抗SARS-CoV-2变异株的广谱mRNA疫苗RQ3013的临床前研究  

Preclinical evaluation of RQ3013,a broad-spectrum mRNA vaccine against SARS-CoV-2 variants

作　　者：谭舒丹 赵京华 胡雪 李玉凤 武子涵 逯国亮 于朝丽 杜彬荷 刘燕 李丽 陈煜琛 李晔 姚艳丰 张小宇 饶具红 高歌 彭云 刘航 袁志明 刘佳 王倩然 胡恒睿 高小博 周辉 俞航 徐颖洁 余巍 冯琳 王曼丽 单超 卢静 林金钟 Shudan Tan;Jinghua Zhao;Xue Hu;Yufeng Li;Zihan Wu;Guoliang Lu;Zhaoli Yu;Binhe Du;Yan Liu;Li Li;Yuchen Chen;Ye Li;Yanfeng Yao;Xiaoyu Zhang;Juhong Rao;Ge Gao;Yun Peng;Hang Liu;Zhiming Yuan;Jia Liu;Qianran Wang;Hengrui Hu;Xiaobo Gao;Hui Zhou;Hang Yu;Yingjie Xu;Wei Yu;Lin Feng;Manli Wang;Chao Shan;Jing Lu;Jinzhong Lin(State Key Laboratory of Genetic Engineering,School of Life Sciences,Zhongshan Hospital,Fudan University,Shanghai 200438,China;Shanghai Institute of Infectious Disease and Biosecurity,Fudan University,Shanghai 200438,China;Zhangjiang mRNA Innovation and Translation Center,Fudan University,Shanghai 200438,China;State Key Laboratory of Virology,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China;Center for Biosafety Mega-Science,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China;Shanghai RNACure Biopharma Co.,Ltd.,Shanghai 200438,China;Shanghai Key Laboratory for Tumor Microenvironment and Inflammation,Department of Biochemistry and Molecular Cell Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Department of Experimental Research,Sun Yat-sen University Cancer Center,State Key Laboratory of Oncology in South China,Guangzhou 510060,China)

机构地区：[1]State Key Laboratory of Genetic Engineering,School of Life Sciences,Zhongshan Hospital,Fudan University,Shanghai 200438,China [2]Shanghai Institute of Infectious Disease and Biosecurity,Fudan University,Shanghai 200438,China [3]Zhangjiang mRNA Innovation and Translation Center,Fudan University,Shanghai 200438,China [4]State Key Laboratory of Virology,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China [5]Center for Biosafety Mega-Science,Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China [6]Shanghai RNACure Biopharma Co.,Ltd.,Shanghai 200438,China [7]Shanghai Key Laboratory for Tumor Microenvironment and Inflammation,Department of Biochemistry and Molecular Cell Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [8]Department of Experimental Research,Sun Yat-sen University Cancer Center,State Key Laboratory of Oncology in South China,Guangzhou 510060,China

出　　处：《Science Bulletin》2023年第24期3192-3206,M0006,共16页科学通报（英文版）

基　　金：supported by Fudan University Special Funds for COVID-19;the National Natural Science Foundation of China(32130063);the National Key Research and Development Program of China(2021YFE0201900 and 2021YFC2301700);China Postdoctoral Science Foundation(2020T130017ZX);the Starry Night Science Fund at Shanghai Institute for Advanced Study of Zhejiang University(SN-ZJU-SIAS-009);the STS Regional Key Project(KFJSTS-QYZD-2021-12-001)from Chinese Academy of Sciences;Hubei Science and Technology Major Project(2021ACB0004)。

摘　　要：全球SARS-CoV-2病毒的不同变异株导致已接种疫苗的人群中突破性感染的比例上升,迫切需要研发更为有效和广谱的COVID-19疫苗.本研究报告了一项mRNA疫苗RQ3013的临床前研究结果,旨在提供对SARS-CoV-2各种变异株(VOCs)的广谱保护.RQ3013疫苗包含经过假尿苷修饰的mRNA,制备成脂质纳米颗粒的形式.该mRNA编码了SARS-CoV-2的刺突(S)蛋白嵌合体,包含与免疫逃逸有关的重要突变位点.我们在多种动物模型中对RQ3013的免疫原性、保护效果和安全性进行了评估.RQ3013在小鼠、仓鼠和非人灵长类动物(NHP)中引发了显著的免疫反应.它能够诱导高滴度的抗体产生,具备对野生型、B.1.1.7、B.1.351、B.1.617.2和奥密克戎系列变异株的广泛中和能力.在小鼠和NHP中,两剂RQ3013疫苗能够有效保护上呼吸道和下呼吸道免受SARS-CoV-2及其变异株的感染.此外,在NHP中对RQ3013的安全性进行了评估,未观察到不良反应.这些结果为在临床试验中评估RQ3013提供了有力的支持,表明它可能成为对抗COVID-19及其变种的广泛保护的有希望的候选疫苗.The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations,calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19.Here we report the preclinical development of RQ3013,an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern(VOCs).RQ3013,which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles,encodes the spike(S)protein harboring a combination of mutations responsible for immune evasion of voCs.Here we characterized the expressed S immunogen and evaluated the immunogenicity,efficacy,and safety of RQ3013 in various animal models.RQ3013 elicited robust immune responses in mice,hamsters,and nonhuman primates(NHP).It can induce high titers of antibodies with broad cross-neutralizing ability against the wildtype,B.1.1.7,B.1.351,B.1.617.2,and the newly emerging Omicron variants.In mice and NHP,two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants.Furthermore,our safety assessment of RQ3013 in NHP showed no observable adverse effects.These results provide strong support for the evaluation of RQ3013 in clinical trials and suggest that it may be a promising candidate for broad protection against COVID-19 and its variants.

关 键 词：RQ3013 COVID-19 mRNA vaccine SARS-CoV-2 Chimeric spike 

分 类 号：R392[医药卫生—免疫学]