Omicron Transmission and Immune Evasion Explained by the Unique Structure of the Omicron Spike
The SARS-CoV-2 Omicron family of variants differs from the original isolates as well as other variants. Omicron viruses contain a minimum of 30 mutations in the Spike protein and another 23 elsewhere in the genome. Figure 1 illustrates how significantly one of the Omicron strains currently in circulation, BA.2.12.1, mutated from the wild-type Wuhan virus. There are also silent mutations which alter the nucleic acid sequence without altering the protein coding ability.
Besides looking different in terms of amino acids, Omicron variants also behave differently. Omicron is by far the most transmissible variant, including both infection rate globally and infectivity between individual hosts. The family is diverse and at least three of the variants have epidemic proportions: BA.4 and BA.5 in South Africa, as well as BA.2.12.1 in the United States. Although the spectrum of disease still requires further investigation, it is clear that Omicron can cause severe disease at high rates in children and the elderly, even in fully vaccinated people.
One of the most salient features of Omicron is the resistance of the family of variants to vaccines and most monoclonal antibodies. Resistance contributes, at least in part, to the rapid spread of Omicron variants. Previously, we described how amino acid changes in the Spike protein alter immune recognition by patient sera and monoclonal antibodies. Persons infected with BA.1 can be re-infected with BA.2 and those infected with BA.2 can be re-infected with BA.4, BA.5 or BA.2.12.1.
Tighter Omicron peak protein
Wang et al. detail how multiple amino acid changes in the Omicron Spike protein not only eliminate antibody binding sites, but also alter form and function The Omicron Spike protein is significantly more compact than that of the original Wuhan variant (D614G ) and the full range of variants that followed. Figure 3 compares the structure of the Omicron Spike with that of the wild type Wuhan (D614G). The Omicron protein is shown in green overlaid with the D614G variant in grey. The view is from the top of the Spike looking down to the base. Major structural rearrangements are evident throughout the structure. My guess is that some antibodies that bind to the looser structures fail to bind to the Omicron Spike not only because of single amino acid changes, but also because of the macro structural differences. I also assume that tighter packing implies it has a more entropic structure, representing a higher energy state. This extra energy can be released during membrane fusion, increasing the efficiency of viral entry.
I also assume that tighter packing implies a more entropic structure, representing a higher energy state. This extra energy can be released during membrane fusion, increasing the efficiency of viral entry.
Wang et al. attribute tighter packing of the Omicron Spike to specific amino acid substitutions. The H655Y mutation induces a closer association of the monomers composing the trimer. Additionally, five mutations in the central helical region, N764K, D796Y, N856K, L981F, and N969K introduce and facilitate additional hydrogen bonding and hydrophobic interactions between S2 trimers (Figure 4).
Changes in Omicron Fusion
The second major structural change involves one of the hallmarks of SARS-CoV-2 over SARS-CoV-1: the initial split at the S1 furin cleavage site. For most variants, furin cleaves the SARS-CoV-2 Spike protein when the virus buds from the cell surface. No such cleavage occurs for Omicron variants, or if it does, efficiency is greatly reduced (Figure 5 by Yamasoba et al.).
The furin-cleaved S1/S2 complex is intrinsically less stable than the uncleaved monomer. Post-cleavage S1 readily dissociates from S2. In fact, one of the advantages of the D614G mutant virus over the original Wuhan variant is that it stabilizes the S1/S2 association. The increased transmission of Omicron compared to other variants can be partially attributed to increased retention of S1 on the mature virus particle.
Wang et al. note that a mutation in the Omicron Spike, H655Y, may explain the reduced furin cleavage at the furin cleavage site. The mutation increases the stability of the 630 loop in the region by interacting with the F643 residue. Wang et al. and Bing Chen believe that increased stiffness of the loop containing the furin cleavage site reduces proteolysis.
The Wuhan strain and all previous variants enter by membrane-to-membrane fusion. The Omicron family, on the other hand, enters through an endosomal entry route. This is the strategy employed by SARS-CoV-1. Endosomal entry is most likely required in the absence of efficient furin cleavage. The S1/S2 cleavage site is at positions 685/686 and the S2 site is at positions 815/816.
This observation raises a paradox. The presence of the furin cleavage site has been hypothesized to be a key event in the acquisition of efficient human-to-human transmission. In fact, such speculation was so prominent that some have suggested that the furin cleavage site was artificially inserted to increase virus infectivity as part of a gain-of-function experiment in the laboratory. Many who have made this speculation seem to have overlooked the fact that many naturally circulating alpha and beta coronaviruses contain furin cleavage sites. It should be noted that even though the Omicron family of viruses contains furin cleavage sites, they are minimally active at best.
The paradox: the Omicron virus family is much more contagious than the previous variants. It is obvious that efficient cleavage is not necessary, either for infection or efficient transmission in the human population.