This week marks four months since South African scientists detected a new variant of the Sars-CoV-2 virus – later named Omicron. Jamie Morton asks what's coming next.
Over the weekend, scientists reported something that wouldn't at all surprise virologists, but should've nonetheless made sobering reading for the rest of us.
In a pre-print study, Canadian biologists described a "new and highly divergent" lineage of the Sars-CoV-2 coronavirus that had been discovered in white-tail deer – and possibly also passed on to humans.
The coronavirus has been found in deer before, along with a colourful variety of species spanning from cats, dogs and pigs to ferrets, rabbits, fruit bats and hamsters.
But this discovery was nonetheless troubling because it underscored the potential of animals becoming new variant reservoirs.
Reverse zoonosis and spillback - or viruses being passed from humans to animals, then sent back in new, mutated forms - was just one way we could expect the Covid-19 threat to keep changing.
And there was absolutely no guarantee the milder characteristics of Omicron would be its future flavour.
Born to spread
From the moment Sars-CoV-2 broke out of China and spread across the globe, the risk of new variants emerging wasn't just a possibility, but a certainty.
Since then, dozens have emerged with genetic links back to that so-called "wild type".
But just a handful, including Omicron and Delta, Beta, Gamma and Alpha before it, have been worrying enough to earn the World Health Organisation's official designation of "variant of concern".
Why new variants arose was well understood.
As viruses spread, they replicated by copying their own genomes. In the process, they sometimes made mistakes - creating what we know better as mutations.
When this happened in other biological entities like ourselves, it was swiftly spotted and fixed.
That's not so easily done in most RNA viruses - but coronaviruses like Sars-CoV-2 did carry that ability to some extent, allowing them to evolve at a rate about half that of influenza.
The longer and more easily a virus was allowed to spread from host to host, the faster it learned how to better infect them. And if it found a certain mutation offered some kind of advantage, like better invading our cells, then that useful "mistake" stuck.
In all of the Covid-19 variants we've seen so far, a key feature has been clever combinations of specific, structure-changing mutations that helped them spread quicker.
These mostly tended to occur around the virus' "spike protein", which it used to latch onto a specific receptor that gave it entry to our cells.
Delta caused such devastation in last year's early waves because some of its 13 mutations proved much better at grabbing onto this receptor, allowing it to infect even more cells and rapidly overwhelm our immune defences.
A grim signature of Delta infections was infection with a higher "viral load" - ravaging the lower respiratory tract, causing violent bouts of coughing, and making people more contagious.
Studies have also found people infected with the variant become more infectious earlier than that of its virus predecessor.
Whatever came next had to outcompete this extremely "fit" variant – and so Omicron did.
Soon after it emerged in South Africa, scientists quickly counted about 50 mutations, and more than 30 within its spike protein alone – about double that of Delta.
Not only did that signal the potential to infect more people, but also to develop more mechanisms with which to escape immunity, given most Covid-19 vaccines work by forming antibodies against the spike protein.
One study indicated that, at just 24 hours after infection, Omicron replicated within the human bronchus around 70 times higher than the Delta variant and the original strain.
Being between two and four times more contagious, Omicron swiftly washed over the world at an incredible pace – squeezing Delta into a minority of recorded infections.
Still, Delta's heavier hit on the human body meant it was still disproportionately represented in our hospitals, where it accounted for more than half of Covid-19 cases today.
What comes after Omicron?
New pandemic-driving variants have tended to turn up every six months - but it wasn't clear whether Omicron would shuffle off the stage so quickly.
"To be able to replace Omicron, [the next variant] will have to be even more contagious – or have a higher transmission rate – as well as be even better at evading vaccines," Otago University virologist Dr Jemma Geoghegan said.
"That's exactly what we saw with Omicron, when it replaced an extremely transmissible Delta."
As for the disease the next variant caused, Geoghegan said it could be less, more, or equally severe as Omicron.
"Predicting that part of the evolution of variants is really difficult because we've seen examples where it's been more so, and with Omicron, where it's been less."
We certainly couldn't assume – as some optimistic predictions have – that Omicron marked a softening pandemic.
University of Auckland computational biologist Dr David Welch said it might be that the next variant targeted both the upper and lower lungs, as well as carrying the molecular machinery needed to spread faster.
"We could definitely see something that clings on to another part of our body and causes really serious disease."
The latest report out of the UK Government's Scientific Advisory Group for Emergencies (SAGE) went as far as calling Omicron's milder symptoms as a "chance event".
"The next variant to achieve UK/global dominance is likely to have the same pathogenicity as previous variants."
Among four scenarios it sketched out was a potential variant that emerged to cause severe disease in a greater proportion of the population than had occurred to date - such as happened with previous coronaviruses Sars-CoV and Mers-CoV, which had case fatality rates of around 10 and 35 per cent respectively.
Another was a drug-resistant variant that emerged as a direct result of anti-viral strategies.
"Ultimately, whatever provides for a selective advantage for the virus to transmit more is going to dictate what happens with severity," Geoghegan said.
She pointed to another obvious influencer: the world's changing immunity profile.
Once a large proportion of the global population had some immunity to the virus, we could expect to see evolution driven more by "immune escape" – or the ability to infect those who've been vaccinated or have natural immunity.
SAGE said a new variant that evaded current vaccines might arise through an immunity-tricking effect called "antigenic shift" - and observed in Omicron.
Still, vaccines and booster shots produced to date have held up impressively well at keeping most people out of hospital.
"Even if we may be dealing with a variant intrinsically more severe," Geoghegan said, "we'll hopefully be better placed to deal with it, given our higher protection from vaccines and past infection."
Just how the next variant emerged – and it may well have already – was another big question.
"There are theories around it arising from someone who's chronically infected and carries the virus for a long time, or it coming from animal populations," said Welch, noting the new white-tailed deer revelations.
"Either one of those settings could be their own variant factories."
The SAGE report further pointed out new variants didn't necessarily need to emerge from globally dominant variants – Omicron's ancestor wasn't Delta but a strain dating back to mid-2020 – nor did would it have to arise from where vaccine selective pressure was greatest.
The group added that, while focus was rightly placed on changes in the spike protein, "our understanding and monitoring of changes at other sites in the genome should not be neglected as these proteins are also major determinants of transmission, fitness and disease outcome in coronaviruses".
As well, even the most successful variant couldn't completely crowd out others.
"In the UK we have seen almost complete replacement of previous variants by Alpha, then Delta, then Omicron," SAGE reported.
"Other parts of the world have less complete replacement, but the general trend is similar, with some co-circulation of different lineages in different parts. This is a feature that we also see in influenza, albeit with some co-circulation of different lineages."
Finding the next variant
Around the world, scientists have been trying to find possible tell-tale signs that could forewarn the pandemic's next turn.
In New York City, scientists have identified several "cryptic" mutations possibly linked to animal origins, such as rats the frequent the city's sewer system.
"We still don't know where the Omicron variant came from, but it had to come from somewhere," said University of Missouri virologist Professor Marc Johnson, whose team published the findings last month.
"These variants are bubbling up everywhere, including Omicron, which eventually spilled into the general population and wreaked havoc.
"We think these weird lineages could be where the next variant of concern for Covid-19 comes from."
In another study published last month, Spanish scientists found mutations in the virus that could help it escape the immune system in specific groups of people.
They used computer modelling to look at how bits of the virus, called epitopes, were recognised by T cells in people.
When they looked at virus samples from around the world they found that around half of these virus bits were mutated in some way - although few samples of the virus had accumulated enough mutations to be a risk to the global population.
Instead, they also found that mutations in the virus can occur in samples from regions where the population naturally has T cells that are less able to respond to the virus.
They found this combination could put these populations more at risk from new variants.
Elsewhere, researchers have tried to use models to answer the question.
Two new US computer models account for factors like the movements of variants within and between countries – and could be used to figure out which emerging variants are likely to become dominant.
While a lack of data made it tough to determine whether they posed a big risk, the US researchers behind the models say their estimates stabilised after several weeks, as more information flowed in.
Wherever the next variant came from, Welch emphasised the SAGE group's grim points.
This pandemic is far from over - and Omicron's successor might well be much more unpleasant.
"Anyone who claims that virulence is always downwards," Welch said, "is just making things up".