When the Omicron variant burst onto the scene, nobody saw it coming. Nobody, that is, except a group of researchers at Harvard Medical School, who had inadvertently predicted quite a few of the new variant’s mutations before they turned up in the real world.

“To get out of this pandemic, we need to stay ahead of this virus, as opposed to playing catch up,” said Katherine Nabel, co-lead author of a study that models potential future mutations of SARS-CoV-2, the virus that causes COVID-19. The study was published last week in the journal Science.

“Our approach is unique in that instead of studying individual antibody mutations in isolation, we studied them as part of composite variants that contain many simultaneous mutations at once – we thought this might be where the virus was headed,” Nabel explained. “Unfortunately, this seems to be the case with omicron.”

All viruses mutate, all the time – we just tend not to notice unless it impacts things like the severity or transmissibility of a disease. Knowing that new lineages of COVID-19 are a question of “when” rather than “if,” the researchers wanted to see how future mutations might change how infectious and immune-resistant the virus becomes.

The team took cues from the chemical and physical structure of the SARS-CoV-2 virus as to how it might evolve, as well as scouring databases for rare mutations that had been detected in immunocompromised individuals. While they couldn’t have known it at the time, that has now turned out to be one theory as to how the Omicron variant evolved.

They focused in particular on the receptor-binding domain – the part of the coronavirus spike protein that latches on to our cells and lets the virus in. Mutations in this area would be cause for concern because that’s where most antibodies are trained – by previous infection, vaccines, or perhaps both – to attack. That’s why the Omicron variant has scientists so worried: it has a mind-boggling 15 mutations in the receptor-binding domain.

When a virus mutates itself under our antibodies’ radar like this, scientists say it has an “escape mutation,” and these are what the research team were looking for. Using what’s called “pseudotype viruses” – lab-made virus stand-ins, built by combining harmless, noninfectious particles with bits of the SARS-CoV-2 virus containing escape mutations – they found several ways in which the virus could potentially evolve a resistance to antibody defenses.

“This virus is a shape-shifter,” said study senior author Jonathan Abraham. “The great structural flexibility we saw in the SARS-CoV-2 spike protein suggests that Omicron is not likely to be the end of the story for this virus.”

The pseudotypes the researchers were working with contained up to seven escape mutations – a number so high that it had not yet been seen in widespread strains of COVID-19. Even so, the team found that the virus was still able to infect humans – and could evade antibody defenses, including those found in the monoclonal antibody cocktails that some states have become virtually semi-reliant on.

When the team were writing the study, such a level of complexity in virus mutations was only hypothetical. But with Omicron, that has changed – the variant has more than twice the highest number analyzed in the study.

“Our findings suggest that great caution is advised with Omicron,” Abraham warned. “These mutations have proven quite capable of evading monoclonal antibodies used to treat newly infected patients and antibodies derived from mRNA vaccines.”

While the findings may seem alarming, it's not all bad news: even the most highly mutated viruses in the study weren’t able to completely beat the defenses in double vaccinated blood serum. That’s why, the team say, that widespread repeated immunization – even with vaccines that were developed against the original virus – could be key to countering COVID-19 mutations.

As Abraham pointed out, the longer the virus is able to replicate in humans, the more likely it is that it will evolve escape mutations, allowing it to spread even in the face of natural immunity, vaccines, and other treatments – so the sooner we all get vaccinated and help to reduce virus transmission, the easier the pandemic will be to cope with.