Mystery of Spike and NSP6 in Omicron BA.1 Attenuation

CME INDIA Presentation by Dr. Rajeev Jayadevan, MD DNB MRCP ABIM (Med/GE) Co-Chairman National IMA COVID Task Force.

Why Omicron is milder than Delta?

It is generally been believed that the numerous mutations on the spike protein of Omicron made it different from Delta and other prior variants, including:
- loss of pathogenicity
- ability to escape immune response.
New research from Boston University shows that it is not just the numerous Spike mutations that change the character of Omicron, but also mutations affecting the NSP6 or non-structural protein-6.

What is NSP6

NSP6 is a non-structural Protein, made by the virus, that is involved with viral replication. It helps the virus multiply within the human cell through a process of generating intracellular ‘bubbles’ called RO (Replication Organelles)
These RO’s are derived from transforming our own cell’s intracellular membranes. (E.g., Some of us recall making tiny “mini balloon bubbles” by blowing inward from balloons as children) Imagine ER is the big balloon and RO is the one we created by blowing inward.
These bubble-like organelles, where viral replications will occur, are attached to the cell’s own Endoplasmic Reticulum (ER). NSP6 helps with the “zippering” part of this process.

What is the implication for the future?

What this means is that continuing mutations within the virus, besides its spike, could also lead to changes in the disease-causing ability of the virus, in addition to the commonly discussed immune escape.
Note: Immune escape refers to ability of the virus to infect a person who had prior infection or Vaccination or both.
Ability to cause disease (pathogenicity) is different, it specifically refers to what organ it prefers to infect, and what damage occurs as a result. We recall what Delta did.
This is one of the reasons we must be vigilant about the arrival of newer variants which are genetically located “far away” from Omicron.

It is well known now that the SARS-CoV-2 Omicron variant is more immune-evasive and less virulent than other major viral variants recognized to date.
Omicron spike (S), with an unusually large number of mutations, is considered the major driver of phenotypes.
It has been shown that the Omicron S-bearing virus robustly escapes vaccine-induced humoral immunity, mainly due to mutations in the receptor-binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicated in cell lines and primary-like distal lung cells.
The vaccine escape of Omicron is driven by mutations in S, the pathogenicity of Omicron is determined by mutations both in and outside of S.
The SARS-CoV-2 coronavirus is continuously evolving by accumulating mutations in its genome.
The viral genome’s diversity is essential in the natural selection process that will make the coronavirus more adapted to its human host.
New mutations reported are targeting the receptor-binding domain (RBD) of the spike protein.
The RBD of the spike protein is critical for the virus’ entry into human cells via its receptor, the Angiotensin-converting enzyme 2 (ACE2), and antibodies against the spike play an essential role in the neutralization of the virions.
New SARS-CoV-2 variants that may escape the immune response to the virus might affect patients, diagnostic tests and vaccines.

Do new variants affect antigen diagnostic tests?
- The majority (90.1%) of rapid antigen tests with EUA detect nucleocapsid protein. The mutations within the nucleocapsid of the emerging variants are minimal and not conserved across the strains.
- It can be well said that antigen tests should be unaffected by the aforementioned strains.

Do new variants affect serology assays?
- Various serology assays target different proteins.
- Based on published studies, it can be said that antibodies produced against B.1.1.7 (or at least a significant portion of them) are detected by serology assays using the spike wild type protein.

References:

Chen, DY., Chin, C.V., Kenney, D. et al. Spike and nsp6 are key determinants of SARS-CoV-2 Omicron BA.1 attenuation. Nature (2023). https://doi.org/10.1038/s41586-023-05697-2
Sigal, A. Milder disease with Omicron: is it the virus or the pre-existing immunity? Nat Rev 351 Immunol 22, 69-71, doi:10.1038/s41577-022-00678-4 (2022). 352
WHO. Tracking SARS-CoV-2 variants, (2022).