Musings about omicron-VOC antigenicity

The spike trimer of the original sars corona virus (named today Wuhan-hu-1) is shown here with all three receptor binding domains (RBD) in the inactive "down" position . This structure is the basis for all vaccines certified in Europe. However, the Wuhan strain is extinct for about two years. Here is the phylogenetic tree of the currant SARS-CoV-2 variants of concern (VOC):

https://doi.org/10.1101/2021.12.14.21267755

Vaccination is meant to induce the production of antibodies, which capture virus particles before entering human cells by neutralizing the virus. Targets for antibodies are free parts of the protein surface between the sugar molecules (brown). An antigenic epitope (the binding interface) is a spot of about 10 amino acids, which are adjacent but not neccessarily in order along the protein chain. The total space needed to bind an antiboty is even larger, and sugar molecules within this space prevent binding. Sugar by itself is not antigenic; the total sugar decoration of the spike shields ca. 40% of the surface from antibodies.

Exchange of an amino acid in a defined epitope by mutation provokes a change of the surface structure (sidechains of amino acids differ both in bulkiness and charge) in this very spot. An antibody designed for this epitope will bind weaker or not at all after the mutation.

The omicron variant excels against variants α to δ by an enormous number of mutations. This means severe consequences for the binding abilities of antibodies raised by vaccination based on the Wuhan strain. Until now (Dec. 2021) no atomic coordinates for the omicron spike are published; so I can indicate the positions only of exchanged amino acids . The mutations in the omicron spike are not new, each one occured in an older corona strain before. It looks like omicron collected all useful mutations from it's ancestors. Fang and Shi investigated data banks and publications to gather all known effects of the mutations found in omicron: most are meant to evade the immune response of the host organism (both antibodies and humoral immunity), many enhance the infectivity.
Mutations in the aminoterminal domain cause changes in the epitopes so antibodies won't recognize them any more (structural changes in the protein by deletions or insertions of amino acids severely change the surface): (shown here symbolically in one spike protein only).
In the receptor binding domain (RBD) there are only amino acid replacements, they all provoke immune evasion: (shown in the pale blue protomer only). Two mutations in the binding motiv enhance the infectivity .
In the carboxy terminal domain are three mutations with unknown effect (they are not at the surface) (again shown in one protomer only). The other mutations lower the binding ability of (Wuhan-) antibodies or enhance the infectivity . In spacefilling view (like antibodies "see" the spike) the carboxyterminal mutations are hardly visible. An interior mutation changing the inner volume may have the effect of denting the surface and thus change the epitope. Some mutations also change the electrostatic properties .

What protection against an omicron infection will remain after a Wuhan vaccination? A multinational clinical investigation showed: nearly nothing. In all vaccination constellations only a booster shot (and only within three months) provided some protection.

https://doi.org/10.1101/2021.12.14.21267755

It is high time to develop an omicron vaccine (BioNTech claimed light speed for their developing capabilities). Some politicians (without molecular biology background?) threaten with laws for compulsory vaccination. Instead they should force the pharmaceutical industry to sell up to date vaccines and discard their old crap. Compulsatory vaccination with outdated vaccines may mean mayhem.

this demonstration.

Literature:
Fang "Flora" Fang & Pei-Yong Shi (2021): Omicron: A Drug Developer's Perspective, Emerging Microbes & Infections, DOI: 10.1080/22221751.2021.2023330
W. F. Garcia-Beltran et al (2021): mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARSCoV- 2 Omicron variant, https://doi.org/10.1101/2021.12.14.21267755
Spike structure: 7jji.pdb