The Omicron variant marked a turning point in the Covid-19 pandemic. With over 60 genetic mutations compared to the original coronavirus strain, this variant promised to be very different from its Alpha, Delta and company predecessors. Indeed, Omicron and its successors (including BA.2, BA.5 and HBV) are much better at avoiding acquired immunity (by prior infection or vaccination) and therefore much more contagious.
Since their arrival, the number of infected people has increased significantly, raising fears of a tenfold increase in serious forms of Covid. Fortunately, this has not happened, partly due to vaccine protection, which effectively limits the development of severe forms. But even if the unvaccinated are still at greater risk of these complications than the vaccinated, they are also less “attacked” by Omicron than its predecessors. This is because this variant appeared to be less virulent, and we finally know why, thanks to a study published January 11, 2023 in the journal Nature by Boston University (USA) researchers.
Mutations in Spike do not cause Omicron’s drop in virulence
Most of the non-synonymous mutations (which change the protein encoded by the mutated gene) in Omicron (37 out of 59) are found in the Spike protein. This protein on the surface of the virus is the main target for antibodies, so it is because of these mutations that our immune system has difficulty recognizing the virus. But it was unclear whether these mutations were also responsible for Omicron’s reduced virulence. To test this, the researchers created “chimeras” (coronaviruses with an original strain body and Omicron’s Spike protein) that they tested in vitro on lab-grown human cells.
This chimera behaved like the original strain, infecting cells faster than Omicron and producing more viral particles. The same was true in mice: Omicron did not cause weight loss or clinical problems, while those infected with the chimera and the original strain experienced a rapid deterioration in health, leading to the death of most of the infected animals. Thus, mutations in the Spike Omicron protein are not responsible for the attenuated virulence of this variant (or at least not entirely).
Omicron’s low virulence is believed to be due to mutations in two proteins.
The researchers attempted to determine which mutations caused such a reduction in Omicron’s danger. To do this, they created other chimeras, replacing one by one all the proteins of the original strain with Omicron proteins. One of these creations showed a strong reduction in viral replication, as was seen with Omicron, as well as with the Spike and nsp6 variant proteins and the rest of the original proteins. This chimera also caused less harm to infected mice with a survival rate of 71% compared to 20% for the chimera with Omicron’s Spike protein alone. Thus, the low virulence of this variant associated with decreased viral replication is due to a combination of mutations in these two proteins, Spike and nsp6.
So how could this novel protein affect coronavirus replication? When it enters a cell, it forms vesicles, compartments within the cell where the virus can safely replicate its genetic material. The nsp6 protein is involved in building these vesicles, so it is possible that mutations in this protein affect these compartments and thus virus replication. Further studies will be required to confirm this hypothesis. But the discovery highlights the importance of studying all coronavirus mutations, not just Spike’s mutations. Because if mutations in nsp6 made Omicron less virulent, others might well have the opposite effect and make the next variant more dangerous.