A new study by an interdisciplinary group of scientists and clinicians from across the UK has demonstrated that the SARS-CoV-2 Omicron variant is capable of significant evasion from neutralising antibodies. The findings – enabled by COG-UK support – were recently published in a leading scientific journal, Nature Microbiology.
When the research team learned that vaccine effectiveness had declined substantially against the Omicron variant of SARS-CoV-2, they set out to understand why. They found that a high number of mutations in the gene encoding the spike protein enabled the Omicron variant to use a different pathway for entry into human cells, as well as making it easier to evade antibodies that recognise the virus.
The Omicron variant and its sub-lineages (sub-divisions that arise during further mutational change) that have come to dominate the majority of infections worldwide contain many mutations in the spike protein of the virus. Using data from the proportion of genomes sequenced in Scotland, Figure 1 below demonstrates the rapid rise in incidence of the Omicron variant and its different sub-lineages relative to the Delta variant.
Vaccines based on the spike protein of SARS-CoV-2 have been critical to the public health response to COVID-19. The emergence of increasingly transmissible variants with mutations to the spike protein now threatens this strategy.
Figure 1. Proportions of genome sequences from Scotland sampled between 1 September 2021 and 29 January 2022, showing the rapid displacement of SARS-CoV-2 Delta by Omicron (represented by the sub-lineages BA.1, BA.1.1 and BA.2). Figure adapted from the article.
In addition to investigating the impact of spike protein mutations on antigenicity – the ability of antibodies to bind to it – the team’s experiments also provided robust evidence for a shift in the Omicron variant’s entry pathway. Earlier SARS-CoV-2 variants of concern relied on direct fusion at the cell surface. However, SARS-CoV-2 Omicron appears to enter cells via endosomal fusion, which involves viral particles being transported into a cell via membrane-bound packages, known as endosomes.
This entry pathway represents a major difference to previous variants, and researchers found that it has likely modified Omicron’s ability to infect, and subsequently replicate, in various tissue types within the human body (it more easily replicates in upper airway tissues, for instance) – a discovery since confirmed by other research groups. The most significant consequence of the altered entry pathway is its relationship to disease severity, which has been dampened relative to previous variants.
For public health planning, the emergence of a highly transmissible variant associated with escape from vaccine-induced immune response means that over time it may be necessary to develop variant-specific vaccines.
While Omicron and its sub-lineages are less virulent than previous variants – primarily due to the changes in preferred cell entry pathway shown in this study – their rapid spread may continue to pose a risk to older people, to those with co-morbidities or compromised immune systems, or to people who are unvaccinated.
Professor Emma Thomson, Clinical Professor of Infectious Diseases at the University of Glasgow’s Centre for Virus Research and a co-author of the study, said in the research briefing accompanying the article:
“The immune evasion characteristics of Omicron confirmed in this research were correctly predicted through genetic sequencing. It is possible, by building on high-scale genomic data, that future vaccines will incorporate multivalent designs that encompass genetic variation of circulating variants.”
Continuous work is needed to gain a better insight into the expected virulence of future variants as they emerge over time. A trajectory of decreasing virulence cannot be guaranteed; the ongoing evolution of SARS-CoV-2 might bring future challenges.
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