Yan-Feng Yao, Ze-Jun Wang, Ren-Di Jiang, Xue Hu, Hua-Jun Zhang, Yi-Wu Zhou, Ge Gao, Ying Chen, Yun Peng, Mei-Qin Liu, Ya-Nan Zhang, Juan Min, Jia Lu, Xiao-Xiao Gao, Jing Guo, Cheng Peng, Xu-Rui Shen, Qian Li, Kai Zhao, Lian Yang, Xin Wan, Bo Zhang, Wen-Hui Wang, Jia Wu, Peng Zhou, Xing-Lou Yang, Shuo Shen, Chao Shan, Zhi-Ming Yuan and Zheng-Li Shi. Protective Efficacy of Inactivated Vaccine against SARS-CoV-2 Infection in Mice and Non-Human Primates[J]. Virologica Sinica, 2021, 36(5): 879-889. doi: 10.1007/s12250-021-00376-w
Citation: Yan-Feng Yao, Ze-Jun Wang, Ren-Di Jiang, Xue Hu, Hua-Jun Zhang, Yi-Wu Zhou, Ge Gao, Ying Chen, Yun Peng, Mei-Qin Liu, Ya-Nan Zhang, Juan Min, Jia Lu, Xiao-Xiao Gao, Jing Guo, Cheng Peng, Xu-Rui Shen, Qian Li, Kai Zhao, Lian Yang, Xin Wan, Bo Zhang, Wen-Hui Wang, Jia Wu, Peng Zhou, Xing-Lou Yang, Shuo Shen, Chao Shan, Zhi-Ming Yuan, Zheng-Li Shi. Protective Efficacy of Inactivated Vaccine against SARS-CoV-2 Infection in Mice and Non-Human Primates .VIROLOGICA SINICA, 2021, 36(5) : 879-889.  http://dx.doi.org/10.1007/s12250-021-00376-w

动物模型测试表明新冠灭活疫苗安全有效

cstr: 32224.14.s12250-021-00376-w
  • 通讯作者: 杨兴娄, yangxl@wh.iov.cn, ORCID: http://orcid.org/0000-0002-5317-8983
    ; 申硕, shenshuo1@sinopharm.com, ORCID: http://orcid.org/0000-0002-5317-8983
    ; 单超, shanchao@wh.iov.cn, ORCID: http://orcid.org/0000-0003-0916-053X
    ; 袁志明, yzm@wh.iov.cn, ORCID: http://orcid.org/0000-0002-3234-9616
    ; 石正丽, zlshi@wh.iov.cn, ORCID: http://orcid.org/0000-0001-8089-163X
  • 收稿日期: 2021-01-23
    录用日期: 2021-02-08
    出版日期: 2021-04-09
  • 新冠病毒引起的COVID-19大流行给我们带来了前所未有的危机,对人类健康和生命造成巨大的威胁,给全球经济带来了灾难性的损失。截止目前全球新冠累计确诊患者数超过1.3亿,新冠感染导致的总死亡人数接近300万。因此开发有效的新冠疫苗迫在眉睫。本研究报道了中国科学院武汉病毒研究所、中国生物武汉生物制品研究所等单位联合研制的新冠灭活疫苗在小鼠和恒河猴上疫苗安全性、免疫原性和保护效果评价。结果显示该疫苗在小鼠和恒河猴体内均可诱导新冠特异性中和抗体产生。攻毒实验显示,疫苗高剂量组可对新冠病毒攻毒提供完全的保护,低剂量组亦可引起部分保护。小鼠被动免疫实验显示疫苗诱导的抗体可以对新冠病毒攻毒提供完全的保护。基于上述研究结果,为该疫苗进入临床研究打下坚实基础。

Protective Efficacy of Inactivated Vaccine against SARS-CoV-2 Infection in Mice and Non-Human Primates

  • Corresponding author: Xing-Lou Yang, yangxl@wh.iov.cn Shuo Shen, shenshuo1@sinopharm.com Chao Shan, shanchao@wh.iov.cn Zhi-Ming Yuan, yzm@wh.iov.cn Zheng-Li Shi, zlshi@wh.iov.cn
  • ORCID: http://orcid.org/0000-0002-5317-8983; http://orcid.org/0000-0002-5317-8983; http://orcid.org/0000-0003-0916-053X; http://orcid.org/0000-0002-3234-9616; http://orcid.org/0000-0001-8089-163X
  • Received Date: 23 January 2021
    Accepted Date: 08 February 2021
    Published Date: 09 April 2021
  • The ongoing coronavirus disease 2019 (COVID-19) pandemic caused more than 96 million infections and over 2 million deaths worldwide so far. However, there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease causative agent. Vaccine is the most effective approach to eradicate a pathogen. The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations. Here we evaluated the safety, immunogenicity, and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates. Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates, and subsequently provided partial (in low dose) or full (in high dose) protection of challenge in the tested animals. In addition, passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice. These results warranted positive outcomes in future clinical trials in humans.


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    1. Bardina SV, Bunduc P, Tripathi S, Duehr J, Frere JJ, Brown JA, Nachbagauer R, Foster GA, Krysztof D, Tortorella D, Stramer SL, Garcia-Sastre A, Krammer F, Lim JK (2017) Enhancement of Zika virus pathogenesis by preexisting antiflavivirus immunity. Science 356: 175–180
        doi: 10.1126/science.aal4365

    2. Baum A, Fulton BO, Wloga E, Copin R, Pascal KE, Russo V, Giordano S, Lanza K, Negron N, Ni M, Wei Y, Atwal GS, Murphy AJ, Stahl N, Yancopoulos GD, Kyratsous CA (2020) Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369: 1014–1018
        doi: 10.1126/science.abd0831

    3. Corbett KS, Edwards DK, Leist SR, Abiona OM, Boyoglu-Barnum S, Gillespie RA, Himansu S, Schafer A, Ziwawo CT, DiPiazza AT, Dinnon KH, Elbashir SM, Shaw CA, Woods A, Fritch EJ, Martinez DR, Bock KW, Minai M, Nagata BM, Hutchinson GB, Wu K, Henry C, Bahl K, Garcia-Dominguez D, Ma L, Renzi I, Kong WP, Schmidt SD, Wang L, Zhang Y, Phung E, Chang LA, Loomis RJ, Altaras NE, Narayanan E, Metkar M, Presnyak V, Liu C, Louder MK, Shi W, Leung K, Yang ES, West A, Gully KL, Stevens LJ, Wang N, Wrapp D, Doria-Rose NA, Stewart-Jones G, Bennett H, Alvarado GS, Nason MC, Ruckwardt TJ, McLellan JS, Denison MR, Chappell JD, Moore IN, Morabito KM, Mascola JR, Baric RS, Carfi A, Graham BS (2020a) SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586: 567–571
        doi: 10.1038/s41586-020-2622-0

    4. Corbett KS, Flynn B, Foulds KE, Francica JR, Boyoglu-Barnum S, Werner AP, Flach B, O'Connell S, Bock KW, Minai M, Nagata BM, Andersen H, Martinez DR, Noe AT, Douek N, Donaldson MM, Nji NN, Alvarado GS, Edwards DK, Flebbe DR, Lamb E, Doria-Rose NA, Lin BC, Louder MK, O'Dell S, Schmidt SD, Phung E, Chang LA, Yap C, Todd JM, Pessaint L, Van Ry A, Browne S, Greenhouse J, Putman-Taylor T, Strasbaugh A, Campbell TA, Cook A, Dodson A, Steingrebe K, Shi W, Zhang Y, Abiona OM, Wang L, Pegu A, Yang ES, Leung K, Zhou T, Teng IT, Widge A, Gordon I, Novik L, Gillespie RA, Loomis RJ, Moliva JI, Stewart-Jones G, Himansu S, Kong WP, Nason MC, Morabito KM, Ruckwardt TJ, Ledgerwood JE, Gaudinski MR, Kwong PD, Mascola JR, Carfi A, Lewis MG, Baric RS, McDermott A, Moore IN, Sullivan NJ, Roederer M, Seder RA, Graham BS (2020b) Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med 383: 1544–1555
        doi: 10.1056/NEJMoa2024671

    5. Coronaviridae Study Group of the International Committee on Taxonomy of V (2020) The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 5: 536–544
        doi: 10.1038/s41564-020-0695-z

    6. Dagotto G, Yu J, Barouch DH (2020) Approaches and challenges in SARS-CoV-2 vaccine development. Cell Host Microbe 28: 364–370
        doi: 10.1016/j.chom.2020.08.002

    7. Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X (2020) Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci USA 117: 9490–9496
        doi: 10.1073/pnas.2004168117

    8. Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M, Li Y, Zhu L, Wang N, Lv Z, Gao H, Ge X, Kan B, Hu Y, Liu J, Cai F, Jiang D, Yin Y, Qin C, Li J, Gong X, Lou X, Shi W, Wu D, Zhang H, Zhu L, Deng W, Li Y, Lu J, Li C, Wang X, Yin W, Zhang Y, Qin C (2020) Development of an inactivated vaccine candidate for SARS-CoV-2. Science 369: 77–81
        doi: 10.1126/science.abc1932

    9. Graham BS (2011) Biological challenges and technological opportunities for respiratory syncytial virus vaccine development. Immunol Rev 239: 149–166
        doi: 10.1111/j.1600-065X.2010.00972.x

    10. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and Is blocked by a clinically proven protease inhibitor. Cell 181: 271–280. e278
        doi: 10.1016/j.cell.2020.02.052

    11. Jiang RD, Liu MQ, Chen Y, Shan C, Zhou YW, Shen XR, Li Q, Zhang L, Zhu Y, Si HR, Wang Q, Min J, Wang X, Zhang W, Li B, Zhang HJ, Baric RS, Zhou P, Yang XL, Shi ZL (2020) Pathogenesis of SARS-CoV-2 in transgenic mice expressing human angiotensin-converting enzyme 2. Cell 182: 50–58. e58
        doi: 10.1016/j.cell.2020.05.027

    12. Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, Balmaseda A, Harris E (2017) Antibody-dependent enhancement of severe dengue disease in humans. Science 358: 929–932
        doi: 10.1126/science.aan6836

    13. Kissler SM, Tedijanto C, Goldstein E, Grad YH, Lipsitch M (2020) Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science 368: 860–868
        doi: 10.1126/science.abb5793

    14. Lundstrom K (2015) RNA-based drugs and vaccines. Expert Rev Vaccines 14: 253–263
        doi: 10.1586/14760584.2015.959932

    15. Luo F, Liao FL, Wang H, Tang HB, Yang ZQ, Hou W (2018) Evaluation of antibody-dependent enhancement of SARS-CoV infection in rhesus macaques immunized with an inactivated SARS-CoV vaccine. Virol Sin 33: 201–204
        doi: 10.1007/s12250-018-0009-2

    16. Menachery VD, Yount BL Jr, Sims AC, Debbink K, Agnihothram SS, Gralinski LE, Graham RL, Scobey T, Plante JA, Royal SR, Swanstrom J, Sheahan TP, Pickles RJ, Corti D, Randell SH, Lanzavecchia A, Marasco WA, Baric RS (2016) SARS-like WIV1-CoV poised for human emergence. Proc Natl Acad Sci USA 113: 3048–3053
        doi: 10.1073/pnas.1517719113

    17. Plotkin S (2014) History of vaccination. Proc Natl Acad Sci USA 111: 12283–12287
        doi: 10.1073/pnas.1400472111

    18. Plotkin SA, Plotkin SL (2011) The development of vaccines: how the past led to the future. Nat Rev Microbiol 9: 889–893
        doi: 10.1038/nrmicro2668

    19. Porter KR, Raviprakash K (2017) DNA vaccine delivery and improved immunogenicity. Curr Issues Mol Biol 22: 129–138

    20. Shan C, Yao YF, Yang XL, Zhou YW, Gao G, Peng Y, Yang L, Hu X, Xiong J, Jiang RD, Zhang HJ, Gao XX, Peng C, Min J, Chen Y, Si HR, Wu J, Zhou P, Wang YY, Wei HP, Pang W, Hu ZF, Lv LB, Zheng YT, Shi ZL, Yuan ZM (2020) Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques. Cell Res 30: 670–677
        doi: 10.1038/s41422-020-0364-z

    21. Stewart AJ, Devlin PM (2006) The history of the smallpox vaccine. J Infect 52: 329–334
        doi: 10.1016/j.jinf.2005.07.021

    22. Tostanoski LH, Wegmann F, Martinot AJ, Loos C, McMahan K, Mercado NB, Yu J, Chan CN, Bondoc S, Starke CE, Nekorchuk M, Busman-Sahay K, Piedra-Mora C, Wrijil LM, Ducat S, Custers J, Atyeo C, Fischinger S, Burke JS, Feldman J, Hauser BM, Caradonna TM, Bondzie EA, Dagotto G, Gebre MS, Jacob-Dolan C, Lin Z, Mahrokhian SH, Nampanya F, Nityanandam R, Pessaint L, Porto M, Ali V, Benetiene D, Tevi K, Andersen H, Lewis MG, Schmidt AG, Lauffenburger DA, Alter G, Estes JD, Schuitemaker H, Zahn R, Barouch DH (2020) Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters. Nat Med 26: 1694–1700
        doi: 10.1038/s41591-020-1070-6

    23. van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR, Avanzato VA, Bushmaker T, Flaxman A, Ulaszewska M, Feldmann F, Allen ER, Sharpe H, Schulz J, Holbrook M, Okumura A, Meade-White K, Perez-Perez L, Edwards NJ, Wright D, Bissett C, Gilbride C, Williamson BN, Rosenke R, Long D, Ishwarbhai A, Kailath R, Rose L, Morris S, Powers C, Lovaglio J, Hanley PW, Scott D, Saturday G, de Wit E, Gilbert SC, Munster VJ (2020) ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques. Nature 586: 578–582
        doi: 10.1038/s41586-020-2608-y

    24. Wang H, Zhang Y, Huang B, Deng W, Quan Y, Wang W, Xu W, Zhao Y, Li N, Zhang J, Liang H, Bao L, Xu Y, Ding L, Zhou W, Gao H, Liu J, Niu P, Zhao L, Zhen W, Fu H, Yu S, Zhang Z, Xu G, Li C, Lou Z, Xu M, Qin C, Wu G, Gao GF, Tan W, Yang X (2020) Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell 182: 713–721. e719
        doi: 10.1016/j.cell.2020.06.008

    25. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G (2020) Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30: 269–271
        doi: 10.1038/s41422-020-0282-0

    26. Wang ZJ, Zhang HJ, Lu J, Xu KW, Peng C, Guo J, Gao XX, Wan X, Wang WH, Shan C, Zhang SC, Wu J, Yang AN, Zhu Y, Xiao A, Zhang L, Fu L, Si HR, Cai Q, Yang XL, You L, Zhou YP, Liu J, Pang DQ, Jin WP, Zhang XY, Meng SL, Sun YX, Desselberger U, Wang JZ, Li XG, Duan K, Li CG, Xu M, Shi ZL, Yuan ZM, Yang XM, Shen S (2020) Low toxicity and high immunogenicity of an inactivated vaccine candidate against COVID-19 in different animal models. Emerg Microbes Infect 9: 2606–2618
        doi: 10.1080/22221751.2020.1852059

    27. WHO (2020a) Coronavirus disease (COVID-2019) situation reports.

    28. Xia S, Duan K, Zhang Y, Zhao D, Zhang H, Xie Z, Li X, Peng C, Zhang Y, Zhang W, Yang Y, Chen W, Gao X, You W, Wang X, Wang Z, Shi Z, Wang Y, Yang X, Zhang L, Huang L, Wang Q, Lu J, Yang Y, Guo J, Zhou W, Wan X, Wu C, Wang W, Huang S, Du J, Meng Z, Pan A, Yuan Z, Shen S, Guo W, Yang X (2020) Effect of an inactivated vaccine against SARS-CoV-2 on safety and immunogenicity outcomes: interim analysis of 2 randomized clinical trials. JAMA 324: 951–960
        doi: 10.1001/jama.2020.15543

    29. Yang J, Wang W, Chen Z, Lu S, Yang F, Bi Z, Bao L, Mo F, Li X, Huang Y, Hong W, Yang Y, Zhao Y, Ye F, Lin S, Deng W, Chen H, Lei H, Zhang Z, Luo M, Gao H, Zheng Y, Gong Y, Jiang X, Xu Y, Lv Q, Li D, Wang M, Li F, Wang S, Wang G, Yu P, Qu Y, Yang L, Deng H, Tong A, Li J, Wang Z, Yang J, Shen G, Zhao Z, Li Y, Luo J, Liu H, Yu W, Yang M, Xu J, Wang J, Li H, Wang H, Kuang D, Lin P, Hu Z, Guo W, Cheng W, He Y, Song X, Chen C, Xue Z, Yao S, Chen L, Ma X, Chen S, Gou M, Huang W, Wang Y, Fan C, Tian Z, Shi M, Wang FS, Dai L, Wu M, Li G, Wang G, Peng Y, Qian Z, Huang C, Lau JY, Yang Z, Wei Y, Cen X, Peng X, Qin C, Zhang K, Lu G, Wei X (2020) A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature 586: 572–577
        doi: 10.1038/s41586-020-2599-8

    30. Yu J, Tostanoski LH, Peter L, Mercado NB, McMahan K, Mahrokhian SH, Nkolola JP, Liu J, Li Z, Chandrashekar A, Martinez DR, Loos C, Atyeo C, Fischinger S, Burke JS, Slein MD, Chen Y, Zuiani A, Lelis FJN, Travers M, Habibi S, Pessaint L, Van Ry A, Blade K, Brown R, Cook A, Finneyfrock B, Dodson A, Teow E, Velasco J, Zahn R, Wegmann F, Bondzie EA, Dagotto G, Gebre MS, He X, Jacob-Dolan C, Kirilova M, Kordana N, Lin Z, Maxfield LF, Nampanya F, Nityanandam R, Ventura JD, Wan H, Cai Y, Chen B, Schmidt AG, Wesemann DR, Baric RS, Alter G, Andersen H, Lewis MG, Barouch DH (2020) DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 369: 806–811
        doi: 10.1126/science.abc6284

    31. Zhang C, Zhou DM (2016) Adenoviral vector-based strategies against infectious disease and cancer. Human Vaccin Immunother 12: 2064–2074
        doi: 10.1080/21645515.2016.1165908

    32. Zheng HY, Zhang M, Yang CX, Zhang N, Wang XC, Yang XP, Dong XQ, Zheng YT (2020) Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell Mol Immunol 17: 541–543
        doi: 10.1038/s41423-020-0401-3

    33. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579: 270–273
        doi: 10.1038/s41586-020-2012-7

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    Protective Efficacy of Inactivated Vaccine against SARS-CoV-2 Infection in Mice and Non-Human Primates

      Corresponding author: Xing-Lou Yang, yangxl@wh.iov.cn
      Corresponding author: Shuo Shen, shenshuo1@sinopharm.com
      Corresponding author: Chao Shan, shanchao@wh.iov.cn
      Corresponding author: Zhi-Ming Yuan, yzm@wh.iov.cn
      Corresponding author: Zheng-Li Shi, zlshi@wh.iov.cn
    • 1. Center for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China
    • 2. Wuhan Institute of Biological Products Co. Ltd, Jiangxia District, Wuhan 430024, China
    • 3. University of Chinese Academy of Sciences, Beijing 100049, China
    • 4. Department of Forensic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430074, China
    • 5. Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China

    Abstract: 

    The ongoing coronavirus disease 2019 (COVID-19) pandemic caused more than 96 million infections and over 2 million deaths worldwide so far. However, there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease causative agent. Vaccine is the most effective approach to eradicate a pathogen. The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations. Here we evaluated the safety, immunogenicity, and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates. Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates, and subsequently provided partial (in low dose) or full (in high dose) protection of challenge in the tested animals. In addition, passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice. These results warranted positive outcomes in future clinical trials in humans.