French Scientist Report New SARS-CoV-2 “MixOmicron” Recombinant Variant That Evades Existing qPCR Platforms! Could be More Transmissible And Lethal!

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! The study findings also indicate that this new recombinant variant could be far more transmissible and even lethal!


 
As Thailand Medical News had been warning since December 2021, the highly volatile BA.2 variant is not only spawning numerous subvariants and third generation variants but also numerous recombinant variants and the world will continue to see many surges and the new variants causing re-infections and even a non-stop cycle of co-infections and new recombinants constantly emerging. Contrary to idiots saying that these new BA.2 subvariants and recombinants being mild because the might for many, only cause asymptomatic or mild symptomatic infections initially as they are well adapted to disrupt and to evade the human host immune responses, they are suited for viral persistence and also tend to replicate much more rapidly, causing disease severity for some later and for many, will cause more dangerous medial and health outcomes later. Europe is also currently the ‘fertile grounds’ from which a lethal variant would most probably emerge as also predicted by us since early February 2022 considering the numbers infected, the vaccination status and wanning immunity of these vaccines, the type of drugs being used in treatment protocols, the relaxation of COVID-19 measures etc.
 
The French study team describe a new SARS-CoV-2 recombinant genome that is mostly that of a Omicron 21L/BA.2 variant but with a 3’ tip originating from a Omicron 21K/BA.1 variant.
 
It was reported that two such genomes were obtained in the study team’s research institute from adults sampled in February 2022 in university hospitals of Marseille, southern France, by next-generation sequencing carried out with the Illumina or Nanopore technologies.
 
Interestingly, the recombination site was located between nucleotides 26,858-27,382.
 
In the two genomic assemblies, mean sequencing depth at mutation-harboring positions was 271 and 1,362 reads and mean prevalence of the majoritary nucleotide was 99.3±2.2% and 98.8±1.6%, respectively.
 
Phylogeny generated trees with slightly different topologies according to whether genomes were depleted or not of the 3’ tip. This 3’ terminal end brought in the Omicron 21L/BA.2 genome a short transposable element of 41 nucleotides named S2m that is present in most SARS-CoV-2 except a few variants among which the Omicron 21L/BA.2 variant and may be involved in virulence.
 
Alarmingly, this recombinant is not detected by currently used qPCR that screen for variants in routine diagnosis.
 
The study findings emphasize the need to survey closely the genetic pathways of SARS-CoV-2 variability by whole genome sequencing, and it could contribute to gain a better understanding of factors that lead to observed differences between epidemic potentials of the different variants.
 
The fact that there are such undetectable BA.2 recombinant variants circulating in Europe raises the alarm that mankind is truly no longer aware of actual current status and kinetics of the current SARS-CoV-2 global crisis and that we can be in for major catastrophic surprises in any time!
 
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
 
In the last 19 months of the coronavirus disease 2019 (COVID-19) pandemic, multiple variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged and circulated, often at the same time.
 
Worryingly, this has set the stage for co-infections with more than one variant or subvariant and recombinant events, which are a common feature of coronaviruses.
 
The study findings describe a new variant that resembles the Omicron BA.2 for the most part, but has a small segment at the 3’ tip that belongs to the BA.1 variant.
 
This new discovery underlines the importance of genomic surveillance in eliciting the reasons for different viral behaviors during the various waves of the pandemic.
 
In late 2021, the Delta variant was still circulating when the Omicron variant began to be identified and began its rise to dominance. As such, there were high chances of coinfection with both strains, which could promote homologous recombinations of genetic material between them.
 
The same study team had already reported a couple of other recombinant SARS-CoV-2 variants, between the Alpha and B.1.160 strains and the second between the Delta and Omicron.
 
Importantly, both these recombinants were identified about 10 weeks after the second variant of the period began to co-circulate in the area.
 
This new study by the same team describes a third recombinant, the so-called MixOmicron.
 
The study team examined nasopharyngeal samples for SARS-CoV-2 genetic material using real-time reverse transcription-PCR (qPCR). The samples came from two adult patients, with the cycle threshold values being 13 and 19, respectively.
 
The initial PCR test detected all targeted genes, including the spike K417N mutation, indicating the presence of the Omicron variant.
 
Subsequently, next-generation sequencing followed, which showed the presence of a hybrid genome of Omicron 21L/BA.2-21K/BA.1. That is, while based upon the 21L/BA.2 sequence, the 3’ region for about 2,500 to 3,000 nucleotides is that of the 21K/BA.1.
 
Interestingly this region has no specifically recognizable mutations.
 
It was found that the recombination occurs between nucleotides 26,858 and 27,382 of the ancestral viral isolate. One specific element of the genome at this point was a short transposable element, 41 km long, called S2m, that is found in the Omicron 21K/BA.1 variant.
 
Importantly, when it comes to the Omicron 21L/BA.2 variant, this sequence misses 26 nucleotides from the middle, and therefore is not detected by currently used tests for SARS-CoV-2 variants. Such tests are based on detecting spike mutations, or sometimes mutations in other parts of the genome.
 
Significantly, in the majority of reads at the mutated positions in this sequence, over 98% of sequences showed the presence of the more common nucleotide, which suggests that there is a low possibility of contamination by the other variant, or of coinfection, which could otherwise explain the presence of sequences from both genomes.


The study team reported that the hybrid genome has 65 mutations setting it apart from the ancestral variant. Of these, 3 or 4 are not characteristic of Omicron, whether BA.1 or BA.2, while all spike mutations are identical to the Omicron mutations, except for one synonymous mutation.
 
Detailed phylogenetic analysis shows that the recombinant sequences were descended from the Omicron BA.2 variant, but with a difference in the way that the whole recombinant genomes were clustered vs the two partial recombinants in this clade. The former formed separate clusters, but the latter formed a nest within it.
 
The research findings show that genetic recombinants are emerging within the SARS-CoV-2 variants.
 
Earlier research has suggested that up to 5% of the circulating strains in the USA and the UK were recombinants. More and more such cases are being reported, as different variants circulate together at high rates in the same area.
https://pubmed.ncbi.nlm.nih.gov/33758853/
 
https://www.biorxiv.org/content/10.1101/2021.08.04.455157v1
 
It was reported that there were over 15,000 BA.1 infections vs less than a thousand BA.2 infections in 11 weeks. As mutations accumulate, recombinants become more recognizable since the mutations occur at shorter intervals.
 
The study team noted that with the same spike protein sequence as that of Omicron BA.2, the hybrid is likely to have the same immune escape characteristics. However, the 3’ terminal sequence has been acquired from the BA.1 variant with the S2m short transposable element. Not only is this motif found in four different single-stranded RNA virus families, including all Sarbecoviruses and most SARS-CoV-2 genomes, but it is very similar to those found in insect genetic material.
 
Importantly, the functional importance of this element may lie in its RNA interference capabilities. It is involved in the viral takeover of host protein synthesis and RNA recombination. It may also mediate pathogenicity and infection in several animal hosts. In fact, it is postulated that it interacts with a cellular miRNA in humans and thus evades detection by the host immune response. All these properties implies that the new variant could be more lethal!
 
It was also noted that in the few variants of SARS-CoV-2 in which S2m was absent or shortened, transmissibility was low. This is also true of Omicron BA.2, which may indicate that S2m is a virulence factor. Its presence in this hybrid BA.2-based genome could lead to a gain of viral transmissibility, which would fuel epidemic spread.
 
Urgent detailed research and surveillance would be necessary to confirm or refute this.
 
The study team concluded, “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.”
 
For more on the various emerging BA.2 subvariants or recombinant variants, keep on logging to Thailand Medical News.