvaccines against MPV,and also the foundation for further development of effective and safe m RNA vaccines for enhanced protection against monkeypox virus outbreak. 关 键 词：monkeypox virus enveloped and mature viron multi-valent mRNA vaccines immune response neutralizing antibody
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