RaDVaC statement on the SARS-CoV-2 Omicron variant

Version 1.0
December 1, 2021

The Omicron variant of SARS-CoV-2 has over 50 mutations, with 32 mutations in the Spike protein alone¹. Both of these numbers are far higher than for any previous variant of concern.

These mutations are so numerous that they are likely to impact transmissibility and virulence, but in ways that are currently impossible to predict. Nevertheless, the effects of certain mutations on specific current therapies and vaccines can be predicted with reasonable confidence. 

Key observations on the high-impact mutations of Omicron variant:

• Omicron has 15 substitution mutations in the 200 amino acid receptor binding domain (RBD) of Spike.
  • About half of these mutations are concentrated in the portion of RBD that interacts with human ACE2 receptor (referred to as the receptor binding motif).
  • Four mutations are substitutions of amino acids that directly contact the ACE2 receptor: Q493R, Q498R, N501Y, Y505H
• For comparison, the Alpha, Beta, and Gamma variants each contain only one mutation in ACE2 contact residues (N501Y), and the Delta variant contains zero².
  • Omicron also has mutations at residues 452 and 484. Mutations at these positions in the Delta variant reduce the effectiveness of vaccines.

Based on structural evidence of interactions between neutralizing antibodies and the Spike protein, we make the following predictions:

• Effect on RBD-based vaccines: We predict that Omicron will substantially reduce effectiveness of RBD-based vaccines, some of which have been reported to be highly effective against previous variants.
• Effect on Spike-based vaccines: The effectiveness of Spike-based vaccines will be compromised because RBD portions of these vaccines will be substantially less effective. Portions of Spike involved in membrane fusion (which RaDVaC has included in multiple generations of published vaccine candidates) are not mutated in Omicron and will provide some protection, but overall protection will be reduced. These vaccines include BioNTech-Pfizer Comirnaty, Moderna Spikevax (mRNA-1273), Janssen/Johnson & Johnson COVID-19 vaccine, and AstraZeneca/Oxford ChAdOx1 (AZD1222).
• Effect on neutralizing antibody therapies:
  • Regeneron monoclonal antibody cocktail REGN-COV2, consisting of antibodies REGN10933 and REGN10987.
    • Two mutations in the Omicron RBD (K417N, E484K) have been shown to essentially abolish binding of antibody REGN10933^3,4 and three mutations in the RBM result in substitutions of amino acids contacted by REGN10987 (N440, G446, Q498)⁵. We therefore predict that the Regeneron cocktail will be largely ineffective against Omicron.
  • Lilly monoclonal antibody cocktail consisting of antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016).
    • LY-CoV555 binding is reduced by mutations at  K417N and E484, while LY-CoV016 binding is likely reduced by K417N^6,7,8,9. We predict that the Lilly cocktail will be substantially less effective against Omicron. 
  • Vir-GlaxoSmithKline sotrovimab. Sotrovimab binds to the glycan of N343 and surrounding amino acids, and should be relatively unaffected by omicron mutations.
• Effect on RaDVaC vaccine candidates:
  • Current RaDVaC peptide vaccine designs are largely resistant to the mutations of Omicron. This is in keeping with the strategy of RaDVaC vaccines to be more robust against variants.
    • RaDVaC core B-cell epitope peptides target the fusion peptide. Only one optional B-cell epitope peptide targets the RBD. Full-length Spike-based vaccines also contain these epitopes, but RBD vaccines do not.
    • Current RaDVaC designs target multiple immunodominant T-cell epitopes, none of which is affected by Omicron. Neither Spike-based vaccines nor RBD-based vaccines contain any of the verified, immunodominant cytotoxic T-lymphocyte epitopes. Such immunodominant T-cell epitopes are key to immunity that is durable and resistant to variation over the long term.
  • Recent discoveries about SARS-CoV-2, in addition to Omicron, have suggested minor refinements to RaDVaC Gen 11. Therefore, RaDVaC will soon release the Gen 12 vaccine design.

Summary: We predict the extensive variation of Omicron will reduce the effectiveness of Spike-based vaccines, and substantially reduce the effectiveness of RBD-based vaccines and antibody therapeutics (other than GSK sotrovimab), yet have little impact on RaDVaC vaccines.

RaDVaC remains committed to producing and distributing free, open-source, and up-to-date vaccine recipes and high-quality vaccine deployment tools, including a vaccine platform that is modular, easy to produce, rapid to adapt, and resilient to pathogen mutation. In addition to updates to our whitepapers, we are now increasing our investment in studies to validate and generalize the technologies we produce in order to create a plug-n-play vaccine platform that provides high confidence of effectiveness when used for the first time against a novel pathogen.

References:

1. https://en.wikipedia.org/wiki/SARS-CoV-2_Omicron_variant#Mutations
2. https://en.wikipedia.org/wiki/SARS-CoV-2_Delta_variant#Mutations
3. https://www.science.org/doi/10.1126/science.abf9302
4. https://www.nature.com/articles/s41586-021-03398-2
5. https://science.sciencemag.org/content/369/6506/1010.abstract
6. https://www.cell.com/cell-host-microbe/pdf/S1931-3128(21)00283-3.pdf
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524965/
8. https://www.nature.com/articles/s41598-021-99827-3
9. https://www.sciencedirect.com/science/article/pii/S2666379121000719