SARS-CoV-2 and Omicron: the need to optimise genome surveillance and tracing – The BMJ

Dear Editor

The advent of the B.1.1.529 variant of SARS-CoV-2, now called Omicron, is bringing significant implications on the course of the COVID-19 pandemic.[1] While the questions on transmissibility, severity of infection and vaccine effectiveness are answered, the testing strategy for Omicron helds a pivotal role in the pandemic response, requiring urgent attention and optimization.

Whole genome sequencing (WGS) has been crucial in studying the evolution and genetic diversity of SARS-CoV-2 during the pandemic.[2] Further, WGS also played an important role in identifying the new variant Omicron which was categorized as a variant of concern (VOC) by WHO. Although whole genome sequencing (WGS) is the gold standard for genomic surveillance, it is not feasible to sequence every suspected case or contact of Omicron.[3]

Earlier, the Alpha version reported S gene target failure (SGTF) in RT-PCR and revealed that it had a considerable diagnostic value.[4,5] The recent South African investigations that led to the announcement of the new VOC Omicron also reported that SGTF was observed for more than 50% of all tested specimens, further recovering SGTF of the PCR assays as a proxy for the variant.[6] Notably, for early detection of the Omicron variant, WHO recommends using diagnostic test kits containing two confirmatory genes, at least one of which is the 'S' gene. As an internal control gene, the kits should ideally include RNaseP, Beta Actin, or any other human housekeeping gene.[1] Earlier, Thermo Fisher Scientific confirmed that its TaqPath Covid-19 test kits can detect Omicron variants with high accuracy. The TaqPath Covid-19 assays identify three gene targets from the orf1a/b, S and N regions of the virus to confirm SARS-CoV-2 infections.[7]

Therefore, SGTF during RT-PCR with kits that detect the S-gene has been used as a proxy test for the Omicron variant pending sequencing confirmation. Moreover, because several nations currently lack sufficient sequencing capacity, SGTF has been employed to screen suspected Omicron cases for WGS. The SGTF growth rate, which was used with the Alpha variant [5], can serve as a suitable surrogate for the level of Omicron community transmission.

However, the SARS-CoV-2 Omicron (B.1.159) lineage is now being proposed to be split into two sub-lineages: BA.1 and BA.2.8

While both lineages share a number of common defining mutations and appear to be co-circulating, the new recognised BA.2 sub-lineage does not carry the Spike del69-70 mutation which may hinder the use of commercially available PCR tests to diagnose Omicron based on S-gene target failure.[8,9]

In fact, recently sequenced cases belonging to the BA.2 sub-lineage have not been flagged by the aforementioned SGTF approach.[9]

Therefore, apart from the WHO's recommendation that a subset of SARS-CoV-2 confirmed cases be sampled for WGS, cases from unique transmission episodes, unexpected disease presentation or severity, vaccination breakthrough, critically ill patients, and overseas travellers should all be included, subject to local sequencing capacity.[1]

More importantly, Governments across the world will need to optimize the RT-PCR kits and their supply chain and adopt a balanced sampling strategy for WGS to confirm the B.1.1.529 variant.

In brief, although SGTF represents an effective testing strategy to contain Omicron through targeted contact tracing and isolation, the rapid evolution of the variants and the unfolding data regarding their genetic profile needs to be fully incorporated into the diagnostics tools if we are to succeed in our quest to conquer the idiosyncrasies of SARS-CoV-2.

All authors have contributed equally

Conflict of InterestNoneFundingNone

References1.WHO. Enhancing Readiness for Omicron (B.1.1.529): Technical Brief and Priority Actions for Member States. Nov 28, 2021 https://www.who.int/publications/m/item/enhancing-readiness-for-omicron-(b.1.1.529)-technical-brief-and-priority-actions-for-member-states (accessed on 03/12/2021)2.Umair M, Ikram A, Salman M, Khurshid A, Alam M, Badar N, Suleman R, Tahir F, Sharif S, Montgomery J, Whitmer S, Klena J. Whole-genome sequencing of SARS-CoV-2 reveals the detection of G614 variant in Pakistan. PLoS One. 2021 Mar 23;16(3):e0248371. doi: 10.1371/journal.pone.0248371.3.Liu T, Chen Z, Chen W, Chen X, Hosseini M, Yang Z, Li J, Ho D, Turay D, Gheorghe CP, Jones W, Wang C. A benchmarking study of SARS-CoV-2 whole-genome sequencing protocols using COVID-19 patient samples. iScience. 2021 Aug 20;24(8):102892. doi: 10.1016/j.isci.2021.102892.4.Migueres M, Lhomme S, Trmeaux P, Dimeglio C, Ranger N, Latour J, Dubois M, Nicot F, Miedouge M, Mansuy JM, Izopet J. Evaluation of two RT-PCR screening assays for identifying SARS-CoV-2 variants. J Clin Virol. 2021 Oct;143:104969. doi: 10.1016/j.jcv.2021.104969.5.Brown KA, Gubbay J, Hopkins J, Patel S, Buchan SA, Daneman N, et al. S-Gene Target Failure as a Marker of Variant B.1.1.7 Among SARS-CoV-2 Isolates in the Greater Toronto Area, December 2020 to March 2021. JAMA. 2021 May 25;325(20):2115-2116. doi: 10.1001/jama.2021.5607.6.European Centre for Disease Prevention and Control. Implications of the emergence and spread of the SARS- CoV-2 B.1.1. 529 variant of concern (Omicron), for the EU/EEA. 26 November 2021. ECDC: Stockholm; 2021.7.Medical Device Network. Thermo Fishers Covid-19 tests can detect Omicron variant. Nov 30, 2021 https://www.medicaldevice-network.com/news/thermo-fishers-covid-19-tests... (accessed on 03/12/2021)8.https://www.gisaid.org, accessed on December 22th9.European Centre for Disease Prevention and Control/World Health Organization Regional Office for Europe. Methods for the detection and characterisation of SARS-CoV-2 variants first update. 20 December 2021. Stockholm/Copenhagen; ECDC/WHO Regional Office for Europe: 2021

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SARS-CoV-2 and Omicron: the need to optimise genome surveillance and tracing - The BMJ