Including an overview of the latest WHO Global Consultation (15/12/2021): What evidence do we have that Omicron is evading immunity and what are the implications?
By Michael Spedding1 and Francesca Levi-Schaffer2, 20/12/22
1 IUPHAR and Spedding Research Solutions SAS, 6 Rue Ampere, Le Vesinet 78110, France
2 IUPHAR and Pharmacology and Experimental Therapeutics Unit, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem Campus, POB 12272, Jerusalem 91120, Israel
Correspondence: michael@speddingresearchsolutions.fr
The COVID pandemic has made immense changes in pharmacology and immunopharmacology since December 2019. The rapid development of vaccines, but the relative failure of drug therapy, and the crucial role of scientific advice, have changed the current practice and the future of pharmacology. The appearance of variants has engendered an ‘arms race’ between the virus and therapy, but humans are now the largest animal biomass on the planet, which can be exploited by viruses that mutate extremely fast (Figures 1, 2, and 3), with immense competition between different strains. Nevertheless, the sudden appearance of Omicron is an enormous global health challenge, with infection rates in the UK currently doubling every two days and an R of 3-5. At present we do not know the severity of ensuing illness, especially in partly vaccinated populations: a real sword of Damocles. Thus, this little update can only be a snapshot at 20/12/2021, but with the advantage of having been able to attend the recent WHO Global Consultation: What evidence do we have that omicron is evading immunity, and what are the implications? chaired by Phil Krause, WHO COVID vaccines research expert group.
A remarkable website, https://nextstrain.org/ncov, shows the evolution of the different strains of SARS-CoV-2. Millions of complete SARS-CoV-2 genomes have been reported and Figure 1. shows how quickly successive mutations outcompete each other. Omicron seems to behave in a similar way, rapidly becoming a dominant strain, because in South Africa the Omicron variant has outcompeted delta, which has now virtually disappeared.
Figure 1. Nextstrain has published the evolution of the virus, with the major mutations in the clades. This graph shows the progressive mutations in the different forms of the virus, taking the site numbering and genome structure of the original strain, Wuhan-Hu-1/2019 as the reference. Red shows the appearance of Omicron, as of 11/12/2012.
Figure 2A. Rectangular plot with the mutations of Omicron in red. The representations are from Nextstrain/ncov, built and maintained by the Nextstrain team, with data from GISAID – Initiative.
Figure 2B. Radial plot with the mutations of Omicron in red. The representations are from Nextstrain/ncov, built and maintained by the Nextstrain team, with data from GISAID – Initiative.
The great number of mutations in the spike protein (Figure 3) is surprising, but increase the fit with its molecular target, ACE2, thereby increasing affinity. The vaccines and most antibodies (including our own if previously infected) are against spike protein. A controversy at the WHO meeting was whether the mutations in spike were stable, or if they changed rapidly between substrains; resolution of this issue is important because flexibility in spike mutations could be serious for the design of future mRNA vaccines, and for sufficiently generalised immunity post-infection. While nearly all discussion to date has centred on the mutations in spike protein (the receptor-binding domain, RBD), other mutations are present and their impact on host response and on COVID-19 symptoms are not yet clear (Figure 4.)
Figure 3. Mutations in the spike protein of Omicron compared with delta (from COG-UK/Mutation Explorer (gla.ac.uk))
Figure 4.
Omicron has at least 50 amino acid mutations and ~ten non-amino acid-altering mutations, some of which may be in regulatory sequences. The spike protein contains at least 36 amino acid changes alone. Spike changes account for increased infectivity by increasing the affinity of the S protein to the ACE2 receptor, as well as increasing the efficiency of viral entry. Therefore, the drugs consisting of anti-spike antibody cocktails developed during the previous variants’ waves such as casirivimab, imdevimab, and bamlanivimab may be less effective in protecting COVID-19 patients. Moreover, to predict the severity of the Omicron infection, we must take into account also the mutations outside of the S protein, such as in the structural proteins, in the viral RNA-dependent RNA polymerase, and even in the untranslated regions. All these non-spike mutations that are overlooked right now, might increase the virus ability for replication, transcription, and translation. Indeed, most non-Spike proteins that lie in the Orf1ab replication complex and required for the formation of the double-membrane vesicle necessary for virus replication. Seven mutations in this replication complex have been found to be unique to Omicron. Last but not least, the Omicron mutations may have some impact on proteolytic processing and nucleic-acid binding efficiency, and on the SARS-CoV-2 main protease, which cleaves the polyprotein during replication and transcription, so the effectiveness of the drugs interfering with the viral RNA-dependent RNA polymerase such as remdesivir and mulnupiravir and the ones binding to the protease active site and inhibiting its activity such as ritonavir and lopinavir, may be affected.
Thus, neutralizing antibody response appears to be effective, if they are present in sufficient titres, but Omicron is the most resistant strain to date to current antibodies whether raised by vaccines or in response to infection by other strains (Chen et al., 2021).
However SARS-CoV-2-specific CD8+ and CD4+ T cells which respond to multiple targets are also a robust defence after infection or vaccination (Grifoni et al., 2020) and Alessandro Sette showed that 85% of T cell responses were still conserved in 3 infected donors, and further bioinformatic analyses suggested that viral evolution was not escaping T cell responses. However, the ratio of different vaccines to evoke T cell responses compared with antibodies is still debated. David Montefiore showed convincing evidence of decline with time in antibody efficiency against Omicron infection (taking sera from vaccinated individuals and challenging the virus with progressive sera dilutions), but the booster injection maintained efficacy (Doria-Rose et al., 2021). There was agreement about this issue over several studies, using either the Pfizer or Moderna vaccine. As the CD8+-T cell responses are resistant to the changes in spike protein mutations then two vaccinations may still protect against severe disease.
This brief report indicates the current status, but the issue of whether Omicron will cause a pandemic of serious disease or reflect a major reduction in the percentages of people with a serious disease, and therefore a step towards adaptation to an endemic virus, will play out over the next few weeks. It must be remembered that a virus is not living, but rather a device that reproduces by rapid molecular roulette in host cells (i.e., Figure 2), so a virus which can spread so effectively, even at presymptomatic stages, is therefore not well biased to the long-term benefit of the host. The stakes are incredibly high.
Chen, J., Wang, R., Gilby, N. B., & Wei, G.-W. (2021). Omicron (B.1.1.529): Infectivity, vaccine breakthrough, and antibody resistance. ArXiv:2112.01318 [q-Bio]. http://arxiv.org/abs/2112.01318
Doria-Rose, N. A., Shen, X., Schmidt, S. D., O’Dell, S., McDanal, C., Feng, W., Tong, J., Eaton, A., Maglinao, M., Tang, H., Atmar, R. L., Lyke, K. E., Wang, L., Zhang, Y., Gaudinski, M. R., Black, W. P., Gordon, I., Guech, M., Ledgerwood, J. E., … Montefiori, D. C. (2021). Booster of mRNA-1273 Vaccine Reduces SARS-CoV-2 Omicron Escape from Neutralizing Antibodies (p. 2021.12.15.21267805). https://doi.org/10.1101/2021.12.15.21267805
Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., Marrama, D., de Silva, A. M., Frazier, A., Carlin, A. F., Greenbaum, J. A., Peters, B., Krammer, F., Smith, D. M., Crotty, S., & Sette, A. (2020). Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell, 181(7), 1489-1501.e15. https://doi.org/10.1016/j.cell.2020.05.015