The Omicron ‘Kraken’ sub-variant: What makes it special.
Many of my readers have been asking me to write about the omicron ‘Kraken’ subvariant so here is the precise article of what I researched about Kraken. The SARS-CoV-2 variant Omicron subvariant XBB1.5 (or in short ‘Kraken’) was first identified in October 2022.
Kraken Mythology
‘Kraken’ is a Greek mythology cephalopod (same family as octopus, squid, or molluscs) first described in 1700 by Italian writer Negri as a massive fish which was many-horned or many-armed.
It was popularised in English literature by Erik Pontoppidan who described it as a tentacled organism known for sinking ships and attracting fish which were in pursuit of its excreta.
Why call a coronavirus, Kraken
As the SARS-CoV-2 has been evolving, scientists found ways to name viruses using Greek Letters like Alpha, Beta, Delta or Omicron. This was easier to communicate to the general public because each new COVID-19 wave could be explained using this nomenclature.
Ever since the end of 2021, the omicron has been the dominant circulating variant. Microevolution in the omicron variant has resulted in hundreds of its subvariants. This has led to difficulty in communicating with the general public on what is causing what, or which type of subvariant someone is being protected from using a vaccine.
Additionally, it is even worse with the numbering system like 1.1 or 1.5 which are numbers loosely explanatory of what the omicron subvariant is capable of causing. Hence, scientists like Dr Ryan Gregory popularised using Greek mythology creatures which explain better how much havoc an omicron subvariant can cause.
Besides Kraken, there is also the Orthrus variant whose full scientific name is SARS-CoV-2 omicron variant XBB sub-variant CH1.1.1 which happens to be a spawn of Kraken.
The way the Kraken spreads its tentacles across the ship as it sinks is used synonymously with how the Omicron Kraken is spreading globally.
Clinical significance of Kraken
According to WHO, Kraken has been noted to have high reinfection rates limited to pre-Omicron COVID-19 patients. As of the end of January 2023, there has been no evidence of immune escape from Omicron lineages-induced immune response.
This is expected because antibodies against pre-omicron lineages lack specificity against omicron-lineage immune-recognition epitopes. The rise in omicron infection globally is due to natural selection most probably due to vaccines acting as the selection pressure, as well-covered in this article.
However, it is worth noting that there have been no distinct clinical outcomes from Kraken compared to its omicron XBB relatives. These clinical outcomes include:
- Incubation period
- Signs and symptoms
- High immune escape
- Upper airway tropisms
- Lower severity especially with prior immunity
The Evolutionary origins of Kraken
According to WHO, Kraken is a recombinant of omicron sub-lineages BA.2.10.1 and BA.2.7.5.
Recombination of viruses usually happens when two closely related viruses infect the same host cell followed by an exchange/swapping of homologous genetic material as illustrated in Fig 1.
This is very similar to the process of crossing over in Prophase I of Meiosis where non-sister chromatids of homologous chromosomes exchange a chunk of DNA which each other. This results in genetically distinct daughter cells, which is a way of achieving variation after fertilization.
Recombination alongside substitution is one of the two major ways in which viruses evolve. Recombination is even the most problematic way in which human immunodeficiency virus (HIV) is evolving because it's way more unpredictable than say Substitution events. Sometimes the recombinant progeny of the viruses might acquire comparable positive characteristics of the two parent viruses.
According to a WHO webinar I attended last week titled, ‘Current COVID-19 situation and what’s next for COVID-19.’’, a number of factors were mentioned to cause genetically divergent SARS-CoV-2 through:
- Uncontrolled transmission and prolonged man-human transmission in areas with limited surveillance and sequencing.
- Viral adaptation following prolonged circulation in susceptible animals.
- Recombination of SARS-CoV-2 with other coronaviruses in animals or humans.
- Persistent SARS-CoV-2 infection in an immuno-compromised patient.
The immune escape from Omicron-lineages-induced immune response is a general adaptive evolution inherited by all omicron XBB coronaviruses, including Kraken.
However, the acquisition of this compensatory mutation has a trade-off in that the omicron XBB sub-lineage variants do not fit tightly into human ACE2 (hACE2) receptors. Fitting nicely is a pre-requisite and crucial step in the survival and proliferation of a virus.
The bulls-eye for Kraken
Luckily, the Kraken regained a pre-omicron variants mutation S486P, which makes it fit tightly with the hACE2 receptor, according to a preprint. Acquisition of this mutation makes the Kraken a fit variant with both high transmissibility and enhanced immune evasion compared to other available variants, omicron or not, according to Dr Maria Van Kerkhove.
The P486 mutation restored the once-abrogated local hydrophobic interaction with hACE2 making the Kraken acquire a higher growth rate advantage compared to its parent lineages.
This kind of back mutation has also been noticed on the N-terminal domain (NTD) — directed neutralising antibodies called G142D. Not to mean the same causation here but this kind of disturbance at G142D reduces immune recognition leading to higher viral loads.
The biochemistry of the S486P mutation
The S486P is a reversion to a past mutation found in other variants but is uniquely absent in all other omicron variants. In S486P, Proline substitutes Serine at amino acid 486 of the spike protein. Spike protein is used as a key with which the Coronavirus use to complementarily unlock entrance into the host cell with the appropriate receptors.
Serine is a polar amino acid which is coded for by 6 codons, making it an easily abundant amino acid in the polypeptide chain.
Proline has a distinctive cyclic structure, which gives an exceptional conformation rigidity compared to other amino acids. Because of its biochemistry, it is usually found as a first residue in alpha-helical secondary structures or in edge strands of beta-sheets of other secondary structures.
Proline causes the spike protein 3D structure to fit nicely into hACE2 by increasing bulkiness and interactions between the two.
Conclusion
Kraken is a very interesting sub-variant in terms of evolution but with current data, these acquired evolutionary characteristics do not bring any changes to clinical outcomes compared to other omicron sub-variants.
