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Coronavirus

Coronavirus

Coronaviruses (CoVs) are single-stranded, positive-sense RNA enveloped viruses with a broad host range, including pets (cats, dogs), livestock (pigs, cattle), birds, bats, and others. To date, seven coronaviruses have been identified to infect human: HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and SARS-CoV-2. The latter three have caused significant global health and economic impacts. Additionally, two animal coronaviruses, Hu-PDCoV and CCoV-HuPn-2018, have been reported to infect humans but without sustained transmission.

During the COVID-19 pandemic, under the strong leadership of the Chinese Communist Party, the Gao lab played a pivotal role in identifying the pathogen, sequencing the viral genome, isolating the virus, and issuing early warnings, implementing President Xi Jinping’s directive for "open, transparent, and responsible" pandemic response. The team conducted systematic research across six domains: viral entry mechanisms, cross-species transmission, SARS-CoV-2 variants, vaccine development, macromolecular therapeutics, and diagnostic assays. Their foundational research yielded 24 publications in top journals (Cell: 7, Science: 1, Nature: 3, Lancet: 7, NEJM: 6). Applied outcomes included the world’s first therapeutic antibody (approved in 17 countries), the first recombinant protein subunit vaccine (approved in 6 countries), and diagnostic kits deployed in over 70 countries.

1. Early Pathogen Identification, Genome Sequencing, and Virus Isolation

At the pandemic’s onset, Prof. Gao, then Director of the Chinese Center for Disease Control and Prevention, recognized the severity of the outbreak with his professional sensitivity and promptly alerted national health authorities. His team received clinical samples on January 2, 2020, sequenced the viral genome by January 3, developed a specific nucleic acid detection kit by January 4, isolated the virus and published its electron micrograph by January 7, shared genomic data with the WHO and GISAID by January 10 and coordinated the distribution of commercialized test kit in Wuhan. Adterwards, they shared critical data and experiences through The New England Journal of Medicine and The Lancet, underscoring China’s responsible global engagement (Lancet, 2020a,b,c; NEJM, 2020a,b).

 

2. Viral Entry and Cross-Species Transmission Mechanisms

Coronavirus infection initiates via spike (S) protein binding to host receptors, a process critical for cross-species transmission and vaccine/antibody design. The Gao lab rapidly identified ACE2 as the SARS-CoV-2 receptor and reported the first S protein receptor-binding domain (RBD)-ACE2 complex structure (Cell, 2020a), later recognized among Cell’s Top 10 Cited Papers of 2020. Subsequent work elucidated mechanisms of receptor recognition for variants of concern (VOCs) (Nat Commun, 2021; Cell, 2022a,b).

Figure 1 Receptor recognition of SARS-CoV-2 RBD interacting with ACE2 receptor

To assess cross-species transmission risks, the team pioneered a receptor-binding screening approach, analyzing ACE2 compatibility across 20+ species and animal-derived coronaviruses (e.g., RaTG13, GD/1/2019, GX/P2V/2017), revealing interspecies receptor recognition patterns (Cell, 2021). This work was selected as one of China’s "Top 10 Advances in Life Sciences" for 2021.

Figure 2 Receptor binding spectra of SARS-CoV-2 and related CoVs

3. Diagnostic, Therapeutic, and Preventive Innovations Facilitates the Pandemic Response

Confronting the unforeseen outbreak, swift development of diagnostic, therapeutic, and preventive products for immunological defenses establishment, proved critical to safeguarding public health and mitigating the pandemic’s impact. During the nascent phase of the SARS-CoV-2 outbreak, the Gao lab mobilized with urgency, dedicating immediate efforts to advancing the development of pivotal medical countermeasures.

Prior to the COVID-19 pandemic, the Gao lab has leveraged basic research on MERS-CoV and proposed a universal strategy for pan-β-CoVs with RBD dimer linked through disulfide bond. The strategy was further optimized as tandem-linked single-chain RBD dimers. In response to the pandemic, the Gao lab exploited such strategy and developed the first SARS-CoV-2 recombinant subunit vaccine (ZF2001) in collaboration with Anhui Zhifei Longcom Biopharmaceutical Co., Ltd. (Cell, 2020b; NEJM, 2022a). This vaccine, approved in six countries, was highlighted in President Xi’s address during his visit to Uzbekistan. Post-Omicron emergence, the team evaluated immune evasion and optimized vaccination protocols (NEJM, 2022b,c; Lancet, 2023a,b), later developed a next-generation vaccine based on Delta-Omicron chimera (Cell, 2022b).

Figure 3 Universal strategy for β-CoV vaccine design

In addition to vaccines, the Gao lab also isolated neutralizing monoclonal antibodies (e.g., JS016/CB6, co-developed with Lilly and authorized in 17 regions) (Nature, 2020; Science, 2020), created a nasal spray peptide inhibitor (HY3000, co-developed with Hybio, in clinical trials), and distributed antigen detection kits globally.

 

Representative publications

1.        Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y. -G., Ren, R., Leung, K. S. M., Lau, E. H. Y., Wong, J. Y., Xing, X., Xiang, N., Wu, Y., Li, C., Chen, Q., Li, D., Liu, T., Zhao, J., Li, M., Tu, W., Chen, C., Jin, L., Yang, R., Wang, Q., Zhou, S., Wang, R., Liu, H., Luo, Y., Liu, Y., Shao, G., Li, H., Tao, Z., Yang, Y., Deng, Z., Liu, B., Ma, Z., Zhang, Y., Shi, G., Lam, T. T. Y., Wu, J. T. K., Gao, G. F., Cowling*, B. J., Yang*, B., Leung*, G. M. and Feng*, Z., 2020a, Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia. The New England Journal of Medicine, 382 (13): 1199-1207.

2.        Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu*, G., Gao*, G. F., Tan*, W and China Novel Coronavirus Investigating and Research Team, 2020b, A novel coronavirus from patients with pneumonia in China, 2019. The New England Journal of Medicine, 382 (8): 727-733.

3.        Wang*, C., Horby, P. W., Hayden, F.G. and Gao, G. F., 2020a, A novel coronavirus outbreak of global health concern. The Lancet, 395 (10223): 470-473.

4.        Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., Wang, W., Song, H., Huang, B., Zhu, N., Bi, Y., Ma, X., Zhan, F,, Wang, L., Hu, T., Zhou, H., Hu, Z., Zhou, W., Zhao, L., Chen, J., Meng, Y., Wang, J., Lin, Y., Yuan, J., Xie, Z., Ma, J., Liu, W. J., Wang, D., Xu, W., Holmes, E. C., Gao, G. F., Wu*, G., Chen*, W., Shi*, W. and Tan*, W., 2020b, Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet, 395 (10224): 565-574.

5.        Li, Z., Song, T., Qi, X., Zhou, L., Li, Y., Sun, X., Wu, D., An, Z., Ren, X., Peng, Z., Chen, W., Zhang, M., Yang, X., Wang, Q., Cui, J., Zhang, T., Qin, Y., Ni, D., Yin, W., Zhang, R., Yu, H., Xia, Y., Rodewald, L., Feng, L., Chen, Q., Gao*, G. F. and Feng*, Z., 2020c, Active case finding with case management is key to tackling the COVID-19 pandemic. The Lancet, 396 (10243): 63-70.

6.        Wang Q, Zhang Y, Wu L, Niu S, Song C, Zhang Z, Lu G, Qiao C, Hu Y, Yuen KY, Wang Q, Zhou H, Yan J, Qi J. 2020a Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2. Cell. 181(4):894-904.e9.

7.        Han, P., Li, L., Liu, S., Wang, Q., Zhang, D., Xu, Z., Han, P., Li, X., Peng, Q., Su, C., Huang, B., Li, D., Zhang, R., Tian, M., Fu, L., Gao, Y., Zhao, X., Liu, K., Qi*, J., Gao*, G. F. and Wang*, P., 2022a, Receptor binding and complex structures of human ACE2 to spike RBD from omicron and delta SARS-CoV-2. Cell, 185 (4): 630-640.e10.

8.        Li, L., Liao, H., Meng, Y., Li, W., Han, P., Liu, K., Wang, Q., Li, D., Zhang, Y., Wang, L., Fan, Z., Zhang, Y., Wang, Q., Zhao*, X., Sun*, Y., Huang*, N., Qi*, J. and Gao*, G. F., 2022b, Higher binding affinity and structural basis of human ACE2 to currently circulating Omicron SARS-CoV-2 sub-variants BA.2 and BA.1.1. Cell, 185 (16): 2952-2960.e10.

9.        Liu, K., Pan, X., Li, L., Yu, F., Zheng, A., Du, P., Han, P., Meng, Y., Zhang, Y., Wu, L., Chen, Q., Song, C., Jia, Y., Niu, S., Lu, D., Qiao, C., Chen, Z., Ma, D., Ma, X., Tan, S., Zhao, X., Qi*, J., Gao*, G. F. and Wang*, Q., 2021, Binding and molecular basis of the bat coronavirus RaTG13 virus to ACE2 in humans and other species. Cell, 184 (13): 3438-3451.e10.

10.    Dai, L., Zheng, T., Xu, K., Han, Y., Xu, L., Huang, E., An, Y., Cheng, Y., Li, S., Liu, M., Yang, M., Li, Y., Chen, H., Yuan, Y., Zhang, W., Ke, C., Wong, G., Qi, J., Qin*, C., Yan*, J. and Gao*, G. F., 2020, A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS. Cell, 182 (3): 722-733.e11.

11.    Xu, K., Gao, P., Liu, S., Lu, S., Lei, W., Zheng, T., Liu, X., Xie, Y., Zhao, Z., Guo, S., Tang, C., Yang, Y., Yu, W., Wang, J., Zhou, Y., Huang, Q., Liu, C., An, Y., Zhang, R., Han, Y., Duan, M., Wang, S., Yang, C., Wu, C., Liu, X., She, G., Liu, Y., Zhao, X., Xu, K., Qi, J., Wu*, G., Peng*, X., Dai*, L., Wang*, P. and Gao*, G. F., 2022b, Protective prototype-Beta and Delta-Omicron chimeric RBD-dimer vaccines against SARS-CoV-2. Cell, 185 (13): 2265-2278.e14.

12.    Dai, L., Gao, L., Tao, L., Hadinegoro, S.R., Erkin, M., Ying, Z., He, P., Girsang, R.T., Vergara, H., Akram, J., Satari, H.I., Khaliq, T., Sughra, U., Celi, A.P., Li, F., Li, Y., Jiang, Z., Dalimova, D., Tuychiev, J., Turdikulova, S., Ikram, A., Lastra, N.F., Ding, F., Suhardono, M., Fadlyana, E., Yan, J., Hu, Z., Li, C., Abdurakhmonov, I.Y. and Gao*, G. F., 2022a, Efficacy and safety of the RBD-dimer-based covid-19 vaccine ZF2001 in adults. The New England Journal of Medicine, 386 (22): 2097-2111.

13.    Zhao, X., Li, D., Ruan, W., Chen, Z., Zhang, R., Zheng, A., Qiao, S., Zheng, X., Zhao, Y., Dai, L., Han, P. and Gao*, G. F., 2022b, Effects of a prolonged booster interval on neutralization of Omicron variant. The New England Journal of Medicine, 386 (9): 894-896.

14.    Zhao, X., Zhang, R., Qiao, S., Wang, X., Zhang, W., Ruan, W., Han, P. and Gao*, G. F., 2022c, Omicron SARS-CoV-2 neutralization from inactivated and ZF2001 vaccines. The New England Journal of Medicine, 387 (3): 277-280.

15.    Dai, L., Duan, H., Liu, X., Zhou, H., Duan, M., An, Y., Yuan, L., Zhao, X., Xu, K., Wu, Q. and Gao*, G. F., 2023a, Omicron neutralisation: RBD-dimer booster versus BF.7 and BA.5.2 breakthrough infection. The Lancet, 402 (10403): 687-689.

16.    Li, D., Duan, M., Wang, X., Gao, P., Zhao, X., Xu*, K. and Gao, G. F., 2023b, Neutralization of BQ.1, BQ.1.1, and XBB with RBD-dimer vaccines. The New England Journal of Medicine, 388 (12): 1142-1145.

17.    Shi, R., Shan, C., Duan, X., Chen, Z., Liu, P., Song, J., Song, T., Bi, X., Han, C., Wu, L., Gao, G., Hu, X., Zhang, Y., Tong, Z., Huang, W., Liu, W. J., Wu, G., Zhang, B., Wang, L., Qi, J., Feng, H., Wang*, F., Wang*, Q., Gao*, G. F., Yuan*, Z. and Yan*, J., 2020, A potent human neutralizing monoclonal antibody targeting the receptor binding site of SARS-CoV-2 virus. Nature, 584 (7819): 120-124.

18.    Wu*, Y., Wang, F., Shen, C., Peng, W., Li, D., Zhao, C., Li, Z., Li, S., Bi, Y., Yang, Y., Gong, Y., Xiao, H., Fan, Z., Tan, S., Wu, G., Tan, W., Lu, X., Fan, C., Wang, Q., Liu, Y., Zhang, C., Qi, J., Gao*, G. F., Gao*, F. and Liu*, L., 2020, A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science, 368 (6496): 1274-1278.

19.    Li, J., Lai, S., Gao, G. F. and Shi, W., 2021, The emergence, genomic diversity and global spread of SARS-CoV-2. Nature, 600 (7889): 408-418.

20.    Tong, Y. -G., Liu, W., Liu, P., Liu, W. J., Wang, Q. and Gao*, G. F., 2021, The origins of viruses: discovery takes time, international resources, and cooperation. The Lancet, 398 (10309): 1401-1402.

21.    Moeti, M., Gao*, G. F. and Herrman, H., 2022, Global pandemic perspectives: public health, mental health, and lessons for the future. The Lancet, S0140-6736 (22) 01328-01329.

22.    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*, G. F., Tan*, W. and Yang*, X., 2020, Development of an inactivated vaccine candidate, BBIBP-CorV, with potent protection against SARS-CoV-2. Cell, 182 (3): 713-721.e9.

23.    Liu*, W. J., Liu, P., Lei, W., Jia, Z., He, X., Shi, W., Tan, Y., Zou, S., Wong, G., Wang, J., Wang, F., Wang, G., Qin, K., Gao, R., Zhang, J., Li, M., Xiao, W., Guo, Y., Xu, Z., Zhao, Y., Song, J., Zhang, J., Zhen, W., Zhou, W., Ye, B., Song, J., Yang, M., Zhou, W., Dai, Y., Lu, G., Bi, Y., Tan, W., Han, J., Gao*, G. F. and Wu*, G., 2024, Surveillance of SARS-CoV-2 at the Huanan seafood market. Nature, 631 (8020): 402–408.

24.    Wang, L., Wang, Q. and Gao*, G. F., 2023, Characterization of SARS-CoV-2 variants in Beijing during 2022– Authors' reply. The Lancet, 403 (10422): 144-145.