Pirola Covid Variant Has Evolved Again, Showing Enhanced Immune Escape

As I’ve said before, our concern is not Pirola itself, but its descendants.

This is a sequel to an article I wrote a few weeks ago titled Pirola (BA.2.86): The Silent Threat That Lurks Within Its Descendants. In the article, I discussed the possibility that mutations in the original Pirola (BA.2.86) may not pose a threat. However, once a certain level of fitness is introduced into its genetics, we may witness the birth of a superspreader.

Chart illustrating the relationship between COVID-19 variants, their predicted immune escape, and binding affinity to the human ACE2 receptor. The higher the variant, the greater its potential for enhanced immune escape. The more it is skewed to the right, the greater its binding affinity to the human ACE2 receptor. The green, red, and blue circles highlight the Pirola clan. (Source, Edited by Author)

According to the displayed chart, it can be observed that the particular strain JN.1 (also known as BA.2.86.1.1) which is highlighted by a red circle, exhibits a notably higher level of immune evasion as compared to the overall omicron variants that are currently circulating around the world.

BA.2.86 (Original Pirola) has less immune evasion compared to its descendants BA.2.86.1 and JN.1. With the mutation to BA.2.86.1, there was a considerable increase in immune evasion, but a decrease in binding to the human ACE2 (hACE2) receptor.

Further mutations of BA.2.86.1 to BA.2.86.1.1 (JN.1) resulted in the gaining back of hACE2 binding affinity, even more than the original Pirola, plus increased immune evasion, making it the most immuno-evasive Omicron variant in circulation globally.

What the secondary structure predictions reveal

I was curious about the secondary structures of JN.1 and how they compare to the receptor-binding domains of BA.2.86.1 (its ancestral lineage) with the results displayed in the image below.

After conducting an analysis, I discovered that one of the reasons for JN.1’s fitness is the smaller size of its secondary structures, particularly the Beta sheets.

This development has resulted in more flexible RBDs, which are smaller in size. A flexible motif means that the RBDs fit better when binding, compared to more compact structures. Additionally, a flexible structure makes the antibodies less specific for binding.

Comparing Secondary Structure Predictions between BA.2.86.1 (top) and JN.1 (bottom), smaller Beta Sheets and 1 alpha helix Highlighted in Yellow for JN.1 (Image by Author)

The next questions would be, what are the expected effects of:

1. Enhanced immune evasion
2. Increased binding affinity to the hACE2 receptor

1. Effects of enhanced immune evasion

• The virus can escape detection and elimination by the immune system, thereby infecting a larger number of individuals and causing more severe disease.
• The virus can evade neutralizing antibodies generated by prior infection or vaccination, reducing the effectiveness of immune protection.
• New mutations acquired by the virus can cause it to become more transmissible, infective, and virulent, which in turn can result in the emergence of new variants that pose a greater risk to public health.
• The virus has the potential to undermine the efficacy of current vaccines and treatments designed to target the S protein or other proteins of the virus. Therefore, the development of new or updated interventions is necessary. But this requires extensive research and validation processes, as well as funding.

2. Effects of increased binding affinity to hACE2 receptors

• The stronger the bond between the S protein and the hACE2 receptor, the higher the chance of the virus attaching itself to the host cell and infecting it. This can lead to an increase in the spread of the virus.
• The S protein’s binding affinity to the hACE2 receptor is proportional to the severity of the damage caused by the virus to the organs expressing hACE2, including the lungs, heart, kidneys, and blood vessels. This can cause severe complications like acute respiratory distress syndrome, myocarditis, renal failure, and vascular inflammation.
• The higher the binding affinity of the S protein to the hACE2 receptor, the more likely the virus can evade the neutralizing antibodies generated by vaccination or prior infection. This can lower the vaccine efficacy and increase the risk of reinfection or breakthrough infection.

Conclusion

The new SARS-CoV-2 variant, JN.1, has high immune evasion and infection as shown in the first chart. It presents a great challenge to the current pandemic response. JN.1 evolved from omicron sub-variant BA.2.86 and has several mutations that increase its binding to the hACE2 receptor, making it difficult for neutralizing antibodies to work.

JN.1’s smaller and more flexible secondary structures help it evade immune detection, making it more transmissible, virulent, and resistant to existing vaccines and treatments than other Omicron variants.

So, it is crucial to closely monitor the emergence and spread of JN.1 and other variants, as well as to develop new vaccines and therapies that can effectively target them.