Researchers from IHU Méditerranée Infection-France, Aix-Marseille University-France and the Publique-Hôpitaux de Marseille-France have reported the identification of a SARS-CoV-2 “MixOmicron” recombinant that evades current variant screening and it’s more transmissible and even lethal.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.medrxiv.org/content/10.1101/2022.03.28.22273010v1
Multiple SARS-CoV-2 variants have been identified since summer 2020 (Lemey et al., 2021; Colson et al., 2022a; Hodcroft et al., 2021; Harvey et al., 2021).
There were periods during which two distinct variants co-circulated with a crossing of their incidence when an old variant was vanishing and a new one was rising. Substantial rates of co-incidence over periods of several weeks have thus been reported recently worldwide for the Delta [WHO denomination (https://www.who.int/fr/activities/tracking-SARS-CoV-2-variants)]/21J [Nextclade classification (Aksamentov et al., 2021) (https://nextstrain.org/)] and Omicron 21K/BA.1 [Pangolin classification (Rambaut et al., 2020) (https://cov-lineages.org/resources/pangolin.html)] variants, and thereafter, to a lesser extent, for the Omicron BA.1 and BA.2 variants (https://covariants.org/per-country) (Hodcroft, 2021; Hadfield et al., 2018), including in our geographical area (Figure 1).
This created the opportunity for coinfections (Rockett et al., 2022; Hosch et al., 2022; Bolze et al., 2022; Belen Pisano et al., 2022), and consequently for homologous genetic recombinations, which constitute a major and very common mechanism of evolution in viruses (Bentley and Evans, 2018).
Such genetic recombinations are extremely frequent for viruses of family Coronaviridae, and they have already been identified for endemic human coronaviruses (Lai, 1996; Zhang et al., 2015; So et al., 2019; Gribble et al., 2020). Regarding SARS-CoV-2, the occurrence of recombinations has been reported or suspected (Yi, 2019; Yeh and Contreras, 2020; Haddad et al., 2021; Ignatieva et al., 2021; Jackson et al., 2021; Taghizadeh et al., 2021; Varabyou et al., 2021; Kreier, 2022; Wertheim et al., 2022; He et al., 2022; Sekizuka et al., 2022; Colson et al., 2022b; Lacek et al., 2022; Lohrasbi-Nejad, 2022; Bolze et al., 2022; Ou et al., 2022; Belen Pisano et al., 2022; Burel et al., 2022).
Very recently, we described the identification and culture of two SARS-CoV-2 recombinants, one between the B.1.160 and Alpha/20I variants in a patient chronically-infected with SARS-CoV-2 (Burel et al., 2022), and another between the Delta/21J AY.4 and Omicron 21K/BA.1 variants in patients infected approximately 10 weeks after the start of the period of co-detection of these two variants in our geographical area (Colson et al., 2022b).
In the present work we show a recombination between Omicron BA.2 and BA.1 variant viruses. In two previous studies, 16 (0.006%) of 279,000 genomes and 1,175 (0.2%) of 537,360 genomes were identified as being recombinants (Jackson et al., 2021; VanInsberghe et al., 2021).
In addition, it was deemed that up to 5% of SARS-CoV-2 that circulated in the USA and UK might have been recombinants (VanInsberghe et al., 2021), and estimated that ≈2.7% of sequenced SARS-CoV-2 genomes might have recombinant ancestry (Turkahia et al., 2021).
As a matter of fact, cases of detection of recombinant genomes are increasingly reported in 2022 (Wertheim et al., 2022; Sekizuka et al., 2022; Colson et al., 2022b; Lacek et al., 2022; Bolze et al., 2022; Ou et al., 2022; Belen Pisano et al., 2022; Burel et al., 2022). Such recombinants are all the more likely to be generated when different variants co-circulate with high incidence levels. In our geographical area, >15,000 infections with the Omicron 21K/BA.1 variant and >1,000 infections with the Omicron 21L/BA.2 variant were diagnosed over the same period of 11 weeks between late December and mid-March (Figure 1).
Moreover, recombinants becomes more easily identifiable during bioinformatic analyses due to the accumulation over time of mutations along SARS-CoV-2 genomes, at intervals of increasingly reduced size. The two phylogeny reconstructions based on whole genomes or on their region that originate from the Omicron 21L/BA.2 variant in the recombinants exhibited slightly different topologies.
This emphasizes that phylogenetic analyses do not accurately handle genomes that are hybrids of sequences with different evolutionary histories, which prompts building separate trees for sequences of different origins in the case of recombinants.
The spike gene of the recombinant virus identified here is typical of that of the Omicron 21L/BA.2 variant, which suggests similar phenotypic features regarding immune escape (Yu et al., 2022; Iketani et al., 2022). However, the acquisition by a Omicron 21L/BA.2 genome of the 3’ terminal part of a Omicron 21K/BA.1 genome is of very particular interest as this Omicron 21K/BA.1 fragment contains a short transposable element named S2m. S2m is a 41-nucleotide long stem loop motif that is present in four different families of positive-sense single-stranded RNA viruses (Robertson et al., 1998; Imperatore et al., 2022) and also shows high levels of similarity with sequences of insects (Tengs et al., 2021). This element is present in sarbecoviruses and in most of the SARS-CoV-2 genomes.
It was proposed to be involved in RNA interference pathways, in hijacking of host protein synthesis, and in RNA recombination events (Imperatore et al., 2022; Gallaher et al., 2022), and it could have initiated viral infection and pathogenicity in various animal hosts. For instance, the s2m element was reported to interact with cellular miRNA-1307-3p in humans, being putatively able to manipulate the host immune response.
Moreover, in SARS-CoV-2, S2m is absent or truncated in a few variants including the Eta (B.1.525), Iota (B.1.526) and B.1.640.1 lineages, which all had a low epidemic spread; and it is also truncated in the Omicron 21L/BA.2 variant.
Taken together these data suggest that S2m could be considered as the equivalent of a virulence factor. The consequence of the S2m acquisition by an Omicron 21L/BA.2 genome as reported here is unknown.
A possibility would be a gain in transmissibility leading to a larger epidemic, which should be investigated by genotypic surveillance among SARS-CoV-2 diagnoses and phenotypic in vitro experiments. Thus, the present observation may contribute to gain a better understanding of factors that enhance SARS-CoV-2 spread and lead to the observed differences between the epidemic potential of the variants (Tao et al., 2021; Campbell et al., 2021).
Finally, the increasing identification of recombinant SARS-CoV-2 genomes worldwide highlights the unpredictable nature of the genetic variability of this virus. The recombinant described here is not detected by current strategies that screen for variants in routine diagnosis by qPCR. This emphasizes the interest of the most exhaustive whole-genome based surveillance possible to allow deciphering the genetic pathways of the variability and investigating their phenotypic consequences regarding transmissibility, clinical severity, and escape from neutralizing antibodies.