Analysis of the emergence of Covid variant KP.2 and its potential impact

It is clear that SARS-CoV-2, the cause of the Covid-19 epidemic, is here to stay. Like influenza, an easily transmitted respiratory virus, SARS-CoV-2 mutates to evade the immune systems of those previously vaccinated, infected, or both. The question remains: how dangerous is each new version of SARS-CoV-2? Again, if you have been previously vaccinated, infected, or both, new variants, like the flu, are not as dangerous. If not, emerging versions of SARS-CoV-2 could be life-threatening to the vulnerable.

Now that summer is approaching, a new series of new species is planned. While these are derived from the original Omicron and share many similarities, they are different enough to cause a new wave of Covid-19 cases.

One new variant, KP.2, could take the lead this coming summer. This newly identified variant is spreading mainly in the United States, Canada and the United Kingdom, with rising levels in Singapore, New Zealand and Australia. To date, 1,816 cases of KP.2 have been reported in the GISAID SARS-CoV-2 database, indicating that thousands, if not tens of thousands, of individuals may already have been infected with this variant as sequencing efforts are underway executed. has been significantly reduced in recent years.

KP.2 belongs to a group recently characterized as the FLiRT variants. This name is derived from the technical designations of two critical mutations in their spike proteins: the F456L mutation and the R346T mutation.

The FLiRT group is a subset of variants on the Omicron tree, which has primarily driven SARS-CoV-2 infections over the past two years. KP.2 is structured similarly to previous major Omicron variants, including BA.2.86, JN.1 and XBB.1.5.

Omicron’s variability is extensive. As has been the case with influenza for many years, past is prologue with the SARS-CoV-2 virus. Over time, new variants emerge with unique mutations not just in the spike protein, but in the entire virus genome. Below is a diagram demonstrating the web of Omicron variants that has emerged in recent months. KP.2 and its FLiRT variant grouping are located in the upper right corner, shaded in light green.

Because JN.1 is the most recent dominant variant, in this article we will compare it with KP.2 to demonstrate how KP.2 can distinguish itself from previous variants and to indicate why it will see a new increase in the number of cases.

Let’s start with the spike protein. SARS-CoV-2 must attach to human cells using the ACE2 receptor, fuse its membrane with the host cell membrane, and ultimately gain access to initiate infection and reproduction in human cells. Importantly, this protein is the main focus for vaccines, antibodies and antiviral treatments against Covid-19.

As with JN.1, many spike protein mutations in KP.2 are also present in previous variants of concern, including E484K and N501Y. These variants, known as the alpha and beta variants of SARS-CoV-2, were first detected in early 2021.

In fact, there are only three differences in the peak protein between KP.2 and JN.1. Two of these are the namesake of KP.2’s FLiRT grouping.

A single mutational variation exists in the N-terminal region, which is involved in viral entry after infection. KP.2 harbors R346T, which could improve virus entry efficiency and enable antibody evasion by introducing N-glycosylation sites.

In the receptor binding domain, just one change from JN.1 could significantly impact F456L, which could increase ACE2 binding affinity or decrease antibody binding efficiency.

Finally, V1104L has been added to the S2 subunit of the spike protein, which can improve the efficiency of the fusion of the viral envelope with the host cell membrane, allowing the viral genome to enter the cell.

I would like to draw attention to mutations that occur outside the peak area and can significantly impact the virus’s ability to cause disease and spread. In different parts of the genetic material, there is a wide range of mutations in the Orf1ab replication-transcription complex (NSP1-16), some in the structural proteins (E, M and N), and some in the accessory proteins (Orf3a-8) . We draw attention to these mutations because changes in specific proteins, especially the N protein, can significantly affect virus replication.

Below is the full catalog of mutations found throughout the virus.

There is only one non-spike mutation difference from JN.1 in KP.2. It lies in the Orf1a collection, which contains 11 proteins involved in a number of replication processes. This mutation is NSP3 T1465I.

Non-structural protein three is one of the most complicated proteins in the SARS-CoV-2 virus. Among its many functions are proteolytic activity, formation of replication-transcription complexes, antagonizing the host immune response, regulating viral translation, and inducing cell death. T1465I could improve all of these features, although it is difficult to determine which ones and to what extent.

I noticed the extensively mutated N protein. Mutations at R203K and G204R have been present in most virus variants during the pandemic and are likely to increase the rate of viral replication. Although these mutations are identical to those in JN.1, the N protein continues to play a crucial role in the pathogenicity of the virus.

The changes in the mutations, both inside and outside the spike protein, have several reasons: the first reason is adaptation to increased infectivity; the second is evasion of neutralizing antibodies; the third is adaptation for more effective development after infection, including replication supported by mutations in the N protein; and the fourth is the prevention of recognition by T cells.

Furthermore, it is worth noting that this virus, along with most sequenced variants during the Covid-19 epidemic, shares three mutations with the first divergent variant of the original Wuhan virus. These are D614G in the spike, P323L in NSP12 and the synonymous C241U mutation in the 5′ end of the virus.

In fact, there are numerous synonymous mutations scattered throughout KP.2, but collecting data on these mutations is much more complex than collecting data on amino acid mutations.

The synonymous mutations do not change the amino acid sequence of the virus, but do affect the tertiary structure of its RNA. Research shows that this may contribute to the virus’s adaptation to the human host environment. These mutations also affect the abundance of viral proteins and immune responses in the infected individual.

It remains to be seen whether KP.2 will cause a new wave of Covid cases in recent years, similar to Alpha or Omicron. Furthermore, current data cannot confirm whether this variant is more pathogenic or viral than JN.1, especially for those previously infected or vaccinated. For those who have not been infected or vaccinated, infection with KP.2 can be very serious and they should be careful.

It is critical that you are aware of these threats before they become widespread, not after. As we enter the summer months, another wave of cases is likely, and KP.2 is a possibility for that.

If you would like to read more of my work, please visit www.williamhaseltine.com.