FRANCE: Risk analysis on emerging variants of SARS-CoV-2 – B.1.640 and B.1.640.2

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In the last two weeks, the French authorities and WHO not only reclassified and upgraded the B.1.640 as a VOI or variant of interest but have also placed alerts on the B.1.640.2 variant as both variants were also found to be also spreading to other countries.
 
It was reported that for the B.1.640 variant, more than 500 new cases has been on the French mainland with cases also discovered in the UK and Germany. Other countries in Europe, from Africa, Asia and North America, have also detected this variant, which could suggest an onset of diffusion.

Public Health France and the National Virus Reference Center for Respiratory Infections jointly and regularly carry out a risk analysis of the different variants of SARS-CoV-2 identified in France and internationally, based on the information available on their dissemination.

The sources used for this risk analysis are as follows: data from the EMERGEN consortium including Flash surveys (see dedicated page on the SpF website ), results of RT-PCR screening, international virological database “Global Initiative on Sharing Avian Influenza Data” (GISAID). For more information on the definition of variant categories, refer to the risk analysis of 28/07/2021 .

The next update of the risk analysis is scheduled in 4 weeks, unless the evolution of the situation justifies an earlier update.

  1. Key points of the risk analysis dated 05/01/2022Several highlights should be noted in this update of the risk analysis related to emerging variants of SARS-CoV-2:Ranking of variants (Table 1):
    • To date, 5 variants are classified as VOC, 3 as VOI and 2 as VUM Changes compared to the previous risk analysis:
    • Variant 20A/C (B.1.640) is now classified as a VOI; this ranking is due to the pursuit ofits circulation in France and to preliminary in vitro data indicating a decrease in the effectiveness of neutralization by vaccine or post-infection antibodies and therefore a possible escape from the immune response.Surveillance by screening for mutations of interest:
    • The screening strategy evolves over time to search for mutations of interest that can be found in the circulating variants. From 20/12/2021, it has been adapted to more specifically follow the VOC Omicron;
    • The proportion of positive samples screened with the L452R mutation (carried mainly by the Delta variant) is decreasing, with 25.9% in week 52 (vs. 57.1% in week 51);
    • In week 52, the proportion of samples screened A0C0 (carrying neither E484K nor L452R) increased significantly (74% vs 42% in week 51), with regional disparities;
    • The search for code D mutations (DEL69/70, K417N, S371L-S373P or Q493R), which are more specific to Omicron, is still being deployed in laboratories and its results must be interpreted with caution. In week 52, 114,476 results indicated the presence of one of Omicron’s target mutations (coded D1), i.e. 76% of interpretable results (vs. 53.5% in week 51).Epidemiology and public health impact of variants of concern (VOC), to be monitored (VOI) and under investigation (VUM)
    • Sequencing data confirms a rapid increase in the distribution of VOC 21K/L/M Omicron (B.1.1.529, BA.*) in metropolitan France: it represented 10.7% of interpretable sequences in the Flash survey of 13 /12/2021 and nearly 50% of those of 20/12/2021. This rapid development is observed in other countries, particularly in Europe. As of January 3, 2022, the Omicron variant has been detected in all regions of mainland France and overseas;
    • International studies confirm an advantage of Omicron over Delta in terms of transmissibility . Vaccine efficacy against infection (37 to 86%), hospitalization (70 to 88%) and severe forms (98%) seems to be maintained against Omicron after administration of a booster dose. The preliminary analyzes conclude that the risk of hospitalization is reduced for Omicron compared to the other variants (up to 81%), but these data should be interpreted with caution because the cases of infection with Omicron are still mainly in a young population, and therefore less at risk;
    • Following its emergence observed in France at the end of November 2021, an investigation was carried out to describe the characteristics of the first detected cases of infection by Omicron . Confirmed cases were investigated by the regional units of Public Health France and the Regional Health Agencies, in conjunction with the clinicians who took charge of the cases. As of 04/01/2022 at 12 p.m., 338 confirmed Omicron cases have been investigated in mainland France and in the Overseas Territories;
    • The VOC 21A/I/J Delta (B.1.617.22, AY*) was still identified in 89% of the interpretable sequences of the Flash survey of 13/12/2021 and 50% for that of 20/12/2021, this proportion seems to be rapidly decreasing;
    • The circulation of the 20A/C variant (B.1.640) continues in metropolitan France, with 0.6% for the Flash survey of 13/12/2021. Several cases have also been detected in Reunion.

      Table 1: Classification of variants on 05/01/2022 and detection in mainland France in Flash surveys
Update of the risk analysis carried out on 05/01/2022. 
The data given concerns metropolitan France. 
The WHO nomenclature assigned to certain variants is added in parentheses (Greek alphabet). 
* indicates inclusion of all known sublineages at this point. 
Flash S50 survey conducted on 12/13/2021: data on 3399 interpretable sequences.
  1. Knowledge available on VOCs, VOIs and VUMsThis chapter presents the new data available on the characteristics and public health impact of VOCs, VOIs and MUVs.
    • Variant Ranking Changes
      The 20A/C variant (B.1.640) has been classified VUM following the preliminary risk analysis of 12/11/2021 . Since then, its circulation on the national territory has been maintained, and it has been detected in all metropolitan regions except Corsica, as well as in Reunion. While its detection frequency during the Flash surveys remains below 1%, it has increased between the Flash S43 and Flash S50 surveys. B.1.640 is still detected in France despite the emergence of Omicron.In vitro workwere conducted by the National Reference Center for Respiratory Infections Viruses to assess the effectiveness of neutralizing antibodies against B.1.640. The tests carried out are pseudotype neutralization studies using sera from previously infected persons, sera from vaccinated persons or monoclonal antibodies, comparing B.1.640 to Delta and the Wuhan strain. These data showed a neutralization of B.1.640 by the antibodies of subjects infected with the Wuhan virus or the Alpha, Beta, Gamma or Delta variants when the antibody levels are high. The antibodies produced after a single dose of vaccine did not induce any neutralization of B.1.640, whatever the vaccine. One month after the second dose, a decrease in neutralization was observed for B.1.640 compared to Delta. Among the monoclonal antibodies tested, no neutralization by Bamlanivimab was observed and Etesivimab or the Bamlanivimab/Etesivimab combination induced less good neutralization of B.1.640 compared to Delta, whereas neutralization was similar for Casirivimab, Imdevimab or their combination (Regeneron). These results areto be interpreted with caution due to the small number of subjects and sera analyzed, and additional analyzes are planned to confirm these results. However, they suggest a decrease in the neutralization of B.1.640 by antibodies post-infection or post-vaccination , in relation to the mutations and deletions identified in protein S.The continued circulation of B.1.640 in France, as well as its potential to escape the immune response post-infection or post-vaccination, justify its classification as a VOI .
    • VOC Alpha, Beta, Gamma and DeltaDuring the summer of 2021, VOC Alpha , Beta and Gamma declined sharply globally in favor of VOC Delta, even in the regions in which they were in the majority (Europe and South America for Alpha, South Africa for Beta, South America for Gamma) (1-3). Delta remained ultra-majority in the world until the emergence of the VOC Omicron, to then see its prevalence decrease rapidly from 98% at the beginning of December 2021 to 30% at the end of December. On average, Delta represented 71% (370,620 / 524,158) of the sequences deposited on GISAID during the month of December 2021. Alpha (n=17), Beta (n=3) and Gamma (n=14) did not been only slightly detected over the same period. For more information on the characteristics of these variants, refer to Tables 5, 6 and 7 of the risk analysis of 07/28/2021 .
    • VOC Omicron 2.3.1.International dataClassificationThe VOC Omicron was initially defined as belonging to clade 21K (according to Nextstrain classification) and lineage B.1.1.529 (according to PANGOLIN classification). For more information on these different classifications, refer to the risk analysis of 02/06/2021 . Since 01/12/2021, the lineage B.1.1.529 , has
      been divided into two sub-lineages, BA.1 and BA.2, BA.1 being the majority lineage and BA.2 sequences having been identified in South Africa, Canada, Denmark and Australia (4). The BA.3 sublineage was defined in mid-December 2021, with sequences detected in the UK and South Africa (5). The Nextstrain classification has also adapted to this diversification of Omicron sequences: on 12/17/2021, the 21K clade was reassigned to the BA.1 sublineage, the 21L clade was defined to correspond to the BA sublineage. 2, and clade 21M includes the entire B.1.1.529 parental lineage (6). The BA.3 sublineage is currently too rare to justify the assignment of a specific clade. For this risk analysis, the different clades sub-lineages of the VOC Omicron are analyzed as a whole, without distinction between them, under the nomenclature “Omicron 21K/L/M (B.1.1.529, BA.*) ”.
      TransmissionSince the last risk analysis, international analyzes have confirmed that Omicron has a growth rate up to 3.7 times higher than Delta (7). This growth rate may reflect intrinsic factors of the virus, responsible for higher transmissibility, but is also impacted by the epidemiological context in which this variant circulates. In particular, the vaccination coverage and the escape properties of Omicron have a significant impact on its circulation, and therefore on the growth rate (7). Based on in vitro studies, Omicron exhibits fundamental changes in the molecular mechanisms of cell entry and fusogenic potential (8-10). These differences could affect the replication properties of SARS-CoV-2, in particular its cell tropism, and therefore have an impact on the transmissibility and severity of Omicron.One of the factors affecting the transmissibility of a variant being the viral load in the airways, several studies have focused on the values ​​of Ct (“Cycle threshold”, cycle threshold in PCR, value inversely correlated to the viral load). While a Danish study observed no difference in Ct values ​​between Delta and Omicron (7), a French study observed higher Ct values, and therefore a lower viral load, for Omicron (11). The use of Ct values ​​as an indicator of transmissibility, however, remains imprecise, as they vary according to the period of infection where the sample was taken, the sampling method and the type of analysis. If the French data is confirmed, the overall Ct value would not have a major impact on the transmissibility of Omicron. A preferential location in the upper airways, a possible lower infective dose, immune evasion and the epidemiological context could play a more important role.
      Vaccine efficacyAfter two doses, vaccine efficacy against Omicron is greatly reduced or absent, and further decreases with time after the second injection. A booster dose is necessary to restore neutralizing antibody titers and reduce the risk of infection (vaccine efficacy between 37 and 86%) (8, 12-14), hospitalization (vaccine efficacy between 70 and 88%) (15, 16) and severe form (98% vaccine efficacy) (14). It has also been shown that the protection against Omicron induced by a previous infection (without vaccination) was higher than that induced by a complete vaccination (two doses) but lower than that induced after a booster dose (three doses) (8) . Additional data is needed to estimate the duration of protection against hospitalization,While neutralizing antibody titers are often used as a proxy for protection against infection, the cellular immune response, particularly the T response, plays a critical role against viral infections. Several studies suggest that a robust T response against Omicron is maintained after vaccination or a previous infection, by approximately 80%, despite the absence or reduction in the level of neutralizing antibodies (17-20). This T response would also contribute to the protection against the severe forms caused by Omicron, which corroborates the first clinical observations made in South Africa and the United Kingdom.
      SeveritySeveral studies have observed a lower risk of hospitalization in cases infected with Omicron compared to Delta, with up to 81% reduced risk of hospitalization after three doses of the vaccine (16). Similar results have been published in the United States and Canada, with a 67–83% lower risk of ICU admission (21, 22). A study from Hong Kong showed that Omicron infects bronchial cells faster but less efficiently lung cells compared to Delta, which could be a factor in lower pathogenicity and/or increased transmissibility (23). Several studies on animal models also support a lower severity of infection with Omicron (24-26). Indeed, these data showed a less severe clinical presentation,Two studies conducted in South Africa compared the Omicron-dominant wave to previous waves. They observed during the Omicron wave fewer hospitalizations, less severe cases and a shorter length of hospital stay (3 days versus 7-8 days) (27, 28). But this Omicron wave affected a younger population with fewer comorbidities than previous waves, which could contribute to this low hospitalization rate.Although a lower risk of hospitalization in patients infected with Omicron seems to be confirmed, it is still too early to conclude that this variant is intrinsically less virulent. Indeed, these severity data are impacted by the characteristics of the population in which it circulates , in particular risk factors and pre-existing immunity. Also of note is a possible bias at the start of the waves, when the number of hospitalized individuals is low, with the admission of patients with mild symptoms as a precaution and the diagnosis of SARS-CoV-2 infection from incidentally in patients admitted for other reasons.
      International epidemiological situationAs of 05/01/22 at 2 p.m. , 149,363 cases of Omicron have been submitted to the international GISAID database (Figure 1). The largest number of sequences deposited in GISAID was reported in the United Kingdom (72,460), the United States (43,699), Denmark (8,185), Australia (2,661) and Germany (2,400). ). The peak in South Africa seems to have been exceeded (29). These figures should be interpreted with caution, however, as the increased scrutiny Omicron has been subject to during its emergence in Europe may have resulted in sampling bias. Representative genomic surveillance data, however, confirm a dominance of Omicron in South Africa, the UK and Denmark.
Figure 1: The proportion of Omicron cases among the total number of sequences deposited on GISAID, by country. 
Data from  03/01/2022 in https://cov-spectrum.org/ .

French data

Following its emergence observed in France at the end of November 2021, an investigation was carried out to describe the characteristics of the first detected cases of infection by Omicron. The investigation, initiated with each confirmation of a case after sequencing by one of the laboratories of the EMERGEN consortium, was carried out by the regional cells of Public Health France in collaboration with the Regional Health Agencies. It aimed to describe the characteristics of the first cases, in particular the clinical signs associated with the infection, risk factors, history of infection, vaccination status and outcome of the patient (hospitalization and death). The aim was to include at least the first twenty cases identified in each region. The survey was carried out by questioning the cases, where necessary with the clinicians providing care. This is a simple descriptive survey, with no objective of comparing the characteristics of Omicron cases to those of cases of infection by other variants,

As of January 4, 2022 , 338 cases of Omicron have been investigated , including 105 (31%) in Île-de-France; the regional distribution does not reflect that of all Omicron cases in each region. Sampling dates ranged from November 21 to December 20, 2021. Sign onset dates ranged from November 22 to December 27, 2021 (median date December 7). The survey of the cases was carried out on average 9 days away from the date of onset of the signs, which invites us to read with caution the results on hospitalization, resuscitation, and vital status, which are potentially underestimated.


Table 2: Characteristics of French Omicron cases included in the study (N=338), as of 04/01/2022

Case of Omicron
not%*
Age category (n=320)0-9113%
10-1493%
15-19196%
20-2910031%
30-397423%
40-494815%
50-644614%
65+134%
Duration of signs (days)min1n / A
max30n / A
median4n / A
Clinical signs (n=246);a case may present several signsAsthenia14559%
Cough13254%
Fever11848%
Headaches10643%
Myalgia9739%
Sore throat7430%
Runny nose6526%
Feeling of fever3213%
Shortness of breath229%
Anosmia229%
Ageusia229%
Diarrhea187%
Nausea/ Vomiting146%
Dyspnea73%
Hospitalization (n=225)Yes52%
No22098%
Not specified113n / A
Duration of hospitalization (days)min1n / A
max14n / A
Presence of risk factor (n=260)Yes3413%
No22687%
Not specified78n / A
Notion of travel (n=301)Yes9732%
No20468%
Not specified37n / A
Vaccination status (n=261)Vaccinated with 1 dose135%
Pfizer125%
Moderna00%
A-Z00%
Janssen00%
Vaccinated with 2 doses17567%
Pfizer14254%
Moderna114%
A-Z62%
Janssen00%
Vaccinated with 2+ booster dose125%
Pfizer114%
Moderna00%
A-Z00%
Janssen00%
Not vaccinated6123%
Not specified77n / A
History of COVID (n=258)Yes3413%
No22487%
Not specified80n / A

* The proportions are related to the completed questionnaires n/a – not applicable

The age of the cases ranged from 2 months to 91 years (median: 32 years) and 55% were female. A total of 97 cases had a notion of travel (including 22 from South Africa). In addition, 175 cases (67%) had received a complete primary vaccination and 12 cases (5%) had received a booster dose. The effectiveness of the booster dose against Omicron may explain the low proportion of cases investigated who received a booster dose. However, the majority age group of these cases (on average younger), who were vaccinated later, was not yet necessarily eligible for the booster dose.The majority of cases were symptomatic (89%, out of 317 cases for which this indication was provided), and reported mostly mild symptoms (Table 2). 

Weakness, cough, fever, headache, myalgia, sore throat or runny nose were the most commonly reported symptoms. This mild clinical presentation may be related to the age of the cases and the low proportion of cases with risk factors (34, or 13%). The duration of signs ranged from 1 to 30 days (median 4 days). Thirty-four cases (13%) had at least one risk factor and 30 of them were symptomatic. Thirty-four cases (13%) had a history of SARS-CoV-2 infection and 31 of them were symptomatic. Only 5 cases were hospitalized (2%), including none in intensive care. Among these 5 cases, 3 were not vaccinated (including one reporting a previous infection), one had received a booster dose and no information was available on the last case. 

These cases were between 26 and 71 years old, and two had risk factors (both unvaccinated). One hospitalized case had presented signs for 15 days (including fever, asthenia, myalgia/body aches, headache, cough, nausea/vomiting and arterial hypotension) and presented with neuromuscular pathology.These preliminary results must be interpreted with caution because the survey scheme put in place does not allow for longitudinal follow-up of the future of patients, since certain data are still being collected. They suggest however that the cases of infection by Omicron thus described are in great majority not severe. They will need to be confirmed on the basis of consolidated data and compared with the characteristics of infections by other variants in circulation, such as Delta or B.1.640.

VOI Lambda, Mu and B.1.640 Lambda and Mu VOIs were detected very little in France (14 and 27 sequences identified during the Flash#11 to Flash#22 surveys, respectively). The prevalence of these two VOIs has strongly decreased worldwide (12 and 10 of the 524,158 sequences deposited on GISAID between 01/12/2021 and 31/12/2021, respectively).A total of 437 sequences of VOI B.1.640were deposited in the international database GISAID on 05/01/2022, of which 72% come from France (315). The other countries that have identified this virus are the Republic of Congo (N=40), the United Kingdom (N=21) and Germany (N=19). 

However, other countries in Europe, Africa, Asia and North America, some of which have limited sequencing capabilities, have detected this variant, which could suggest an onset of dissemination. The identified B.1.640 sequences mostly correspond to the B.1.640.1 sublineage. Among these 437 sequences, 21 carry the E484K mutation, characteristic of the B.1.640.2 subline (ie 4.8%, according to GISAID data) (30). If the E484K mutation has an impact on the escape of the immune response, too few cases have currently been detected to draw conclusions on the characteristics of B.1. 640.2 over B.1.640.1. In this risk analysis, no distinction will be made between these two sub-lineages.2.5. VUM B.1.1.318 and C.1.220B (B.1.1.318) and 20D (C.1.2) are currently very little detected in France and internationally (1 and 3 sequences deposited on GISAID between 01/12/2021 and 31/12/2021 , respectively).

Evolution of the detection of mutations of interest targeted by screening in France

Adaptations of the screening strategyWhen they were set up, the RT-PCR screening tests made it possible to suspect the presence of VOC Alpha and not distinctly from VOC Beta or Gamma . Since 05/31/2021, the screening strategy has evolved to search for certain mutations of interest that can be found in different variants. It therefore no longer makes it possible to assign the infection with certainty to a specific variant but makes it possible to follow the evolution over time and in the territory of the proportion of infections due to a virus carrying these mutations.For the first phase of deployment, the E484K, E484Q and L452R mutationswere selected because they were potentially linked to immune escape and/or increased transmissibility. 

The combination of these mutations may allow certain variants to be suspected, but sequencing is necessary to confirm this. Due to the rendering of the results of these PCRs in shorter delays than sequencing, specific measures can be implemented as soon as cases carrying mutations of interest are detected in order to slow down their dissemination (reinforcement of contact tracing, targeted screening or vaccination campaigns). Screening results for these three mutations are submitted in the SI-DEP database under nomenclature A (E484K), B (E484K) and C (L452R). 

For these three indicators, the absence of the mutation sought is noted 0 and its presence is noted 1.Following the emergence of the VOC Omicron, an evolution of the screening doctrine has recently been initiated. More than 99% of the Omicron variants not presenting any of the 3 mutations mentioned above, a reinforced follow-up of the A0B0C0 screening results (carrying neither E484K nor E484Q nor L452R) was first set up. But this mutation profile not being specific to Omicron, a new variable Dwas included in the SI-DEP database. This variable D combines several mutations carried by Omicron. The indication D1 corresponds to the identification of one or more of these mutations and D0 to the search and the absence of identification of one or more of these mutations.

 Between 11/29 and 12/19/2021, variable D included the 69/70 deletion and the N501Y and K417N mutations. As of 12/20, variable D includes deletion 69/70 and substitutions K417N, S371L-S373P and Q493R. Since the same date, the E484Q mutation (variable B) is no longer screened for, and enhanced monitoring of the A0C0 results has been put in place.The presence of the 69/70 deletion or the K417N, S371L-S373P or Q493R substitutions (D1 results) must however be interpreted with caution, as they are also carried by other variants. 

In addition, some laboratories were carrying out in December 2021, in the initial phase of deployment of this new strategy, screens for these four D mutations only for certain ABC screening results, which could distort the relative proportions of D0 and D1. This is why, currently still, the proportion of A0C0 (carrying neither E484K nor L452R) is the preferred indicator for monitoring the presence of Omicron.From 06/01/2022, the data available in OpenData on GEODES and data.gouv will integrate this new screening strategy.

Indications A, B and C: E484K, E484Q and L452R mutationsThe knowledge available on the impact of each of these three mutations, as well as the list of VOCs, VOIs and VUMs that carry these mutations, are indicated in Table 2 of the risk analysis of 08/25/2021.

The proportion of detection of the E484K mutation has remained at very low levels since the beginning of August; it was 0.1% in S52 among all the interpretable screened tests for this mutation (according to the data in the old ABC nomenclature);

The share of positive tests for the E484Q mutation has fluctuated since spring 2021 but remains low (<2%). It was 0.6% in S52 among all the interpretable screened tests for this mutation (according to the data in the old ABC nomenclature);

The proportion of detection of the L452R mutation , present mainly in Delta, has been decreasing rapidly since week 50. It was 25.9% in W52 against 57.1% in S51 (according to the data in the new ABCD nomenclature).Omicron does not carry any of the mutations included in the screening strategy formerly deployed in France, and therefore has a profile named A0B0C0 in the SI-DEP database (Figure 2). The rapid increase in the proportion of A0B0C0 since week 49 highlights the increasing circulation of Omicron. An analysis of screening data from a French laboratory from 25/10 to 18/12/2021, in particular A0B0C0 profiles, has been published (11). 

Based on approximately 130,000 PCR results, this study uses screening results as a proxy for circulating variants (A0B0C1 for Delta, A0B0C0 for Alpha, Omicron or an ancestral variant, A1B0C0 for Beta or Gamma). At the end of November 2021, A0B0C0 had a 50% transmission advantage over A0B0C1, an advantage that increased to 105% in December 2021. The viral load of A0B0C0 samples was lower than that of A0B0C1 (Ct of 24.9 vs. 23.4). 

Different epidemiological models suggest that, even if the reduced severity of Omicron is confirmed, its increased transmissibility risks critically affecting French hospital capacities. With the current modification of the screening doctrine, these nomenclatures will change between now and the next risk analysis, with a discontinuation of the monitoring of the E484Q mutation (coded B).In W52, the proportion of A0C0 samples increased significantly (74% or 259,794 results, vs 42% in W51), with regional disparities. In metropolitan France, the proportion of A0C0 varied according to the regions between 51% (Provence-Alpes-Côte D’Azur) and 90% (Ile-de-France).

The proportion of A0C0 is also increasing in Guadeloupe, Martinique and Reunion, even if it remains lower than in mainland France. Conversely, the proportion of positive samples screened with the L452R mutation (mainly carried by the Delta variant) continues to decrease throughout the country, with 25.9% in S52 (vs 57.1% in S51).

Figure 2: Number of samples positive for SARS-CoV-2 screened A0B0C0 (absence of E484K, E484Q and L452R mutations in the Spike protein, red curve) and percentage of A0B0C0 samples among the samples screened (blue curve), by week of collection, in mainland France and in the DROMs (source: SIDEP, as of 05/01/2022).
    • Indication D: 69/70 deletion or substitutions K417N, S371L-S373P or Q493RThe analysis of the results concerning the specific mutations of Omicron (code D) must currently remain very cautious given the progressive deployment of the new screening strategy in the laboratories, especially since these mutations were initially searched for in two stages (preferably on A0C0 samples) in certain laboratories; their proportion is therefore overestimated but trends can be informative. Thus, 114,476 results indicated in S52 the presence of one of Omicron’s target mutations (coded D1), ie 76% of the interpretable results (vs. 53.5% in S51).
  1. Evolution of the detection of VOCs, VOIs and MUVs in France in the context of genomic surveillance
    • In FranceSince the summer of 2021, the VOC Delta (21A/I/J, B.1.617.2 and AY.* ) has been the dominant variant in mainland France, where it has replaced the VOC Alpha (Table 3, Figure 3 and 4) . However, since the detection of the VOC OmicronMetropolitan France at the end of November 2021, we observe an increase in the proportion of this variant to the detriment of VOC Delta. While the Omicron VOC had never been detected during Flash surveys until Flash S47 (11/22/2021), it accounted for 0.2% of interpretable sequences for Flash S48 (11/29), 1.4 % for Flash S49 (06/12), 10.7% for Flash S50 (13/12) and 49% for Flash S51 (20/12). However, for unconsolidated weeks, the proportion of Omicron VOC may be overestimated due to the attention it receives and possible sequencing prioritization of suspected cases. This bias is more marked for the data for all sequencing indications combined (Figure 3) compared to the Flash surveys (Table 3). The Omicron sequences identified in France mainly correspond to the BA.1 sub-lineage, with only three BA.2 sequences and no BA.3. The VOC Beta and Gamma have not been detected during Flash investigations since Flash #24 (09/14/2021). A case of VOC Alpha was detected during Flash S49 (06/12/2021, <0.1% of interpretable sequences).

Table 3: Detection of variants during Flash S47 – Flash S51 surveys, metropolitan France. * indicates inclusion of all known sublineages at this point.

Number of interpretable sequences: Flash S47: 4883; Flash S48: 5702; Flash S49: 4749; Flash S50: 3399; Flash S51: 922* Flash S50 and Flash S51 data is preliminary
Figure 3: Evolution of the share of each VOC, VOI and VUM per sampling week, all sequencing indications combined, metropolitan France (source: EMERGEN, as of 12/03/2021 
at 12 p.m. ). 
Data for weeks 2021-W50 and 2021-W51 are preliminary
Figure 4: Distribution of Omicron sequences by department of residence (source: EMERGEN, as of 
03/01/2022 at 12 p.m. )

The Lambda VOI has not been detected since Flash #16 (07/20/21). The VOI Mu (21H, B.1.621 and B.1.621.1), was first detected during Flash #14 (06/07/21) during which it represented 0.5% of the sequences. Since then, this variant represents less than 0.1% of sequences from Flash #15 to Flash #22 and has not been detected since Flash #23. All sequencing indications combined, the VOI Mu has not been detected since week 37.

The 20A/C variant B.1.640, classified as VOI from 05/01/2022, continues to circulate in metropolitan France: it represented 0.5% of interpretable sequences for Flash S48 (29/11) and S49 (06/12), 0.6% for Flash S50 (12/13, Table 3). VOI B.1.640 has been detected in 12 of the 13 regions of mainland France since the beginning of October 2021 (Figure 5). The regions where the most cases have been identified are Hauts-de-France (N=189, in particular the Nord department), Île-de-France (N=185) and Normandy (n=152, Figures 5 and 6). A full update on the characteristics of cases infected with VOI B.1.640 is available in the risk analysis update of 15/12/2021 .

Figure 5: Number of sequenced samples classified as VOI B.1.640, by region and by week of sampling (source: EMERGEN, at 
03/01/2022 at 12 p.m. )
Figure 6: Distribution of B.1.640 sequences by department of residence (source: EMERGEN, as of 
03/01/2022 at 12 p.m. )
    • VUM 20B (B.1.1.318) has never been detected frequently in Flash surveys (a peak of 0.5% during Flash #12) and accounts for less than 0.1% of sequences since Flash# 16 (7/20/21). VUM 20D (C.1.2) has not been detected in France to date.
    • In the DROMsThe screening data indicate the decrease in the detection of VOC Delta compared to VOC Omicron in all DROMs. In S52, the proportion of screening tests positive for the L452R mutation (mainly carried by Delta) was 80% in Reunion, 35% in Martinique, 29% in Guyana and 23% in Guadeloupe. In Guyana, Mayotte, Saint-Barthélemy and Saint-Martin, Omicron already seems to be largely in the majority, with 69%, 91%, 82% and 94% of A0C0 screenings in week 52, respectively.During the summer of 2021, Delta quickly replaced the variants that were predominant in these territories (Alpha in the Antilles, Beta in Réunion and Mayotte, and Gamma in Guyana). Since week 40, Deltarepresents more than 95% of the sequences in Réunion and Guyana, and 100% of the sequences in Guadeloupe and Martinique (EMERGEN data as of 03/01/2022, all sequencing indications combined). The Flash S49 survey (12/13/2021) identified, for all DROMs, 99% of VOC Delta (out of 104 interpretable sequences). However, Omicron VOC is beginning to be detected in DROMs by sequencing (EMERGEN data as of 01/03/2022, all sequencing indications combined), and screening data support an increase in Omicron detection in the DROMs. In the West Indies, 3 cases of infection by Omicron were detected in Martinique in week 50 outside the Flash survey, and other suspected cases are being sequenced. In Guyana, no Omicron VOC sequences were detected during Flash surveys but 49 cases were identified under other sequencing indications during weeks 50, 51 and 52. In Réunion, 9 Omicron VOCs were identified by sequencing, including two within the framework of the Flash surveys (Flash S47 and Flash S49). VOI B.1.640 was also detected in Réunion, with three cases in total, including one case identified as part of the Flash S43 survey (25-29/10/2021).
  1. Conclusion as of 05/01/2022

The past few weeks have seen a global shift in the circulation of variants , both domestically and internationally. Since summer 2021, VOC Delta was the dominant variant in France and worldwide, but VOC Omicron 21K/L/M (B.1.1.529, BA.*) , which emerged in southern Africa in November 2021 , demonstrated a competitive advantage over Delta. Its circulation is progressing very rapidly worldwide as well as in France, where it was detected in all regions of metropolitan France and the DROMs one month after the detection of the first cases. Omicron already accounted for more than 10% of cases sequenced in random genomic surveillance on 12/13/2021 and almost 50% on 12/20/2021.

According to international studies, the competitive advantage of Omicron compared to Delta could come from a high transmissibility but above all from a greater escape from the immune response.. However, vaccine efficacy against symptomatic forms and hospitalizations seems to be maintained against Omicron after administration of a booster dose. The post-infection or post-vaccination cellular response, which remains effective against Omicron, could also provide protection against severe forms. Preliminary analyzes conclude that the risk of hospitalization is reduced for Omicron compared with the other variants, but these data should be interpreted with caution. Indeed, cases of infection by Omicron are still mainly detected in a young population, and therefore less at risk of developing serious forms. Moreover, even if this reduced risk of hospitalization in cases infected with Omicron is confirmed in the general population,

While the current epidemiological situation makes it likely that the other variants will be replaced by Omicron in the coming weeks, other variants are still circulating today . Delta VOC was still identified in 50% of cases sequenced the week of 12/20/2021, but this proportion is rapidly decreasing. Given the time between infection, onset of symptoms and hospitalization, it is possible that Delta still represents a significant proportion of severe forms currently hospitalized. The circulation of the 20A/C variant (B.1.640) continues in France, despite the emergence of Omicron. Preliminary in vitro dataproduced by the National Virus Reference Center for respiratory infections indicate a decrease in the effectiveness of neutralizing antibodies post-infection or post-vaccination, and therefore a possible escape from the immune response. Variant B.1.640 is therefore now classified as a VOI (variant to follow).

The current period seems to correspond to a transition period between the VOC Delta and the VOC Omicron. A follow-up of the situation in the coming weeks will make it possible to follow the dynamics of replacement and its geographical distribution. The increased transmission and greater immune escape of Omicron are two concerning features, despite preliminary data supporting less severity. The risk of saturation of the hospital system by cases of Omicron infection is real, and other variants are still circulatingcan also contribute to this saturation. The administration of a booster dose makes it possible to restore a certain level of protection against the symptomatic forms and especially against the severe forms of infection by Omicron . Continued vaccination efforts therefore remain necessary to reduce the circulation of Omicron and its impact on the healthcare system. In order to limit the circulation of SARS-CoV-2, whatever the variant, it is also necessary to reinforce the respect of barrier gestures and the follow-up of recommendations in the event of diagnosis of infection or close contact with a case.

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