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It’s a story perhaps more appropriate for Halloween than for the festive holiday season, given its scary implications. Four Omicron subvariants of the virus that causes COVID-19 will be the most common strains going from person to person this winter, new research predicts.

Not too dire so far, until you consider what else the researchers found.

The BQ.1, BQ1.1, XBB, and XBB.1 subvariants are the most resistant to neutralizing antibodies, researcher Qian Wang, PhD, and colleagues report. This means you have no or “markedly reduced” protection against infection from these four strains, even if you’ve already had COVID-19 or are vaccinated and boosted multiple times, including with a bivalent vaccine.

On top of that, all available monoclonal antibody treatments are mostly or completely ineffective against these subvariants.

What does that mean for our immediate future? The findings are definitely “worrisome,” said Eric Topol, MD, founder and director of the Scripps Translational Research Institute in La Jolla, California, and editor-in-chief of Medscape.

But evidence from other countries, specifically Singapore and France, show that at least two of these variants turned out not to be as damaging as expected, likely because of high numbers of people vaccinated or who survived pervious infections, he said.

Still, there is little to celebrate in the new findings, except that COVID-19 vaccinations and prior infections can still reduce the risk for serious outcomes such as hospitalization and death, the researchers write.

In fact, Centers for Disease Control and Prevention (CDC) data released Friday shows that people who have received four shots of the original COVID-19 vaccines as well as the bivalent booster were 57% less likely to visit an urgent care clinic or emergency room, regardless of age. 

The “Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants” study was published online this week in the journal Cell.

It comes at a time when BQ.1 and BQ.1.1 account for about 70% of the circulating variants, data show. In addition, hospitalizations are up 18% over the past 2 weeks and COVID-19 deaths are up 50% nationwide, The New York Times reports.

Globally, in many places, an “immunity wall” that has been built, Topol said. That may not be the case in the United States.  

“The problem in the US, making it harder to predict, is that we have a very low rate of recent boosters, in the past 6 months, especially in seniors,” he said. For example, only 36% of Americans 65 and older, the group with highest risk, have received an updated bivalent booster.

An Evolving Virus

The subvariants are successfully replacing BA.5, which reigned as one of the most common Omicron variants over the past year. The latest CDC data show that BA.5 now accounts for only about 10% of the circulating virus. The researchers write, “This rapid replacement of virus strains is raising the specter of yet another wave of infections in the coming months.”

BQ.1 and BQ.1.1 evolved directly from BA.5 — adding more and some novel mutations to the SARS-CoV-2 virus. XBB and XBB.1 are the “offspring” of a combination of two other strains, known as BJ.1 and BA.2.75.

The story sounds familiar to the researchers. “The rapid rise of these subvariants and their extensive array of spike mutations are reminiscent of the appearance of the first Omicron variant last year, thus raising concerns that they may further compromise the efficacy of current COVID-19 vaccines and monoclonal antibody therapeutics,” they write. “We now report findings that indicate that such concerns are, sadly, justified, especially so for the XBB and XBB.1 subvariants.”

To figure out how effective existing antibodies could be against these newer subvariants, Wang and colleagues used blood samples from five groups of people. They tested serum from people who had three doses of the original COVID-19 vaccine, four doses of the original vaccine, those who received a bivalent booster, people who experienced a breakthrough infection with the BA.2 Omicron variant, and those who had a breakthrough with a BA.4 or BA.5 variant.

Adding the new subvariants to these serum samples revealed that the existing antibodies in the blood were ineffective at wiping out or neutralizing BQ.1, BQ.1.1, XBB, and XBB.1.

The BQ.1 subvariant was six times more resistant to antibodies than BA.5, its parent strain, and XBB.1 was 63 times more resistant compared with its predecessor, BA.2.

This shift in the ability of vaccines to stop the subvariants “is particularly concerning,” the researchers write.

Wiping Out Treatments Too

Wang and colleagues also tested how well a panel of 23 different monoclonal antibody drugs might work against the four subvariants. The therapies all worked well against the original Omicron variant and included some approved for use through the US Food and Drug Administration emergency use authorization (EUA) program at the time of the study.

They found that 19 of these 23 monoclonal antibodies lost effectiveness “greatly or completely” against XBB and XBB.1, for example.

This is not the first time that monoclonal antibody therapies have gone from effective to ineffective. Previous variants have come out that no longer responded to treatment with bamlanivimab, etesevimab, imdevimab, casirivimab, tixagevimab, cilgavimab, and sotrovimab. Bebtelovimab now joins this list and is no longer available from Eli Lilly under EUA because of this lack of effectiveness.

The lack of an effective monoclonal antibody treatment “poses a serious problem for millions of immunocompromised individuals who do not respond robustly to COVID-19 vaccines,” the researchers write, adding that “the urgent need to develop active monoclonal antibodies for clinical use is obvious.”

A limitation of the study is that the work is done in blood samples. The effectiveness of COVID-19 vaccination against the BQ and XBB subvariants should be evaluated in people in clinical studies, the authors note.

Also, the current study looked at how well antibodies could neutralize the viral strains, but future research, they add, should look at how well “cellular immunity” or other aspects of the immune system might protect people.

Going forward, the challenge remains to develop vaccines and treatments that offer broad protection as the coronavirus continues to evolve.

In an alarming ending, the researchers write: “We have collectively chased after SARS-CoV-2 variants for over 2 years, and yet, the virus continues to evolve and evade.”

Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology, and critical care. Follow Damian on Twitter: @MedReporter.

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