Making sense of spike D614G in SARS-CoV-2 transmission


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of the current coronavirus disease 2019 (COVID-19) pandemic, has evolved to adapt to human host and transmission over the past 12 months. One prominent adaptive mutation is the asparagine-to-glycine substitution at amino acid position 614 in the viral spike protein (D614G), which has become dominant in the currently circulating virus strains. Since spike protein determines host ranges, tissue tropism, and pathogenesis through binding to the cellular receptor of angiotensin converting enzyme 2 (ACE2), the D614G mutation is hypothesized to enhance viral fitness in human host, leading to increased transmission during the global pandemic. Here we summarize the recent progress on the role of the D614G mutation in viral replication, pathogenesis, transmission, and vaccine and therapeutic antibody development. These findings underscore the importance in closely monitoring viral evolution and defining their functions to ensure countermeasure efficacy against newly emerging variants.


  1. 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., et al. (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, doi:

  2. Dai, L., and Gao, G.F. (2020). Viral targets for vaccines against COVID-19. Nat Rev Immunol, doi:

  3. Daniloski, Z., Guo, X., and Sanjana, N.E. (2020). The D614G mutation in SARS-CoV-2 Spike increases transduction of multiple human cell types. bioRxiv, doi:

  4. Davies, N.G., Barnard, R.C., Jarvis, C.I., Kucharski, A.J., Munday, J., Pearson, C.A.B., Russell, T.W., Tully, D.C., Abbott, S., Gimma, A., et al. (2020). Estimated transmissibility and severity of novel SARS-CoV-2 Variant of Concern 202012/01 in England. medRxiv, doi:

  5. Hou, Y.J., Chiba, S., Halfmann, P., Ehre, C., Kuroda, M., Dinnon Iii, K.H., Leist, S.R., Schäfer, A., Nakajima, N., Takahashi, K., et al. (2020a). SARS-CoV-2 D614G variant exhibits efficient replication ex vivo and transmission in vivo. Science eabe8499.

  6. Hou, Y.J., Okuda, K., Edwards, C.E., Martinez, D.R., Asakura, T., Dinnon Iii, K.H., Kato, T., Lee, R.E., Yount, B.L., Mascenik, T.M., et al. (2020b). SARS-CoV-2 reverse genetics reveals a variable infection gradient in the respiratory tract. Cell 182, 429–446.e14.

    CAS  Article  Google Scholar 

  7. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., et al. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506.

    CAS  Article  Google Scholar 

  8. Imai, M., Iwatsuki-Horimoto, K., Hatta, M., Loeber, S., Halfmann, P.J., Nakajima, N., Watanabe, T., Ujie, M., Takahashi, K., Ito, M., et al. (2020). Syrian hamsters as a small animal model for SARS-CoV-2 infection and countermeasure development. Proc Natl Acad Sci USA 117, 16587–16595.

    CAS  Article  Google Scholar 

  9. Jaimes, J., Millet, J., and Whittaker, G. (2020). Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1/S2 site. SSRN J, doi:

  10. Korber, B., Fischer, W.M., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., Hengartner, N., Giorgi, E.E., Bhattacharya, T., Foley, B., et al. (2020). Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182, 812–827.e19.

    CAS  Article  Google Scholar 

  11. Lorenzo-Redondo, R., Nam, H.H., Roberts, S.C., Simons, L.M., Jennings, L.J., Qi, C., Achenbach, C.J., Hauser, A.R., Ison, M.G., Hultquist, J.F., et al. (2020). A unique clade of SARS-CoV-2 viruses is associated with lower viral loads in patient upper airways. medRxiv, doi:

  12. Muruato, A.E., Fontes-Garfias, C.R., Ren, P., Garcia-Blanco, M.A., Menachery, V.D., Xie, X., and Shi, P.Y. (2020). A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation. Nat Commun 11, 4059.

    CAS  Article  Google Scholar 

  13. Omotuyi, I.O., Nash, O., Ajiboye, O.B., Iwegbulam, C.G., Oyinloye, E.B., Oyedeji, O.A., Kashim, Z.A., and Okaiyeto, K. (2020). Atomistic simulation reveals structural mechanisms underlying D614G spike glycoprotein-enhanced fitness in SARS-CoV-2. J Comput Chem 41, 2158–2161.

    CAS  Article  Google Scholar 

  14. Plante, J.A., Liu, Y., Liu, J., Xia, H., Johnson, B.A., Lokugamage, K.G., Zhang, X., Muruato, A.E., Zou, J., Fontes-Garfias, C.R., et al. (2020). Spike mutation D614G alters SARS-CoV-2 fitness. Nature, doi:

  15. Rambaut, A., Loman, N., Pybus, O., Barclay, W., Barrett, J., Carabelli, A., Connor, T., Peacock, T., Robertson, D.L., Volz, E. (2020). Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. Virological,

  16. Shang, J., Wan, Y., Luo, C., Ye, G., Geng, Q., Auerbach, A., and Li, F. (2020). Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA 117, 11727–11734.

    CAS  Article  Google Scholar 

  17. Smith, E.C., Blanc, H., Surdel, M.C., Vignuzzi, M., and Denison, M.R. (2013). Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog 9, e1003565.

    CAS  Article  Google Scholar 

  18. Tegally, H., Wilkinson, E., Giovanetti, M., Iranzadeh, A., Fonseca, V., Giandhari, J., Doolabh, D., Pillay, S., San, E.J., Wibmer, K., et al. (2020). Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. medRxiv, doi:

  19. Walsh, E.E., Frenck Jr., R.W., Falsey, A.R., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Neuzil, K., Mulligan, M.J., Bailey, R., et al. (2020). Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N Engl J Med 383, 2439–2450.

    CAS  Article  Google Scholar 

  20. Wang, C., Liu, Z., Chen, Z., Huang, X., Xu, M., He, T., and Zhang, Z. (2020). The establishment of reference sequence for SARS-CoV-2 and variation analysis. J Med Virol 92, 667–674.

    CAS  Article  Google Scholar 

  21. Weissman, D., Alameh, M.G., de Silva, T., Collini, P., Hornsby, H., Brown, R., LaBranche, C.C., Edwards, R.J., Sutherland, L., Santra, S., et al. (2020). D614G spike mutation increases SARS CoV-2 susceptibility to neutralization. Cell Host Microbe 29, 23–31.e4.

    Article  Google Scholar 

  22. Xie, X., Muruato, A., Lokugamage, K.G., Narayanan, K., Zhang, X., Zou, J., Liu, J., Schindewolf, C., Bopp, N.E., Aguilar, P.V., et al. (2020). An infectious cDNA clone of SARS-CoV-2. Cell Host Microbe 27, 841–848.e3.

    CAS  Article  Google Scholar 

  23. Xie, X., Zou, J., Fontes-Garfias, C.R., Xia, H., Swanson, K.A., Cutler, M., Cooper, D., Menachery, V.D., Weaver, S., Dormitzer, P.R., et al. (2021). Neutralization of N501Y mutant SARS-CoV-2 by BNT162b2 vaccine-elicited sera. Res Sq,

  24. Yurkovetskiy, L., Wang, X., Pascal, K.E., Tomkins-Tinch, C., Nyalile, T.P., Wang, Y., Baum, A., Diehl, W.E., Dauphin, A., Carbone, C., et al. (2020). Structural and functional analysis of the D614G SARS-CoV-2 spike protein variant. Cell 183, 739–751.e8.

    CAS  Article  Google Scholar 

  25. Zhang, L., Jackson, C.B., Mou, H., Ojha, A., Rangarajan, E.S., Izard, T., Farzan, M., Choe, H. (2020). The D614G mutation in the SARS-CoV-2 spike protein reduces S1 shedding and increases infectivity. bioRxiv, doi:

  26. Zhou, B., Thao, T.T.N., Hoffmann, D., Taddeo, A., Ebert, N., Labroussaa, F., Pohlmann, A., King, J., Portmann, J., Halwe, N.J., et al. (2020a). SARS-CoV-2 spike D614G variant confers enhanced replication and transmissibility. bioRxiv, doi:

  27. Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., et al. (2020b). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273.

    CAS  Article  Google Scholar 

  28. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 382, 727–733.

    CAS  Article  Google Scholar 

Download references


We thank colleagues for helpful discussion during this study.

Author information



Corresponding author

Correspondence to Xuping Xie.

Additional information

Compliance and ethics

The author(s) declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Shi, A.C., Xie, X. Making sense of spike D614G in SARS-CoV-2 transmission. Sci. China Life Sci. (2021).

Download citation


  • SARS-CoV-2
  • D614G
  • COVID-19