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Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023

Haars et al., Microorganisms, doi:10.3390/microorganisms11102417
Sep 2023  
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21st treatment shown to reduce risk in May 2021
 
*, now with p = 0.00036 from 21 studies, recognized in 7 countries. Efficacy is variant dependent.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19early.org
Analysis of 7,950 SARS-CoV-2 samples from central Sweden collected between March 2022 and May 2023 tracking the prevalence of omicron sublineages and mutations in the spike protein conferring resistance to monoclonal antibodies over time. Authors found the dominant sublineages shifted from BA.2 to BA.5 and its descendants during mid 2022, then to more diverse mix of BA.2 and BA.5 sublineages and their descendants towards end of 2022 and into 2023. Notably, mutations such as R346T, K444T, and V445P became increasingly common, rendering current monoclonal antibodies ineffective for most patients in the region. The findings highlight the continued need to monitor evolving SARS-CoV-2 mutations and develop new monoclonal antibodies targeting conserved spike protein regions.
Efficacy is highly variant dependent. In Vitro research suggests a lack of efficacy for omicron1-5.
Study covers bamlanivimab/etesevimab, regdanvimab, casirivimab/imdevimab, sotrovimab, tixagevimab/cilgavimab, and bebtelovimab.
Haars et al., 27 Sep 2023, Sweden, peer-reviewed, 9 authors. Contact: johan.lennerstrand@medsci.uu.se (corresponding author), jonathan.haars@uu.se, johan.lindh@icm.uu.se, patrik.ellstrom@medsci.uu.se, rene.kaden@medsci.uu.se, n.palanisamy@chester.ac.uk, frans.wallin@regionorebrolan.se, paula.molling@oru.se, martin.sundqvist@oru.se.
This PaperBamlaniv../e..All
Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023
Jonathan Haars, Navaneethan Palanisamy, Frans Wallin, Paula Mölling, Johan Lindh, Martin Sundqvist, Patrik Ellström, René Kaden, Johan Lennerstrand
Microorganisms, doi:10.3390/microorganisms11102417
Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. In the present study, 7950 SARS-CoV-2 positive samples from the Uppsala and Örebro regions of central Sweden, collected between March 2022 and May 2023, were whole-genome sequenced using amplicon-based sequencing methods on Oxford Nanopore GridION, Illumina MiSeq, Illumina HiSeq, or MGI DNBSEQ-G400 instruments. Pango lineages were determined and all single nucleotide polymorphism (SNP) mutations that occurred in these samples were identified. We found that the dominant sublineages changed over time, and mutations conferring resistance to currently available mAbs became common. Notable ones are R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, such as the K444T and V445P mutations, were also observed in the samples. This study highlights that resistance mutations have over time rendered currently available mAbs ineffective against SARS-CoV-2 in most patients. Therefore, there is a need for continued surveillance of resistance mutations and the development of new mAbs that target more conserved regions of the RBD.
The repeated events of evolved resistance to mAbs means that the development of new mAbs and other antiviral treatments remains important for patients infected with SARS-CoV-2. The rapid increase in resistance to tixagevimab and cilgavimab highlights that these changes need to be communicated quickly by labs and scientists to the public. Therefore, the continued surveillance of SARS-CoV-2 through whole-genome sequencing is essential for understanding the evolution of the virus and for providing scientists, physicians, patients, decision makers, and drug manufacturers with correct and updated information for curbing this infection in the population. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/microorganisms11102417/s1, Figure S1 Author Contributions: Conceptualization, J.H., N.P. and J.L. (Johan Lennerstrand); methodology, J.H. and J.L. (Johan Lennerstrand); software, J.H. and R.K.; formal analysis, J.H.; investigation, J.H., F.W., P.M., P.E., R.K. and J.L. (Johan Lennerstrand); resources, J.L. (Johan Lindh), M.S. and R.K.; data curation, J.H. and F.W.; writing-original draft preparation, J.H.; writing-review and editing, J.H., N.P., F.W., P.M., P.E., J.L. (Johan Lindh), M.S., R.K. and J.L. (Johan Lennerstrand); visualization, J.H.; supervision, R.K. and J.L. (Johan Lennerstrand); funding acquisition, J.L. (Johan Lennerstrand). All authors have read and agreed to the published version of the..
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In the present study, 7950 SARS-CoV-2 positive samples ' 'from the Uppsala and Örebro regions of central Sweden, collected between March 2022 and May ' '2023, were whole-genome sequenced using amplicon-based sequencing methods on Oxford Nanopore ' 'GridION, Illumina MiSeq, Illumina HiSeq, or MGI DNBSEQ-G400 instruments. Pango lineages were ' 'determined and all single nucleotide polymorphism (SNP) mutations that occurred in these ' 'samples were identified. We found that the dominant sublineages changed over time, and ' 'mutations conferring resistance to currently available mAbs became common. Notable ones are ' 'R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab ' 'and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, ' 'such as the K444T and V445P mutations, were also observed in the samples. 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