Dear Editor,
As the SARS-CoV-2 virus spreads around the globe, a number of variants of concern (VOCs) have successively dominated geographical incidences of the pandemic of coronavirus disease 2019 (COVID-19)1,2. These VOCs are characterized by particular constellations of genetic mutations that are often associated with the change of molecular features of viral proteins promoting viral infectivity and transmissibility, as well as clinical manifestations3. Therefore, tracing the origin and spreading patterns of emerging SARS-CoV-2 variants is critical for evaluating and guiding the measures to ameliorate the impact of the virus on public health.
Recently, between late February and early July 2022, the city of Shanghai was hit by a wave of SARS-CoV-2 infections, leading to a total of almost 650,000 laboratory-confirmed cases of COVID-19 and 595 deaths (crude case fatality rate: 0.092%)4,5. To identify the SARS-CoV-2 variant(s) causing this outbreak, we used whole-genome targeted sequencing technology to obtain 253 high-quality SARS-CoV-2 genome assemblies from COVID-19 patients diagnosed during the early-to-mid stages of the outbreak (Fig. 1a; Supplementary Table S1). These genomes were then combined with a reference set of SARS-CoV-2 genomes at the Global Initiative on Sharing All Influenza Data (GISAID) database6 for an unsupervised phylogeny analysis. The result showed that all our cases clustered into a branch corresponding to the Omicron BA.2.2 lineage, which is characterized by three gained mutations — S:I1221T, ORF1a:T1543I, ORF1a:T4087I — as compared to other strains of SARS-CoV-2 (Fig. 1b; Supplementary Fig. S1). A further analysis using 3,424 BA.2.2 genomes from the GISAID database deposited before April 22nd, 2022 indicated that 239 cases investigated in this study have additionally accumulated two linked mutations — C26789T (M:G89G, synonymous) and A28119G (ORF8:I76V) (Fig. 1c–f; Supplementary Fig. S2) — which characterize BA.2.2.1, a new subvariant of the Omicron BA.2.2 family.
To determine whether BA.2.2.1 originated from Shanghai, we blasted our BA.2.2.1 sequences against SARS-CoV-2 genomes in the GSIAID database (published as of June 13th, 2022), and found 38 cases of BA.2.2.1. Of them, 6 were reported before the onset of the Shanghai outbreak at mid-late February 2022, whereas the other 32 were reported from the Anhui province of China after March 24th, 2022, when the Shanghai outbreak was already under way. It is noteworthy that the 6 earliest BA.2.2.1 genomes were, respectively, reported from Hong Kong Special Administrative Region (2), Canada (2), Japan (1), and USA (1), and in none of these regions BA.2.2.1 was the dominant circulating SARS-CoV-2 strain (Fig. 1c). Together, these observations suggested that BA.2.2.1 was one minor strain that originated outside of mainland China, which was imported to Shanghai.
On the other hand, while BA.2.2.1 accounted for most of the cases in this study, this was not so during the first 2–3 weeks of the recent outbreak. Between March 1st and March 9th, only half of the cases (5 out of 10) in our study were infected by BA.2.2.1, whereas the other half were infected by BA.2.2 without the linked C26789T (M:G89G, synonymous) and A28119G (ORF8:I76V) mutations (i.e., non-BA.2.2.1 cases, heretofore referred to as BA.2.2). Only later the BA.2.2.1/BA.2.2 ratio gradually increased and BA.2.2.1 became the dominant strain by March 31st (Fig. 1g). This could be the fortuitous result that BA.2.2.1 accidentally outcompeted BA.2.2, for example, by escaping early non-pharmaceutical public health measures that limit their spreading in the community. An alternative, non-excluding, explanation could be that BA.2.2.1 was positively selected over BA.2.2 in the local population in Shanghai. Indeed, based on the published crystal structure of ORF8 (Fig. 1h; Supplementary Fig. S3), the A28119G (ORF8:I76V) mutation undermines a putative dimerization surface that potentially allows ORF8 interactions with host immune response factors7. Consistent with this, analysis of a panel of inflammatory factors indicated that IL-5, IL-6, IL-10, IL-12P70 were more significantly activated in the plasma of BA.2.2.1 cases (Supplementary Fig. S4). Moreover, we transduced plasmids expressing wild-type or I76V-mutated ORF8 into A549 cells (a lung epithelial cell line commonly used in the study of respiratory infections) and found that ORF8:I76V differentially upregulated expression of genes encoding the factors related to cytokine-mediated signaling pathways such as IL6, CXCL8, CCL20, and IL11, as well as ACE2, the host receptor of SARS-CoV-2 (Supplementary Fig. S5). These preliminary results suggested that ORF8:I76V might confer a transmission advantage to BA.2.2.1 via promoting expression of inflammatory factors for a more permissive immune response to the virus and/or facilitating the viral entry into the host cells. Of course, the precise molecular function of ORF8:I76V and its relationship with BA.2.2.1 infectivity and host immune responses require further in vitro and/or in vivo studies.
Taken together, our analyses indicate that BA.2.2.1 is a newly emerged Omicron BA.2.2 subvariant that shall be closely monitored given its detrimental role in driving the recent outbreak in Shanghai. It is noteworthy that between early February and late April 2022, Jilin, a province located at northeastern China, also experienced a large wave of SARS-CoV-2 infections, with over 60,000 laboratory-confirmed cases and 3 deaths. Preliminary analysis of 20 genome sequences obtained from the Jilin cases (unpublished) indicates that they were of the Omicron BA.2.1 subvariant. Thus, at least two independent Omicron subvariants were responsible for recent large-scale COVID-19 outbreaks in China in the spring of 2022. It is necessary to continuously monitor all variants, including the more recent BA.4/BA.5 subvariants8, in China at population and genome levels and assess their clinical manifestations.
Data availability
The data that support the findings of this study are available from the corresponding authors on reasonable request.
References
Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020).
Zhang, X. et al. Viral and host factors related to the clinical outcome of COVID-19. Nature 583, 437–440 (2020).
Telenti, A., Hodcroft, E. B. & Robertson, D. L. The evolution and biology of SARS-CoV-2 variants. Cold Spring Harb. Perspect. Med. 12, a041390 (2022).
Zhang, X., Zhang, W. & Chen, S. Shanghai’s life-saving efforts against the current omicron wave of the COVID-19 pandemic. Lancet 399, 2011–2012 (2022).
Chen, Z. et al. Epidemiological characteristics and transmission dynamics of the outbreak caused by the SARS-CoV-2 Omicron variant in Shanghai, China: A descriptive study. Lancet Reg. Health West. Pac. 29, 100592 (2022).
Shu, Y. & McCauley, J. GISAID: Global initiative on sharing all influenza data — from vision to reality. Eur. Surveill. 22, 30494 (2017).
Flower, T. G. et al. Structure of SARS-CoV-2 ORF8, a rapidly evolving immune evasion protein. Proc. Natl. Acad. Sci. USA 118, e2021785118 (2021).
Chinese National Health Commission. Transcript of the Press Conference of the State Council’s Joint Prevention and Control Mechanism on June 28, 2022. http://www.nhc.gov.cn/xcs/s3574/202206/31172e49d76b429089e71fa7c98f1dba.shtml (2022).
Acknowledgements
We thank the financial support from Double First-Class Project (WF510162602) of the Ministry of Education of China, State Key Laboratory of Medical Genomics, Overseas Expertise Introduction Project for Discipline Innovation (111 Project, B17029), the National Natural Science Foundation of China (82100158 and 81861148030), the National Key R&D Program of China (2019YFA0905902), the Natural Science Foundation of Shanghai (21ZR1480900 and 21YF1427900), Shanghai Clinical Research Center for Hematologic Disease (19MC1910700), Shanghai Major Project for Clinical Medicine (2017ZZ01002), Shanghai Shenkang Hospital Development Center (SHDC2020CR5002), Innovative Research Team of High-level Local Universities in Shanghai, and Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research (2019CXJQ01). We thank Prof. Wenbo Xu (Chinese Center for Disease Control and Prevention) for discussion.
Author information
Authors and Affiliations
Contributions
S.-J.C., X.F., S.-Y.W., S.C., and X.Z. jointly supervised the study. Y.L. and D.W. collected clinical samples. G.L., F.L., Y.T., and J.X. conducted bioinformatic analyses. S.W., S.Y., and F.J. conducted sequencing experiments. X.X. and Y.T. conducted the biological experiments. F.L., S.C., Y.T., S.-J.C., and G.L. wrote the manuscript. All authors reviewed and approved the final version.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Ling, Y., Lu, G., Liu, F. et al. The Omicron BA.2.2.1 subvariant drove the wave of SARS-CoV-2 outbreak in Shanghai during spring 2022. Cell Discov 8, 97 (2022). https://doi.org/10.1038/s41421-022-00468-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41421-022-00468-1
This article is cited by
-
Clustering analysis for the evolutionary relationships of SARS-CoV-2 strains
Scientific Reports (2024)
-
Prevalence of Neutralizing Autoantibodies Against Type I Interferon in a Multicenter Cohort of Severe or Critical COVID-19 Cases in Shanghai
Journal of Clinical Immunology (2024)
-
Lessons drawn from Shanghai for controlling highly transmissible SARS-CoV-2 variants: insights from a modelling study
BMC Infectious Diseases (2023)
-
Long-term oral ACEI/ARB therapy is associated with disease severity in elderly COVID-19 omicron BA.2 patients with hypertension
BMC Infectious Diseases (2023)
-
An expanded RT-PCR melting temperature coding assay to rapidly identify all known SARS-CoV-2 variants and sub-variants of concern
Scientific Reports (2023)