An array of different mutations or combinations of mutations may help the Omicron variant of SARS-CoV-2 escape immune responses or therapeutic antibodies, according to a study published today in eLife.
The study may help scientists understand how the SARS-CoV-2 virus evolves. It could also help them predict how new mutations might affect the virus’ ability to escape previous immunity, or which therapies may work against emerging variants.
The Omicron BA.1 variant of SARS-CoV-2 is able to reinfect people who have previously had an earlier strain of the virus. Mutations in the Omicron strain affecting the spike protein, which allows the virus to bind to and infect cells, made it harder for immune system antibodies generated in response to earlier strains to recognise the spike protein and neutralise the virus.
“Most studies have focused on how single mutations allow SARS-CoV-2 variants to escape pre-existing antibodies,” says co-lead author Alief Moulana, a graduate student in the Department of Organismic and Evolutionary Biology at Harvard University in Cambridge, Massachusetts, US. “But we wanted to understand how interactions between multiple mutations affect the virus’ ability to dodge antibodies or infect cells.”
Moulana was an equal contributor and co-lead author of the study with Harvard colleagues Thomas Dupic, a postdoctoral fellow; and Jeffrey Chang, a graduate student; and former Harvard colleague Angela Phillips, who is now an assistant professor in the Department of Microbiology and Immunology at the University of California, San Francisco, US.
The team had previously created a library of all the possible configurations of the antibody-binding portion of the spike protein between the original strain of SARS-CoV-2 and Omicron. In this region, Omicron BA.1 differs from the original strain by 15 amino acid substitutions. In the current study, they created a library containing the 32,768 variants with every possible combination of these 15 mutations. They then genetically engineered yeast to express binding regions with each genetic combination and systematically tested how they interacted with four monoclonal antibodies used to treat COVID-19.
They found that just one or two mutations with dramatic effects on the binding region of the spike protein can allow it to dodge multiple antibodies. Combinations of many mutations with less pronounced effects can also enable the virus to escape specific antibodies.
But they also identified significant trade-offs. For example, some mutations that allow the virus to dodge one antibody can make it susceptible to another. Mutations that enable antibody escape can also dramatically weaken the spike protein’s ability to bind and infect cells. However, other mutations can help compensate for lost binding and infective capacity.
“We show how the Omicron BA. 1 variant evolves to dodge antibodies while maintaining its ability to infect cells,” says Dupic. “Our work suggests that this evolution is driven both by immune escape and the need for compensatory mutations that make up for the negative effect of the escape mutations on the variant’s ability to bind host cells.”
The authors say more studies are needed to confirm that the interactions observed in their laboratory experiments are relevant to real-world infections. But in the meantime, their approach may reveal additional insights about the evolution of SARS-CoV-2.
“Our techniques could enable us to study how mutations in newer strains of SARS-CoV-2 help escape the immune system,” explains senior author Michael Desai, Professor of Organismic and Evolutionary Biology at Harvard University. “It may also help us understand how mutations in the virus can allow it to infect different species.”
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