When the Omicron variant of SARS-CoV-2 was first identified, we applied our molecular modeling methods to assess how this new variant would impact the ongoing pandemic. Since we published our initial findings, the ubiquitous nature of Omicron infections, coupled with the publications of several excellent studies, has compelled us to update our last entry on the subject. These new studies may help us make sense of the current situation while possibly predicting where we are headed, keeping in mind that this update is not intended to be comprehensive.
Our calculations predicted that the fifteen mutations in Omicron’s Receptor Binding Domain (RBD) would show an improved binding ability when compared to the original Wuhan variant. One recent article reports that the SARS-CoV-2 Omicron RBD binds mouse ACE2 with a ~2.4 fold enhanced affinity relative to the Wuhan variant RBD. Also noted is an increase in the viral copy number in Omicron-infected human nasal airway epithelial cells. Omicron appears to therefore be significantly more adept at attaching to airway cells and to persisting in the nasal cavity.
A second feature of Omicron which we have previously discussed is the set of distinctive mutations in the S1/S2 site. In this site, furin cleavage leads to spike protein rearrangement and viral fusion to the cell membrane. We identified the mutation from proline to arginine at position 681 in the Delta variant as being beneficial compared to the Wuhan variant. In contrast, the proline-to-histidine mutation at position 681, combined with the asparagine-to-lysine mutation at 679 in Omicron, makes the S1/S2 site less favorable for cleavage by furin.
New evidence supports the conclusion that Omicron has a reduced ability to fuse to the cell membrane through the S1/S2 cleavage mechanism. The cleavage mechanism is even less successful than the original Wuhan strain. Interestingly, Omicron may be using an endosomal fusion mechanism in airway cells instead of the viral fusion mechanism preferred in earlier variants.
In vivo studies conducted in mouse and hamster models confirm that the Omicron variant is less efficient at entering lung tissue. Compared to other variants, Omicron is found in higher titers in the upper respiratory tract but lower viral titers in the lung. Lung tissue damage, a marker of disease severity, is also lower with Omicron. This has indeed been observed in the clinic, where the percentage of patients having serious respiratory illness has declined for Omicron. These observations point to reduced viral membrane fusion – which is dependent upon furin cleavage – as a key factor in reduced respiratory illness associated with Omicron
These findings confirm our predictions regarding the Omicron variant: (1) mutations in the RBD increase the affinity of spike protein for ACE2 and help the virus to become more transmissible; and (2) mutations at the S1/S2 site lessen furin cleavage and hinder virus infectivity. The S1/S2 site mutations lessen membrane fusion between virus and lung cells that, in turn, reduces lung tissue damage, and result in an overall less severe form of disease. These changes have led to the Omicron variant: highly transmissible, but with lower disease severity.
As SARS-CoV-2 transitions from pandemic to endemic, we will hopefully soon see overall lower infection rates along with generally milder cases. As always, Antibody Solutions will continue to review new research and discoveries and provide updates and insights as appropriate. Of course, we would love to hear what you’re working on. Drop us a line or give us a call at 650-938-4300 or 888-843-1069 (toll-free).
Author of more than 40 publications, John’s current research interests include new technologies for improving therapeutic antibody discovery, properties of next-generation antibody-like molecules, and best practices for critical reagents used in biologics development.