What to Know About the New Delta Sublineage

As the now ubiquitous Delta variant continues to mutate, it's spawned a new descendant that's spread in the U.K. and made its way to the U.S.

The Delta sublineage, known as AY.4.2, is characterized by two "S-gene mutations" on A222V and Y145H, both located on the gene that encodes the spike glycoprotein of SARS-CoV-2.

CDC Director Rochelle Walensky, MD, acknowledged during the White House's latest COVID-19 Response Team press briefing that the AY.4.2 sublineage has been identified "on occasion" in the U.S. without increased frequency or clustering to date.

Since August, AY.4.2 with these mutations has appeared in a total of three cases in the U.S.: in California, North Carolina, and Washington, D.C., according to Outbreak.info, which collects COVID-19 sequencing data from GISAID, a global genomic data-sharing initiative.

"At this time, there is no evidence that the sub-lineage AY.4.2 impacts the effectiveness of our current vaccines or therapeutics, and we will continue to follow up," Walensky said.

Experts think the new Delta sublineage is slightly more transmissible, but say it's likely less worrisome than its predecessor Alpha or Delta variants, which made bigger jumps in transmissibility. There's a level of uncertainty over its exact advantage in spreading, however.

"There was a bit of a hope that Delta had, ideally, reached a kind of bound in transmissivity, so that will be a bit of a disappointment," said Francois Balloux, PhD, computational biologist at University College London and director of the UCL Genetics Institute, in an interview.

Balloux predicted that at some point, almost everyone will be exposed to the "already so bloody transmissible" Delta variant, which makes up around 80% of sequenced cases in the U.K. He said AY.4.2 could be up to 15% more transmissible.

A lower estimate comes from Christina Pagel, PhD, the director of University College of London's Clinical Operational Research Unit. On Twitter, she said that AY.4.2 could be up to 10% more transmissible: "We don't know if it's (a bit) more transmissible than other Delta strains *or* if it just got caught up in some superspreader events that seeded it." That is, a large gathering of people could have amplified the effect of a strain that wasn't intrinsically better at spreading.

"No reason to think it's more immune evasive & might well be nothing. Something to keep an eye on but not panic over," Pagel added.

The CDC lists AY.1 and AY.2 in its COVID Data tracker, and AY lineages generally under its "Variants of Concern" classification, but does not list AY.4 or AY.4.2 specifically. Balloux said that in the U.K., unlike the U.S., the genetic sequencing effort is nationally centralized. This makes it easier to track variants more quickly and accurately.

AY.4.2 was first spotted this spring in the U.K., where it represents 14,247 cases for a cumulative prevalence of 1% there at the time of publication, according to Outbreak.info.

The U.K. Health Security Agency reported on October 15 that AY.4.2 "is currently increasing in frequency" and that it made up 6% of the sequences analyzed. Balloux estimated that a more up-to-date number would be 7% to 8% because of a week-long lag in sequencing.

Notably, AY.4.2 spreads despite being characterized by S-gene mutations that are not known to make the virus intrinsically more transmissible. "Fundamentally, these are two very boring mutations," Balloux said.

He clarified that this strain of SARS-CoV-2 is not "Delta plus" because it lacks a different mutation that defined that sublineage.

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