Coronavirus: What Do We Know About the Nature of SARS-CoV-2 Variants?

In this article

The vast majority of viruses are characterized by constant genetic evolution, which occurs at varying rates depending on the virus. This evolution results primarily from changes (mutations), additions (insertions), or deletions in their genetic code. For a virus like SARS-CoV-2, the emergence of variants over time is therefore an expected phenomenon.

During the pandemic, several SARS-CoV-2 variants have had a significant impact on public health (increased transmissibility, increased severity of infection, or immune escape). They are identified through risk assessments and designated as variants of concern (VOCs) when they exhibit such characteristics.

Variants of Concern (VOCs)

The first variants of concern (VOCs) emerged starting in late 2020 and were named after letters of the Greek alphabet (Alpha, Beta, Gamma, and Delta), as well as the Omicron parent lineage (B.1.1.529). Under the new WHO classification, they are currently considered non-circulating VOCs. To date, no lineage is classified as a VOC.

Variants of interest (VOI)

Other variants, carrying mutations that distinguish them from the reference viral strains of SARS-CoV-2, are also regularly identified, partly due to this increased sequencing capacity.
For some of these newly detected variants, their public health impact has not been formally demonstrated, but their virological, clinical, and/or epidemiological characteristics justify their classification as “variants of interest” (VOI).

In May 2021, the WHO assigned Greek letters to designate VOCs and VOIs. Since March 15, 2023, Greek letters have been assigned only to VOCs, while VOIs are designated using pre-established scientific nomenclature systems.

In France, Santé publique France and the National Reference Center for Respiratory Viruses jointly conduct regular “risk assessments.”

These analyses are based on national data (sequencing, including Flash surveys, RT-PCR screening results, and additional investigations) and international data (the international genomic database “Global Initiative on Sharing All Influenza Data” or GISAID, data from the scientific literature, documents produced by the WHO and the ECDC, etc.).

This analysis focuses on the various SARS-CoV-2 variants identified in France and internationally, based on available information regarding their spread and characteristics, virological functional analysis conducted in France—particularly by the CNR—and the WHO’s definition of variants. The system for classifying SARS-CoV-2 variants based on their potential public health impact was established by the WHO on February 25, 2021, and updated on March 15, 2023. This update better reflects the current global situation regarding variants, enables an independent assessment of circulating Omicron sublineages, and allows for a clearer classification of new variants, where applicable.

The criteria for classifying a variant are divided into several categories:

  • variant under investigation, or VUM ("variant under monitoring"): a variant characterized by genetic changes that may affect its characteristics AND:

    • early signs of a growth advantage BUT

    • uncertainties regarding its epidemiological and clinical impact

  • variant of interest, or VOI: a variant characterized by genetic changes with a possible or demonstrated effect on its characteristics AND:

    • an advantage in transmission in more than one WHO region associated with an increase in the number of cases or other epidemiological signals suggesting an increased risk to public health

  • Variant of Concern (VOC): a variant that meets the definition of a VOI and satisfies one of the following criteria:

    • increased severity OR;

    • a significant reduction in vaccine efficacy against severe disease OR;

    • changes in characteristics that may affect the capacity of healthcare systems to manage COVID-19 patients

Since classification as a VOC is based on the characteristics of the variants, VOCs that are no longer detected internationally are not downgraded but are considered “non-circulating VOCs.”

Impact of classification as a variant of concern, variant of interest, or variant to monitor

  • Variant of Concern (VOC): specific surveillance and management measures are implemented at the national level.

  • Variant of interest (VOI): The CNR Virus des infections respiratoires and Santé publique France implement enhanced national and international monitoring as well as specific virological analyses to assess their virological, clinical, and epidemiological characteristics.

Classification table of SARS-CoV-2 variants throughout France (mainland and overseas departments and regions), 09/09/24

Variants of Concern (VOC) Variants of Interest (VOI) Variants under monitoring (VUM)

JN.1 (24A-24B) 1
18%		 KP.3.1.1 (24C)
56%

KP.3 (24C)2
16%

KP.2 (24B)
5%

LB.1 (24A)
3%
Not detected in S33-2024

JN.1.7 (24A)
Not detected since Flash S27-2024

Risk analysis updated on 09/09/2024

Flash S33-2024 survey dated 08/12/2024 (latest consolidated data): 109 interpretable sequences.
The nomenclature has been adjusted according to the changes in the WHO classification as of 07/19/2024, described above.
Each classified lineage includes all its sublineages that are not subject to a specific classification.

1. JN.1.7, JN.1.18, KP.2, KP.3, KP.3.1.1, and LB.1 excluded
2. KP.3.1.1 excluded

View the risk assessments and characteristics of variants of interest to monitor

In addition to risk assessments, data on the circulation of SARS-CoV-2 variants obtained through Flash surveys are included in the national and regional epidemiological reports published on a regular basis. Each region provides feedback to its partners involved in SARS-CoV-2 variant surveillance.

Where can I find SARS-CoV-2 genomic surveillance data?

  • The consolidated results of Flash surveys #5 through #29 are available in the summary documents titled "Le point sur" posted on the website;

  • Starting with Flash survey #30, the results of Flash surveys considered sufficiently representative (more than 400 interpretable sequences or spanning more than 3 weeks) are available via the InfoCovidFrance dashboard (the "Variants" tab—data through 06/30/23), Géodes, and as open data on data.gouv.fr.

  • Since 10/04/22, indicators tracking the sequencing activity of the EMERGEN consortium have been available via the EMERGEN-DB dashboard;

  • National submission activity to GISAID (Global Initiative on Sharing All Influenza Data), to which EMERGEN network laboratories contribute for SARS-CoV-2, is available at: GISAID - Global Submission Tracker.

The nature of the variants circulating in the country and their potential impact in terms of transmissibility, virulence, or potential immune escape justifies the implementation of specific surveillance and management measures at the national level with the aim of containing their spread.

Santé publique France and its partners have established a comprehensive and responsive surveillance system for the COVID-19 pandemic and its variants, which has evolved over time. Until now, monitoring relied on two techniques: screening and sequencing. Since the repeal of the June 1, 2021, decree, which took effect on June 30, 2023, monitoring now relies solely on sequencing.

Immediate screening of positive samples following an RT-PCR test

The goal of screening was to identify mutations indicative of certain known variants within approximately 24 hours of the infection diagnosis. The results were reported to Santé publique France via the SIDEP information system and enabled the production of indicators that facilitated highly responsive monitoring of suspected cases of the main variants circulating in the country. These indicators were published daily on the InfoCovidFrance, TousAntiCovid, and Géodes dashboards, as well as in open data format on data.gouv.fr.

Since the emergence of the Omicron variant, significant genetic diversification has been observed, with the same mutations appearing independently in different sublineages. Screening is therefore no longer sufficient to track SARS-CoV-2 variants accurately.

Full sequencing of the viral genome from positive samples following an RT-PCR test

Sequencing is the gold standard method for confirming suspected variants. The goal of sequencing is to definitively characterize the type of variant responsible for the infection. It can identify any variant, known or unknown, by analyzing its genetic sequence. Sequencing thus makes it possible to detect any new variant and track its spread across the country, although this process takes longer than screening (7 to 14 days). Sequencing results are compiled at the national level through the EMERGEN Consortium.

Three complementary sequencing strategies are implemented:

  • Representative sequencing allows for the mapping, at a given point in time, of SARS-CoV-2 variants circulating in mainland France and the overseas departments and regions (DROM). It is organized as Flash surveys, repeated at regular intervals, which involve randomly selecting RT-PCR samples positive for SARS-CoV-2 for which the viral genome is sequenced. Flash surveys are a priority focus of the national genomic surveillance strategy coordinated by Santé publique France and ANRS|Emerging Infectious Diseases within the framework of the EMERGEN Consortium.

  • Targeted sequencing allows for the specific investigation of SARS-CoV-2 variants associated with a particular profile, which are of interest for individual patient care (treatment resistance, for example) or public health (vaccine failures, severe cases). Indications for targeted sequencing are defined by Santé publique France (for surveillance purposes) and by professional societies of microbiologists and clinicians (for patient care).

  • Interventional sequencing is an investigative tool that can be deployed at the request of national or local public health authorities, for example to investigate clusters or to strengthen surveillance of an emerging variant (by sequencing suspected cases). It also enables the investigation of a variant associated with a specific context.

Genetic variations of SARS-CoV-2 are monitored globally, and the sequences generated in each country are shared in international databases, including the GISAID (Global Initiative on Sharing Avian Influenza Data) database.

Further investigations

In addition to tracking the circulation of different variants, these data enable the identification of signals requiring investigation. In particular, when variants emerge for which available data are insufficient to assess their potential public health impact, the first French cases are investigated (clinical characteristics and progression, medical history, risk factors, vaccination status, etc.) to inform the need for specific measures. The results of these investigations are then published in Santé publique France’s COVID-19 epidemiological bulletins and/or variant risk analyses. Some of these investigations, which were conducted by positions funded by the European HERA project, are detailed on the project’s webpage.

Omicron: Enhanced Surveillance Across the Country

Closely monitoring the emergence of the Omicron variant, which appeared in France in 2021, is a major public health priority. Various methods for monitoring variants have been deployed to ensure this surveillance:

  • The screening strategy, which enables reactive monitoring, was adapted to track the Omicron variant in France starting in November 2021. Omicron did not carry any of the mutations included in the screening strategy at the time of its emergence in late November 2021 (E484K, E484Q, and L452R). While this screening profile (absence of the three target mutations) was not specific to Omicron, it was a minority profile, and changes in its proportion allowed for estimating the spread dynamics of Omicron in France. This profile was therefore added to the indicators monitored daily by Santé publique France and, as of January 6, 2022, made available as open data on the Géodes platform and on data.gouv.fr.

  • Since the profile characterized by the absence of the three mutations included in the screening was not found exclusively in Omicron, a complementary screening strategy was implemented. This strategy involved searching for several mutations more specific to the Omicron variant. The identification of one of these mutations was considered strong evidence of Omicron.

  • Confirmation of infection by a variant requiring a sequencing result was strengthened to closely monitor the first cases in the country. A major mobilization of the EMERGEN Consortium laboratories, which were asked to systematically and prioritized sequence suspected cases of Omicron infection (travelers returning from Southern Africa or absence of the three target mutations in screening), enabled the confirmation and identification of the first cases with significantly reduced sequencing times.

Thus, the first case of infection with the Omicron variant was confirmed by sequencing on November 30, 2021, by one of the sequencing laboratories of the EMERGEN Consortium in Réunion.

Genomic surveillance: a cornerstone of the fight against the COVID-19 pandemic

Genomic surveillance of SARS-CoV-2 is now one of the pillars of the fight against the COVID-19 pandemic at both the national and international levels. While certain RT-PCR “screening” tests identify the presence of specific mutations and have made it possible to suspect already known variants, whole-genome sequencing of the virus remains the only technique capable of confirming them, detecting emerging variants, and identifying the mutations that characterize them.

In France, this surveillance falls under the remit of the National Reference Center (CNR) for Respiratory Infections (Hospices Civils de Lyon) and its associated laboratories (Institut Pasteur, Institut Pasteur de la Guyane, and CHU de La Réunion); it is conducted in close collaboration with Santé publique France. However, the emergence of SARS-CoV-2 variants has made it necessary to supplement the sequencing capabilities already in place at the CNR with additional resources, in order to enable more precise and responsive monitoring of variant circulation across the country (EMERGEN Consortium).

What is the purpose of SARS-CoV-2 genomic surveillance?

  • To identify the proportion of different variants circulating in the country (nationally and regionally) in order to describe and track their circulation and evolution over time within the country (Flash survey).

  • To identify new variants through continuous analysis of the national database comprising sequencing results and associated metadata, regardless of their source (surveillance, clusters, reinfection, etc.)

Who are the key players?

  • Four laboratories of the CNR Respiratory Infections Virus (CNR Link): virology platforms, two of which have high-throughput sequencing capabilities, that centralize and analyze samples for surveillance-focused sequencing (Flash surveys). The CNR is also responsible for conducting the virological characterization of newly identified variants when it is necessary to assess their potential risk to public health.

  • The EMERGEN Consortium (Consortium for Surveillance and Research on Infections Caused by EMERgent Pathogens via Microbial Genomics).