Increased pathogenicity and aerosol transmission for one SARS-CoV-2 B.1.617.2 Delta variant over the wild-type strain in hamsters

Xinghai Zhang; Shaohong Chen; Zengguo Cao; Yanfeng Yao; Junping Yu; Junhui Zhou; Ge Gao; Ping He; Zhuo Dong; Jie Zhong; Jing Luo; Hongping Wei; Huajun Zhang

doi:10.1016/j.virs.2022.09.008

December 2022

. doi: 10.1016/j.virs.2022.09.008

Citation: Xinghai Zhang, Shaohong Chen, Zengguo Cao, Yanfeng Yao, Junping Yu, Junhui Zhou, Ge Gao, Ping He, Zhuo Dong, Jie Zhong, Jing Luo, Hongping Wei, Huajun Zhang. Increased pathogenicity and aerosol transmission for one SARS-CoV-2 B.1.617.2 Delta variant over the wild-type strain in hamsters .VIROLOGICA SINICA, 2022, 37(6) : 796-803. http://dx.doi.org/10.1016/j.virs.2022.09.008

一株SARS-CoV-2 B.1.617.2 Delta变异株在仓鼠中致病性和传播力增加

张醒海 ^a,, ,
陈少红 ^a,b ,
曹增国 ^a ,
姚艳丰 ^a ,
余军平 ^a ,
周俊辉 ^a,b ,
高歌 ^a ,
何萍 ^a,b ,
董卓 ^c ,
钟洁 ^c ,
罗静 ^c ,
危宏平 ^a,, ,
张化俊 ^a,,

a 中国科学院武汉病毒研究所, 病毒学国家重点实验室, 特殊病原体与生物安全重点实验室, 武汉, 430071;
b 中国科学院大学, 北京, 101409;
c 湖北省国际旅行保健中心(武汉海关口岸门诊部),武汉,430040

通讯作者： 张醒海, zhangxh@wh.iov.cn; 危宏平, hpwei@wh.iov.cn; 张化俊, hjzhang@wh.iov.cn
收稿日期： 2022-02-17
录用日期： 2022-09-26

摘要

本文对一株新的B.1.617.2 Delta毒株（Delta630）与原始野生型病毒WIV04毒株（WIV04）的复制、感染性、致病性和传播性进行了体内外综合评估分析。我们证明了Delta630在人源细胞中的复制效率高于WIV04。仓鼠鼻内接种时，Delta630导致更多的体重减轻和更严重的疾病，感染104 PFU的Delta630后约1周导致40%的死亡率。此外，Delta630在竞争性空气传播实验中较WIV04具有更强的竞争优势。总之，Delta630毒株在仓鼠中比WIV04具有更高的复制能力、致病性和传播性。据我们所知，这是第一个在仓鼠模型中导致死亡的SARS-CoV-2毒株，该模型将有助于评估针对SARS-CoV-2 Delta变异株的疫苗和抗病毒药物。
- SARS-CoV-2
- , Delta变异株
- , 金黄地鼠
- , 致病性
- , 传播

Increased pathogenicity and aerosol transmission for one SARS-CoV-2 B.1.617.2 Delta variant over the wild-type strain in hamsters

Xinghai Zhang ^a,, ,
Shaohong Chen ^a,b ,
Zengguo Cao ^a ,
Yanfeng Yao ^a ,
Junping Yu ^a ,
Junhui Zhou ^a,b ,
Ge Gao ^a ,
Ping He ^a,b ,
Zhuo Dong ^c ,
Jie Zhong ^c ,
Jing Luo ^c ,
Hongping Wei ^a,, ,
Huajun Zhang ^a,,

a State Key Laboratory of Virology, Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, China;
b University of Chinese Academy of Sciences, Beijing, 101409, China;
c Hubei International Travel Healthcare Center (Wuhan Customs Port Outpatient Department), Wuhan, 430040, China

Corresponding author: Xinghai Zhang, zhangxh@wh.iov.cn Hongping Wei, hpwei@wh.iov.cn Huajun Zhang, hjzhang@wh.iov.cn
Received Date: 17 February 2022
Accepted Date: 26 September 2022

Abstract

During the two-year pandemic of coronavirus disease 2019 (COVID-19), its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been evolving. SARS-CoV-2 Delta, a variant of concern, has become the dominant circulating strain worldwide within just a few months. Here, we performed a comprehensive analysis of a new B.1.617.2 Delta strain (Delta630) compared with the early WIV04 strain (WIV04) in vitro and in vivo, in terms of replication, infectivity, pathogenicity, and transmission in hamsters. When inoculated intranasally, Delta630 led to more pronounced weight loss and more severe disease in hamsters. Moreover, 40% mortality occurred about one week after infection with 10⁴ PFU of Delta630, whereas no deaths occurred even after infection with 10⁵ PFU of WIV04 or other strains belonging to the Delta variant. Moreover, Delta630 outgrew over WIV04 in the competitive aerosol transmission experiment. Taken together, the Delta630 strain showed increased replication ability, pathogenicity, and transmissibility over WIV04 in hamsters. To our knowledge, this is the first SARS-CoV-2 strain that causes death in a hamster model, which could be an asset for the efficacy evaluation of vaccines and antivirals against infections of SARS-CoV-2 Delta strains. The underlying molecular mechanisms of increased virulence and transmission await further analysis.
- SARS-CoV-2
- , B.1.617.2 Delta variant
- , Syrian hamsters
- , Pathogenicity
- , Transmission

References
1. Abdelnabi, R., Boudewijns, R., Foo, C.S., Seldeslachts, L., Sanchez-Felipe, L., Zhang, X., Delang, L., Maes, P., Kaptein, S.J.F., Weynand, B., Vande Velde, G., Neyts, J., Dallmeier, K., 2021. Comparing infectivity and virulence of emerging SARS-COV-2 variants in Syrian hamsters. EBioMedicine 68, 103403.
2. Allen, H., Vusirikala, A., Flannagan, J., Twohig, K.A., Zaidi, A., Chudasama, D., Lamagni, T., Groves, N., Turner, C., Rawlinson, C., Lopez-Bernal, J., Harris, R., Charlett, A., Dabrera, G., Kall, M., 2022. Household transmission of COVID-19 cases associated with SARS-COV-2 delta variant (B.1.617.2): National case-control study. Lancet Reg Health Eur 12, 100252.
3. Chakraborty, C., Bhattacharya, M., Sharma, A.R., 2021. Present variants of concern and variants of interest of severe acute respiratory syndrome coronavirus 2: their significant mutations in S-glycoprotein, infectivity, re-infectivity, immune escape and vaccines activity. Rev. Med. Virol. 32, e2270.
4. Chan, J.F.W., Zhang, A.J., Yuan, S., Poon, V.K.M., Chan, C.C.S., Lee, A.C.Y., Chan, W.M., Fan, Z., Tsoi, H.W., Wen, L., Liang, R., Cao, J., Chen, Y., Tang, K., Luo, C., Cai, J.-P., Kok, K.H., Chu, H., Chan, K.H., Sridhar, S., Chen, Z., Chen, H., To, K.K.W., Yuen, K.Y., 2020. Simulation of the clinical and pathological manifestations of coronavirus disease 2019 (covid-19) in a Golden Syrian hamster model: implications for disease pathogenesis and transmissibility. Clin. Infect. Dis. 71, 2428-2446.
5. Chen, Y., Wang, J., Liu, C., Su, L., Zhang, D., Fan, J., Yang, Y., Xiao, M., Xie, J., Xu, Y., Li, Y., Zhang, S., 2020. IP-10 and MCP-1 as biomarkers associated with disease severity of COVID-19. Mol. Med. 26, 97.
6. Cucinotta, D., Vanelli, M., 2020. WHO declares COVID-19 a pandemic. Acta Biomed.:Atenei Parmensis. https://pubmed.ncbi.nlm.nih.gov/32191675. (Accessed 9 October 2022).
7. Dagpunar, J., 2021. Interim estimates of increased transmissibility, growth rate, and reproduction number of the COVID-19 B.1.617.2 variant of concern in the United Kingdom. medRxiv. https://doi.org/10.1101/2021.06.03.21258293.
8. Daniloski, Z., Jordan, T.X., Ilmain, J.K., Guo, X., Bhabha, G., tenOever, B.R., Sanjana, N.E., 2021. The spike D614G mutation increases SARS-CoV-2 infection of multiple human cell types. Elife 10, e65365.
9. Earnest, R., Uddin, R., Matluk, N., Renzette, N., Turbett, S.E., Siddle, K.J., Loreth, C., Adams, G., Tomkins-Tinch, C.H., Petrone, M.E., Rothman, J.E., Breban, M.I., Koch, R.T., Billig, K., Fauver, J.R., Vogels, C.B.F., Bilguvar, K., De Kumar, B., Landry, M.L., Peaper, D.R., Kelly, K., Omerza, G., Grieser, H., Meak, S., Martha, J., Dewey, H.B., Kales, S., Berenzy, D., Carpenter-Azevedo, K., King, E., Huard, R.C., Novitsky, V., Howison, M., Darpolor, J., Manne, A., Kantor, R., Smole, S.C., Brown, C.M., Fink, T., Lang, A.S., Gallagher, G.R., Pitzer, V.E., Sabeti, P.C., Gabriel, S., MacInnis, B.L., , New England Variant Investigation Team, Tewhey, R., Adams, M.D., Park, D.J., Lemieux, J.E., Grubaugh, N.D., 2022. . Comparative transmissibility of SARS-CoV-2 variants Delta and alpha in New England, USA. Cell Rep Med 3, 100583.
10. Feng, L., Wang, Q., Shan, C., Yang, C., Feng, Y., Wu, J., Liu, X., Zhou, Y., Jiang, R., Hu, P., Liu, X., Zhang, F., Li, P., Niu, X., Liu, Y., Zheng, X., Luo, J., Sun, J., Gu, Y., Liu, B., Xu, Y., Li, C., Pan, W., Zhao, J., Ke, C., Chen, X., Xu, T., Zhong, N., Guan, S., Yuan, Z., Chen, L., 2020. An adenovirus-vectored COVID-19 vaccine confers protection from SARS-CoV-2 challenge in rhesus macaques. Nat. Commun. 11, 1-11.
11. Fisman, D.N., Tuite, A.R., 2021. Progressive increase in virulence of novel SARS-CoV-2 variants in Ontario, Canada, February to June, 2021. medRxiv. https://doi.org/ 10.1101/2021.07.05.21260050.
12. Han, H., Ma, Q., Li, C., Liu, R., Zhao, L., Wang, W., Zhang, P., Liu, X., Gao, G., Liu, F., Jiang, Y., Cheng, X., Zhu, C., Xia, Y., 2020. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. Microb. Infect. 9, 1123-1130.
13. Huang, K., Zhang, Y., Hui, X., Zhao, Y., Gong, W., Wang, T., Zhang, S., Yang, Y., Deng, F., Zhang, Q., Chen, X., Yang, Y., Sun, X., Chen, H., Tao, Y.J., Zou, Z., Jin, M., 2021. Q493K and Q498H substitutions in spike promote adaptation of SARS-CoV-2 in mice. EBioMedicine 67, 103381.
14. Imai, M., Iwatsuki-Horimoto, K., Hatta, M., Loeber, S., Halfmann, P.J., Nakajima, N., Watanabe, T., Ujie, M., Takahashi, K., Ito, M., Yamada, S., Fan, S., Chiba, S., Kuroda, M., Guan, L., Takada, K., Armbrust, T., Balogh, A., Furusawa, Y., Okuda, M., Ueki, H., Yasuhara, A., Sakai-Tagawa, Y., Lopes, T.J., Kiso, M., Yamayoshi, S., Kinoshita, N., Ohmagari, N., Hattori, S.I., Takeda, M., Mitsuya, H., Krammer, F., Suzuki, T., Kawaoka, Y., 2020. Syrian hamsters as a small animal model for SARSCoV-2 infection and countermeasure development. Proc. Natl. Acad. Sci. USA 117, 16587-16595.
15. Konings, F., Perkins, M.D., Kuhn, J.H., Pallen, M.J., Alm, E.J., Archer, B.N., Barakat, A., Bedford, T., Bhiman, J.N., Caly, L., Carter, L.L., Cullinane, A., de Oliveira, T., Druce, J., El Masry, I., Evans, R., Gao, G.F., Gorbalenya, A.E., Hamblion, E., Herring, B.L., Hodcroft, E., Holmes, E.C., Kakkar, M., Khare, S., Koopmans, M.P., Korber, B., Leite, J., MacCannell, D., Marklewitz, M., Maurer-Stroh, S., Rico, J.A., Munster, V.J., Neher, R., Munnink, B.O., Pavlin, B.I., Peiris, M., Poon, L., Pybus, O., Rambaut, A., Resende, P., Subissi, L., Thiel, V., Tong, S., van der Werf, S., von Gottberg, A., Ziebuhr, J., Van Kerkhove, M.D., 2021. SARS-CoV-2 variants of interest and concern naming scheme conducive for global discourse. Nat. Microbiol. 6, 821-823.
16. Lee, C.Y., Lowen, A.C., 2021. Animal models for SARS-COV-2. Curr. Opin. Virol. 48, 73-81.
17. Li, B., Deng, A., Li, K., Hu, Y., Li, Z., Shi, Y., Xiong, Q., Liu, Z., Guo, Q., Zou, L., Zhang, H., Zhang, M., Ouyang, F., Su, J., Su, W., Xu, J., Lin, H., Sun, J., Peng, J., Jiang, H., Zhou, P., Hu, T., Luo, M., Zhang, Y., Zheng, H., Xiao, J., Liu, T., Tan, M., Che, R., Zeng, H., Zheng, Z., Huang, Y., Yu, J., Yi, L., Wu, J., Chen, J., Zhong, H., Deng, X., Kang, M., Pybus, O.G., Hall, M., Lythgoe, K.A., Li, Y., Yuan, J., He, J., Lu, J., 2022. Viral infection and transmission in a large, well-traced outbreak caused by the SARSCoV-2 Delta variant. Nat. Commun. 13, 460.
18. Liu, Y., Rocklöv, J., 2021. The reproductive number of the Delta variant of SARS-COV-2 is far higher compared to the ancestral SARS-CoV-2 virus. J. Trav. Med. 28 taab124.
19. Mlcochova, P., Kemp, S.A., Dhar, M.S., Papa, G., Meng, B., Ferreira, I.A.T.M., Datir, R., Collier, D.A., Albecka, A., Singh, S., Pandey, R., Brown, J., Zhou, J., Goonawardane, N., Mishra, S., Whittaker, C., Mellan, T., Marwal, R., Datta, M., Sengupta, S., Ponnusamy, K., Radhakrishnan, V.S., Abdullahi, A., Charles, O., Chattopadhyay, P., Devi, P., Caputo, D., Peacock, T., Wattal, C., Goel, N., Satwik, A., Vaishya, R., Agarwal, M., Indian SARS-CoV-2 Genomics Consortium (INSACOG);Genotype to Phenotype Japan (G2P-Japan) Consortium; CITIID-NIHR BioResource COVID-19 Collaboration, Mavousian, A., Lee, J.H., Bassi, J., Silacci-Fegni, C., Saliba, C., Pinto, D., Irie, T., Yoshida, I., Hamilton, W.L., Sato, K., Bhatt, S., Flaxman, S., James, L.C., Corti, D., Piccoli, L., Barclay, W.S., Rakshit, P., Agrawal, A., Gupta, R.K., 2021. SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion. Nature 599, 114-119.
20. Mohandas, S., Yadav, P.D., Shete, A., Nyayanit, D., Sapkal, G., Lole, K., Gupta, N., 2021. SARS-CoV-2 delta variant pathogenesis and host response in Syrian hamsters. Viruses 13, 1773.
21. Port, J.R., Yinda, C.K., Avanzato, V.A., Schulz, J.E., Holbrook, M.G., van Doremalen, N., Shaia, C., Fischer, R.J., Munster, V.J., 2022. Increased small particle aerosol transmission of B.1.1.7 compared with SARS-CoV-2 lineage a in vivo. Nat. Microbiol. 7, 213-223.
22. Port, J.R., Yinda, C.K., Owusu, I.O., Holbrook, M., Fischer, R., Bushmaker, T., Avanzato, V.A., Schulz, J.E., Martens, C., van Doremalen, N., Clancy, C.S., Munster, V.J., 2021. SARS-CoV-2 disease severity and transmission efficiency is increased for airborne compared to fomite exposure in Syrian hamsters. Nat.Commun. 12, 1-15.
23. Rosenke, K., Meade-White, K., Letko, M., Clancy, C., Hansen, F., Liu, Y., Okumura, A., Tang-Huau, T.L., Li, R., Saturday, G., Feldmann, F., Scott, D., Wang, Z., Munster, V., Jarvis, M.A., Feldmann, H., 2020. Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection. Emerg. Microb. Infect. 9, 2673-2684.
24. Sia, S.F., Yan, L.M., Chin, A.W., Fung, K., Choy, K.T., Wong, A.Y., Kaewpreedee, P., Perera, R.A., Poon, L.L., Nicholls, J.M., Peiris, M., Yen, H.-L., 2020. Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. Nature 583, 834-838.
25. Sun, S.H., Chen, Q., Gu, H.J., Yang, G., Wang, Y.X., Huang, X.Y., Liu, S.S., Zhang, N.N., Li, X.F., Xiong, R., Guo, Y., Deng, Y.Q., Huang, W.J., Liu, Q., Liu, Q.M., Shen, Y.L., Zhou, Y., Yang, X., Zhao, T.Y., Fan, C.F., Zhou, Y.S., Qin, C.F., Wang, Y.C., 2020.A mouse model of SARS-CoV-2 infection and pathogenesis. Cell Host Microbe 28, 124-133 e124.
26. Sun, S., Gu, H., Cao, L., Chen, Q., Ye, Q., Yang, G., Li, R.T., Fan, H., Deng, Y.-Q., Song, X., Qi, Y., Li, M., Lan, J., Feng, R., Guo, Y., Zhu, N., Qin, S., Wang, L., Zhang, Y.F., Zhou, C., Zhao, L., Chen, Y., Shen, M., Cui, Y., Yang, X., Wang, X., Tan, W., Wang, H., Wang, X., Qin, C.F., 2021. Characterization and structural basis of a lethal mouseadapted SARS-CoV-2. Nat. Commun. 12, 1-16.
27. Teyssou, E., Delagréverie, H., Visseaux, B., Lambert-Niclot, S., Brichler, S., Ferre, V., Marot, S., Jary, A., Todesco, E., Schnuriger, A., Ghidaoui, E., Abdi, B., Akhavan, S., Houhou-Fidouh, N., Charpentier, C., Morand-Joubert, L., Boutolleau, D., Descamps, D., Calvez, V., Marcelin, A.G., Soulie, C., 2021. The delta SARS-CoV-2 variant has a higher viral load than the beta and the historical variants in nasopharyngeal samples from newly diagnosed COVID-19 patients. J. Infect. 83, e1-e3.
28. Twohig, K.A., Nyberg, T., Zaidi, A., Thelwall, S., Sinnathamby, M.A., Aliabadi, S., Seaman, S.R., Harris, R.J., Hope, R., Lopez-Bernal, J., 2021. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B. 1.617. 2) compared with alpha (B.1.1.7) variants of concern: a cohort study. Lancet Infect. Dis. 22, 35-42.
29. World Health Organization (WHO), 2022a. Weekly Epidemiological Update on COVID-19- 7 September 2022. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19—7-september-2022. (Accessed 7 September 2022).
30. World Health Organization (WHO), 2022b. Tracking SARS-CoV-2 Variants. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/. (Accessed 11 August 2022).
31. Zhang, J., Xiao, T., Cai, Y., Lavine, C.L., Peng, H., Zhu, H., Anand, K., Tong, P., Gautam, A., Mayer, M.L., Walsh, R.M., Rits-Volloch, S., Wesemann, D.R., Yang, W., Seaman, M.S., Lu, J., Chen, B., 2021. Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 delta variant. Science 374, 1353-1360.
32. Zhang, L., Jackson, C.B., Mou, H., Ojha, A., Peng, H., Quinlan, B.D., Rangarajan, E.S., Pan, A., Vanderheiden, A., Suthar, M.S., Li, W., Izard, T., Rader, C., Farzan, M., Choe, H., 2020. SARS-COV-2 spike-protein D614G mutation increases virion spike density and infectivity. Nat. Commun. 11, 6013.
33. Zhang, Q., Zhang, H., Gao, J., Huang, K., Yang, Y., Hui, X., He, X., Li, C., Gong, W., Zhang, Y., Zhao, Y., Peng, C., Gao, X., Chen, H., Zou, Z., Shi, Z.-L., Jin, M., 2020. A serological survey of SARS-CoV-2 in cat in Wuhan. Emerg. Microb. Infect. 9, 2013-2019.
34. Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., Chen, H.D., Chen, J., Luo, Y., Guo, H., Jiang, R.-D., Liu, M.Q., Chen, Y., Shen, X.-R., Wang, X., Zheng, X.-S., Zhao, K., Chen, Q.J., Deng, F., Liu, L.L., Yan, B., Zhan, F.X., Wang, Y.Y., Xiao, G.F., Shi, Z.L., 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270-273.
Proportional views
Electronic Supplementary Material

10.1016j.virs.2022.09.008-ESM.docx