XBB.1.5 fastest spreading variant since first Omicron wave

Projections from the Centers for Disease Control and Transmission (CDC) estimate that the new XBB.1.5 variant of SARS-CoV-2 has exploded in prevalence in the United States, jumping from just 3% to more than 40% in a matter of weeks. The variant is believed to have originated in New York and the researchers say early studies indicate it can bind to human cells more effectively than previous variants.

As the world celebrates the dawn of a new year and we enter the fourth year of the pandemic, another twist in the history of COVID has appeared with the emergence of XBB.1.5, a new sub-variant of Omicron which seems to be spreading rapidly across the world. United States. The variant appears to be the first recombinant mutation to have a relevant impact on the trajectory of the pandemic.

A recombinant is a virus that is a mixture of genomes from different variants. They can appear when a person is infected with two or more variants simultaneously.

“When a virus copies itself, it can ‘pattern change’ between different floating genomes,” said researcher Emma Hodcroft. “If they’re all the same, the end product is no different! But if distinct lineages are present at the same time, we can spot these ‘chimera’ children – recombinants!”

Virus researcher Emma Hodcroft explains recombination
Virus researcher Emma Hodcroft explains recombination

Many SARS-CoV-2 recombinants have appeared lately, often resulting in hyperbolic headlines announcing the threat of an emerging “deltacron” strain. However, until very recently, no SARS-CoV-2 recombinant has ever spread significantly enough to generate a relevant wave of infection.

The first recombinant to make a serious appearance appeared a few months ago and was dubbed XBB. The unique variant is a combination of BJ.1 (aka BA.2.10.1.1) and BM.1.1.1 (aka BA.2.75.3.1.1.1).

XBB was initially identified in India in August and Singapore was the first country to experience an XBB wave in October. This surge peaked relatively quickly without causing too much trouble for the nation’s healthcare system, suggesting that XBB might not cause too many problems around the world and leading many researchers to breathe a sign of relief.

A look at the rise and fall of XBB in Singapore
A look at the rise and fall of XBB in Singapore

But the past year has demonstrated that no variant of SARS-CoV-2 stays the same for too long, and as XBB traveled the world, it quickly detected new mutations. Enter XBB.1.5, perhaps the first disturbing variant to emerge from the United States.

The first reported XBB.1.5 sample dates back to October 22 in New York. A week later, the variant was detected in Rhode Island and Washington. Scattered detections were then detected in India and Indonesia in early November, but by the middle of the month a number of European countries detected the new variant.

Tracking XBB.1.5 samples over time by variant researcher Raj Rajnarayanan
Tracking XBB.1.5 samples over time by variant researcher Raj Rajnarayanan

Until last week, the CDC’s variant tracking model had not separated XBB.1.5 from XBB. But just before the start of the new year, his new forecast appeared, and suddenly XBB.1.5 was included, projected to account for over 40% of all cases in the United States.

Because of the slowness of genomic sampling, the CDC uses a modeling system called Nowcast to predict variant changes in real time. Nowcast’s current model estimates that XBB.1.5 cases have doubled in the United States over the past week, and in the northeast of the country account for more than 75% of all confirmed cases.

The latest CDC Nowcast modeling showing the rapid spread of XBB.1.5
The latest CDC Nowcast modeling showing the rapid spread of XBB.1.5

CDC

As always, the million dollar question is whether XBB.1.5 causes more severe disease than previous Omicron variants. Eric Topol of the Scripps Research Institute said New York can be seen as an indicator for XBB.1.5, and the region has seen a concerning rise in hospitalizations in recent weeks. According to Topol, this spike in hospitalizations may not be entirely due to the ramp-up of XBB.1.5, but the new variant is almost certainly playing a part.

Hospitalizations in New York State Throughout the Pandemic
Hospitalizations in New York State Throughout the Pandemic

“Of course, other factors are likely contributing, such as decreased immunity, indoor/holiday gatherings, cold weather, lack of attenuation,” Topol explained on his blog. “But it should be noted that the New York Covid hospital admission rate is the highest since late January (and also surpasses the Delta wave of summer 2021, but with some ambiguity as to how hospitalizations were categorized then and now).”

Alongside these epidemiological observations, new experimental data from researcher Yunlong Cao indicate that a key mutation in XBB.1.5 may explain how this variant can bind more efficiently to human cells. Dubbed F486P, the mutation improves the virus’s ability to bind to certain receptors on human cells. While other mutations help this particular variant evade immune antibodies developed from previous infections, F486P means the virus can enter human cells more efficiently.

Researcher Yunlong Cao posted his latest findings on Twitter in late December
Researcher Yunlong Cao posted his latest findings on Twitter in late December

About a year ago, Jesse Bloom, a researcher who tracks the evolution of viruses, flagged 486 as a key genomic site for future problematic SARS-CoV-2 mutations. Current antibodies induced by vaccines and infections specifically rely on this location to effectively neutralize the virus.

Thus, most mutations at site 486 lead to a more immune evasive variant, but its evolution comes at a cost. Studies have linked earlier 486 mutations to less efficient binding to human cell receptors. This means that earlier variants of SARS-CoV-2 sacrificed cell binding to avoid antibodies.

In late 2021, the Bloom Lab reported 486 as a key site for Omicron's neutralization, suggesting that mutations here could be particularly evasive of the immune system.
In late 2021, the Bloom Lab reported 486 as a key site for Omicron’s neutralization, suggesting that mutations here could be particularly evasive of the immune system.

The big difference between XBB.1.5 and its parent lines (XBB and XBB.1) is that it swapped an F486S mutation for F486P, and F486P is the only 486-site mutation that overlaps the best of both worlds, the escape antibodies without sacrificing affinity efficiency for human receptors.

“Therefore, XBB.1.5 should not have more antibody escape than XBB.1 (which had already mutated F486), but it should have higher ACE2 affinity,” Bloom recently explained. “So it’s greater ACE2 affinity (and maybe RBD [receptor binding domain] stability) which gives XBB.1.5 its boost in transmissibility, and makes it skyrocket.”

Yunlong Cao also speculates that XBB.1.5’s unique cell-binding affinity may make it more likely to generate other new mutations in the future. So, of course, XBB.1.5 is unlikely to be the end of the road for SARS-CoV-2 variants.

“Another important observation is that the hACE2 binding affinity of XBB.1.5 is almost comparable to that of BA.2.75, which may allow XBB.1.5 to obtain more mutations, similar to those of BA.2.75” , Cao suggested on Twitter. “It’s just that XBB.1.5 hasn’t felt much immune pressure yet.”

None of this means that XBB.1.5 will necessarily generate more severe disease than previous variants, but it does mean that XBB.1.5 may be able to infect more people, more easily, and subsequently track down people who are the most severe. more vulnerable to COVID-19 – namely, the elderly, the under-vaccinated, and the immunocompromised. XBB.1.5 by no means takes us back to square one, but it could certainly prolong the pandemic, increase infections and put pressure on healthcare systems again.

Another potential concern of XBB.1.5 is its impact on long COVID. Yale researcher Akiko Iwasaki noted that the increased cell-binding affinity for this new variant could hypothetically lead to a new wave of long COVID infections due to the virus’ increased ability to infect human cells.

“I am concerned due to the putative ability of XBB.1.5 to have an increased ability to infect cell types that express even lower levels of ACE2,” Iwasaki tweeted recently. “This will increase tropism and possibly persistence in long-lived cell types.”

Vaccine specialist Peter Hotez said XBB.1.5 raises many new questions that need to be answered, but we shouldn’t be afraid or overreact. He points to a recently published study showing that the new bivalent COVID vaccine is still effective against new variants such as XBB. Thus, XBB1.5 may have increased cell-binding affinity, but our vaccines are still likely to be useful in reducing disease severity.

Should we look to add a new goal to update the vaccine in 2023, Hotez asks. It’s a question scientists and variant trackers will invariably ask themselves as the new year rolls on and SARS-CoV-2 continues to change shape around our defenses.

“I was hoping 2022 would work out better than 2021,” Hotez wrote on Twitter. “Maybe a little, but not that much…hopefully now 2023 will be better than 2022.”

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