What’s been dubbed a “subvariant soup” may push daily Covid-19 cases over 11,000 this summer. Science reporter Jamie Morton explains the ingredients within it.
It’s an ever-evolving, hydra-like menace with so many forms and faces that scientists are battling to keep up with it.
Yet the Omicron that burst through our borders last summer was a simpler beast – and Kiwis infected in that first major wave most likely would’ve caught the virus in one of two varieties.
That was BA.1 - its “original” type, thought to have evolved on a distinct track spanning right back to the pandemic’s opening months – and BA.2, its more agile mark-two.
By travelling to every corner of the globe, these earliest editions of Omicron have gone on to spawn several hundred monitored lineages, with fresh ones being catalogued each week.
While that might seem an impressive amount of diversity to jam into the space of a year, it’s hardly surprising to scientists who study viruses like Sars-CoV-2.
In simple terms, the longer and more easily a virus is able to jump between us, the quicker it learns how to infect us.
This happens through viruses copying their own genomes through replication, a process that inevitably causes mistakes - or what we know better as mutations.
If it finds a certain mutation offers some kind of advantage, like better invading our cells, then that useful “mistake” sticks.
And 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 help them spread even 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 – and it’s just what’s played out within Omicron’s evolution.
BA.2 joined BA.1 in driving New Zealand’s first Omicron wave, before effectively squeezing its cousin out of local circulation by mid-autumn.
Within half a year, however, BA.2 was itself out-competed by smarter relatives, and now made up a fraction of sequenced cases.
Our winter subvariants
With winter bearing down on the country, modellers already knew what was coming with it: BA.4 and BA.5.
First detected in South Africa back in early 2022, this pair arrived armed with extra mutations that’d helped them dominate the globe.
These included a key change labelled L452R – something earlier found in Delta, and thought to help the virus better latch on to human cells – and another designated F486V, which likely aided them in dodging our immune response.
Over June and July, they drove a flood of infections that pushed New Zealand’s reported daily cases past 10,000.
That figure most certainly under-represented the true scale of infection, but nonetheless fell short of what modellers had estimated – suggesting a vast number of Kiwis had already picked up some immunity in the BA.2 wave.
Today, it appeared increasingly likely that BA.5 - though still responsible for about three quarters of national cases – might prove our last all-dominant Omicron subvariant.
ESR’s bioinformatics and genomics lead, Dr Joep de Ligt, said most BA.5-like lineages his colleagues were reporting looked to be trending downward.
“So today it’s really just the off-shoots that we’re picking up – and there now appears to be about 50 different lineages, or grandchildren of BA.5, that are doing the rounds.”
That’s no different to what’s been observed on those other main branches of the Omicron tree, with myriad lineages of BA.2 and BA.4 co-circulating with their own genetic machinery.
Remarkably, scientists have watched many of these strains develop independently – but all while acquiring similar traits in response to the same selective pressures – making for one of the world’s most fascinating cases of “convergent” evolution.
None of this boded well for us - especially considering these strains had often evolved to knock out specific parts of the viral spike protein that our vaccines and monoclonal antibody treatments target.
In New Zealand and elsewhere, some have managed to carve out larger slices of our infection pie than others: namely BA.2.75, better known as Centaurus.
Around the time our winter wave was building, scientists detected our first cases of this second-generation subvariant of BA.2, which packed eight extra mutations in its spike protein.
“Back when there was a heavy skew of BA.2.75 in places like India, we thought there’d be an explosion of cases of it here – yet it’s been more of a slow increase,” Otago University virologist Dr Jemma Geoghegan said.
It now made up about one in 10 local cases.
Meanwhile, a Centaurus lineage with an additional three spike protein mutations, and dubbed BR.2.1, has been on the rise in New South Wales and was circulating at low levels here.
Also showing good potential to spread was BA.2 descendant BN.1, recorded in more than 30 countries, and behind a growing proportion of US cases.
With our open borders and relaxed testing requirements, scientists think that’s only a matter of time before more of these new variants gain a foothold here.
That didn’t always mean they’d cause a big splash.
Take BA.4.6, which sparked headlines when it arrived here over spring, carrying the immune evasion-linked mutation R346T.
Like Centaurus its impact has been limited, accounting for about 3 per cent of cases.
“When we look at the estimated proportion of cases that are BA.4.6, it seems to be either stable to slowly decreasing,” said de Ligt, adding that under-reporting made it difficult to be precise.
At the same time, BA.5 subvariants BQ.1 and BQ.1.1 - nicknamed Typhon and Cerberus respectively – have risen to cause around 5 per cent of our sequenced cases.
Linked to a tide of infections in France over recent months, while also gaining a large foothold in the US, these subvariants have shown themselves to be much more adept at escaping first and booster vaccines than previous variants.
While some countries like the US now have a BA.5-targeted “bivalent” booster that’s also just been shown to protect against Typhon and Cerberus, New Zealand wasn’t one of them.
Recombinants and reinfection
Deeper within our subvariant soup is a small dollop of recombinants: strains created by two viruses swapping genetic material and typically designated with an X.
They sometimes arise from a person being infected twice at the same time – as may have happened with the very first major Omicron recombinant that Kiwis learned of.
That was XE, a hybrid of BA.1 and BA.2, that was initially estimated to have been about 10 per cent more transmissible than BA.2 when it was detected here for the first time in late April.
While drawing plenty of attention at the time, University of Auckland computational biologist Dr David Welch rightly predicted XE wasn’t a game-changer.
Whether any of these cross-breeds emerged as a big threat remained to be seen.
One example was XBB - an especially immune-evasive hybrid of BA.2.75 and another BA.2 sub-lineage, BA.2.10.1 - that’s grown to make up about two per cent of our cases.
Having caused small surges in Singapore and Bangladesh without mass mortality, XBB isn’t thought to be any more severe than BA.5, although researchers are still trying to more accurately gauge its severity.
Already, however, it’s evolved into the XBB.1, XBE and XBF variants.
“Most of the recombinants we’re seeing are results of Omicron-on-Omicron, which is what we’d expect, given it’s been the major variant for such a long time,” de Ligt said.
“One exception to that rule is XBC, where Omicron has found a reservoir of Delta and then recombined with that.”
XBC, which packed a staggering 130 mutations, happened to be one of several so-called “Deltacron” subvariants now floating about the world.
While any lineage with the potential to combine Omicron’s faster transmissibility with Delta’s higher severity might be worrying, none of the mostly Asian countries that have registered XBC cases have seen any notable rise in deaths.
Some other freshly-emerged Omicron off-shoots have struck scientists as intriguingly exotic.
One was CH.1.1, a subvariant linked back to BA.2, yet sporting the same major mutations as the much more recent BQ.1.1, and described by one researcher as a “curious exemplar of convergent evolution”.
With our subvariant landscape growing ever more complex – scientists also aren’t discounting another entirely new Greek letter replacing Omicron itself - de Ligt expected we’d come to discuss the risk of waves differently to how we long have.
That meant focusing not on single strains like BA.2, BA.5 or Centaurus, but the collective reinfection potential of a host of viral newbies.
A key way to do that was measuring what are called receptor binding domain or RBD levels, which related to a part of the viral spike protein where mutations caused important changes in amino acids.
It was also the portion of the protein the virus used to infect our cells, and which antibodies targeted to launch a strong immune response.
“What we’re seeing now is those sublineages with higher RBD levels – think those that are the fifth or sixth generations along – are the ones on the rise in our current wave, and causing reinfections,” de Ligt said.
“Over time, we’re seeing increasingly fewer people who haven’t had Covid at all; so we’re definitely watching these new kids on the block.”
That these various strains could spread and power waves together explained why health officials are warning daily cases could peak at more than 11,000 over summer.
“If you’ve got one variant with a 10 per cent growth advantage over BA.5, and something else with the same edge, then you’d expect them both to co-circulate,” Welch said.
“It’s really no different from having just one variant with the same advantage, but which is more widespread.”
De Ligt said it also didn’t seem to matter which of these lineages infected people, with studies showing little notable difference in their disease severity thus far.
Fortunately, the immune memory most Kiwis have gained from vaccination and natural exposure still offered protection against the very worst outcomes of any Omicron infection.
Yet, with Covid-19 still hospitalising and killing people each week, and leaving countless more with long-lingering symptoms, experts’ best advice about the virus remained unchanged: avoid it.
