New Delta Sub-Variant Possessing Kappa’s S:E484Q Mutation And Iota’s S:T95I Mutation

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French researchers in a new study have identified a new Delta sub-variant that is of concern as it not only possess the unique mutation S:E484Q found on the Kappa variant but it also has the S:T95I mutation found on the Iota variant that is associated with breakthrough infections.

Alarmingly other mutations were also found on the new Delta sub-variant phylogenetic cluster including the following substitutions that are not found in most of the other Delta sequences ie: ORF1a:T403I, ORF1a:D1167N and ORF1b:A1219S.
 
More worrying was the fact that these new Delta-subvariants were associated with doubling times and transmission advantage.
 
The study findings were published on a preprint server in the last 36 hours and are currently being peer reviewed.
https://www.medrxiv.org/content/10.1101/2021.09.13.21263371v1
 
The French researchers from Laboratoire Cerba,  Université de Montpellier and Laboratoire de Virologie-CHU de Montpellier had been analyzing 92,598 variant screening tests performed on SARS-CoV-2 positive samples collected in France between 1 July and 31 August 2021.
 
The analysis showed an increase of Kappa-like infections but full genome sequencing revealed that most of these sequencings corresponded to Delta variants bearing the S:E484Q mutation.
 
Interestingly most of these sequences also belonged to a phylogenetic cluster and also bears the S:T95I mutation which has been associated with breakthrough infections according to a previous study. https://www.nejm.org/doi/full/10.1056/NEJMoa2105000
 
The study team noticed an increase in infections caused by the Delta variants bearing the E484Q mutation in the Paris area. The significant transmission advantage they estimated for this mutation is consistent with it being associated with immune evasion and with the high vaccination coverage in France.
 
Note that other lineages bearing a mutation in position S:484 were found to spread earlier in 2021 but their transmission advantage was more limited (approximately 17% versus 35 to 63% here) and the reference strain was the Alpha variant, whereas is less contagious that the Delta variant and has less immune evasion properties.
 
However the detection of the new delta sub-variant ie Delta+E484Q shows that there is a transmission advantage driven by an undocumented superspreading event in the area of Paris in August that would leave traces in virus genomes.

This could be consistent with the fact that the number of sequences from Delta+E484Q in the GISAID database is currently very low (935 of the 937,570 Delta sequences in GISAID).
 
Furthermore, combining these new sequences with 8 Delta sequences per month (April to September) from Italy, Spain, France, UK, Belgium, and Germany did not identify a clear link with the phylogenetic cluster of interest.
 
In vitro studies using viral culture assays could be instrumental to understand this phenomenon. SARS-CoV-2 prevalence remains high and the beginning of the school term in France is likely to increase virus spread.

Therefore, the alternative, more worrying, interpretation of these results, which is an adaptive advantage of a combination of the S:E484Q and S:T95I mutations, warrants close monitoring of these genomic pattern
 
The study team says that further monitoring is needed to determine if this trend is driven by undocumented super-spreading events or an early signal of future viral evolutionary dynamics.
 
The SARS-CoV-2 Variants study findings have already been reported to the WHO and also to the US.CDC. in the last 24 hours.
 
It must be noted that the Delta variant is mutating rapidly due to pressure from vaccinations and also the use of various monoclonal and polyclonal antibody therapeutics. Coupled with the fact that more infections are rampant and also the dynamics of the populations of those vaccinated versus those unvaccinated are all contributing factors to the virus mutations rates.
 
To date there are  more than 130 Delta sub-variants with unique mutations and deletions found on them that have emerged in this short time and scientists have only classified about less than 25 % of them!
 
The coming weeks as we have always been saying are going to be real interesting times as those living in the illusion that the COVID-19 pandemic is going to be tamed and that things will return to normal soon or that the mass vaccination programs are going to solve everything are going to be in for rude shock.

The SARS-CoV-2 virus still has a lot in its sleeve to meet its goal of eradicating a sizeable amount of the human population. It has yet to even start what it was created for and to date as only being going through its ‘dry-run’ phases only.


Analysing 5,061 variant-specific tests performed on SARS-CoV-2 positive samples collected in France between 31 May and 8 June 2021 reveals a rapid growth of the δ variant in the Île-de-France region. The next weeks will prove decisive but the magnitude of the estimated transmission advantage (with a 95% confidence interval between 67 and 120%) could represent a major challenge for public health authorities.

The evolution of SARS-CoV-2 variants has caused major epidemics in the United Kingdom (UK) [1, 2], Brazil [3], or South-Africa [4]. In May 2021, the δ variant, which was first detected in India, was associated with an epidemic rebound in the United Kingdom (UK) [5].

According to Public Health England [6], this variant has a transmission advantage of approximately 66% (95% confidence interval (CI): [28,113]%) over the α variant based on within-household transmission. It is also slightly more prone to immune evasion [7]. As shown in 2021 with the emergence of the α variant, there is a two-month shift between the epidemic situation in France and the UK [8, 9].

Therefore, it is timely to investigate the potential early spread of the δ variant to devise appropriate public health responses.

We analysed 5,061 RT-PCR variant-specific screening tests (VirSNiP assay, TIB Molbiol, Genova, Italy) performed on samples collected in France between 31 May and 8 June 2021 that were tested positive for SARS-CoV-2. The assay screens for the presence of the E484K, the E484Q, and the L425R mutations (Supplementary Methods). A 484K+/484Q-/452R- profile is consistent with the B.1.351, P.1, and B.1.525 Pango lineages (i.e. variants β, γ, and η), whereas a 484K-/484Q-/452R+ profile is consistent with the B.1.617.2 lineage (i.e. variant δ) [10].

These tests originated from different French regions, with a dominance of the Île-de-France and the Paris area (2,443/5,061 tests, i.e. 48%). Most of the tests originated from non-hospitalised individuals (4,775/5,061 tests, i.e. 94%) (Supplementary Table S1).

Discussion
Screening for SARS-CoV-2 mutations bore by the δ variant on samples collected between 31 May and 8 June 2021 indicates that this variant might already be spreading rapidly in the area of Paris, and potentially in other regions of France. According to our estimates, by mid-June 2021 its frequency in the Île-de-France region could already be above 10%.

There are several potential biases to this analysis, which we attempted to correct. First, since our dataset gathers results from local laboratories, there can be delays in data centralisation. To address this, we collected the data available on 16 June 2021, which included tests results as recent as June 14, and only analysed the data up to June 8.

Another potential issue has to do with the specificity of the test used. Our estimated frequency of δ variants, which is in the order of 4% of the positive tests on June 8, is consistent with the outcome of national sequencing studies (0.2% on 11 May 2021 [14]) although with a short doubling time (approximately 8 days). Furthermore, our estimate is conservative since we treat all the samples that are uninterpretable or where the signal is weak as non-δ variant samples.

Regarding the sampling scheme, the French authorities have announced strict monitoring of the spread of the δ variant, which means that contact tracing could be more intense. This could artificially enrich the data in δ variant positive test. We do not know the context in which most tests were performed, except for that in a hospital setting, mainly for hospitalised patients.

We expect hospital samples to be less impacted by a potential bias related to contact tracing because, aside from nosocomial infections, the contacts of a hospitalised person are unlikely to be hospitalised. We find no effect of the hospitalisation status in the multinomial model and running the analyses on the hospitalised samples only yielded a similar trend (although with a large 95% CI: 81% [19,166]%).

Finally, our estimation of the transmission advantage assumes that the transmission fitness of the different lineages do not vary over time. This is unlikely to be the case with the ongoing vaccination campaign and the variations in natural immunity. However, the short time period considered for this analysis justifies this assumption.

The estimated transmission advantage in the Île-de-France is higher than that estimated in the UK [6]. One interpretation is that this results from the aforementionned contact-tracing bias. Another interpretation is that the vaccination coverage in France compared to the UK [15]. Indeed, early evidence suggests that the δ variant could be evading immunity more than the α variant [7]. Finally, not that are estimates are consistent with recent transmission advantages from phylodynamics approaches [16].

These results have major public health implications because they imply that variant δ could already be spreading rapidly. In absence of specific interventions and based on the current vaccine rollout, our model tailored to the French epidemic suggests that this could cause another epidemic wave starting in August 2021.

The magnitude and exact timing of this wave would depend on the exact transmission advantage of the variant and on the increase in vaccination coverage. Finally, this picture could be further complicated by the spread of other variants since the dominant variant α could be transmitting less than variants β and γ [11].

reference link:https://www.medrxiv.org/content/10.1101/2021.06.16.21259052v2.full

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