COVID-19 study finds 'broader' antibody response maintains immunity to Omicron variant

Six different monoclonal antibodies developed to fight COVID-19 maintained a neutralizing response to the variant by targeting parts of the virus that haven't mutated.

Since the announcement of a variant of the SARS-CoV-2 virus on November 26th, researchers have been moving on multiple fronts to gauge the severity of the disease caused by the new variant, but also its likelihood to resist existing vaccines.

A study published Monday by biotech firm Vir Biotechnology of Switzerland, in conjunction with multiple research institutions, suggests some monoclonal antibodies developed to fight COVID-19 may work better when they have what the researchers call "broadly neutralizing" tendencies, meaning that they recognize many parts of the mutated virus. 

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"Strikingly, we found three potent neutralizing mAbs that bind to the RBM that are not affected by Omicron mutations," write lead author Elisabetta Cameroni of Vir, along with dozens of collaborating authors from the University of Washington in Seattle, Washington University in St. Louis, the Università di Milano, the Institute of Medical Science in Tokyo, and multiple other research institutions, in the paper, "Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift," posted on the BioarXiv pre-print server.

The authors conclude that antibodies that act "broadly," meaning, they recognize parts of the virus that don't change, can be a key weapon against mutations.

The paper has subsequently been published online by Nature magazine as a peer-reviewed report.

Also: COVID-19 Study finds some individuals both recovered and vaccinated maintain good immunity to Omicron variant

Antibodies are one of the bodies most prevalent defenses against viruses. If you've contracted COVID-19 and recovered, one way you may find out you've had it is via an antibody test that indicates the presence of antibodies in your bloodstream, among which the most common of which is immunoglobulin G, or "IgG."

Drug companies create a form of antibodies known as monoclonal antibodies that can be specific in what they target in a virus or other pathogen — a given target, or "epitope," as its known. 

The element of Omicron that has struck researchers is how much it has mutated versus the previous four strains of the virus. In particular, the spike protein, where the "receptor binding domain" dwells, has undergone more than thirty transformations from its form in prior variants. 

That proliferation of mutations may be enabling what's called "immune escape," whereby the virus not only is more transmissible but is better able to evade the antibody response. 

Since it appeared, Omicron has caused alarm because of how fast it spreads.

The U.S. Centers for Disease Control on Monday announced that Omicron now makes up 73% of U.S. cases of SARS-CoV-2, up from 13%. That pace has outstripped the CDC's expectations, according to The Financial Times's Peter Wells and Kiran Stacey.

The RBD is the main target for antibodies that can block the virus's activity, and so scientists are trying to determine to what extent the mutations are allowing the virus to escape antibodies' neutralizing effects. 

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Different monoclonal antibodies can target parts of the "receptor binding domain" of the spike protein of SARS-CoV-2 that don't change despite Omicron's many mutations.

Cameroni et al.

In the Vir study, the scientists proceeded in multiple stages.

They first tested the blood sera of both recovered and vaccinated individuals, including all subjects representing the major available vaccines, including the Moderna "mRNA-1273," the Pfizer/BioNtech "BNT162b2" and the AstraZeneca "AZD1222."

The researchers noted a general loss of immunity in both the recovered and the vaccinated individuals, including with some showing no immune response, and some showing immune responses that were up to to 44 times less potent.

Interestingly, the scientists note there was a "broadening" of immune response for those individuals who had both recovered from COVID-19 and also been vaccinated. 

That echoes findings in a study put out this week by researchers at Stockholm's Karolinska Institute. 

As the authors write,

Interestingly, this decrease was less pronounced for vaccinated individuals who were previously infected (5-fold), consistent with broadening of antibody responses as a consequence of affinity maturation driven by multiple antigenic stimulations. 

Next, they tested the action of 44 different monoclonal antibodies against Omicron in vitro, meaning, in the lab, not in human subjects. The researchers synthesized a "pseudovirus" of Omicron, a version prepared in the lab by harvesting from "seed" cells, a process known as vesicular stomatitis virus (VSV) pseudotyping that is common in studying pathogens.

Up against the synthesized particles of virus, they tested eight monoclonal antibodies that are "currently authorized or approved." They noticed that only one of the monoclonal antibodies retained any effectiveness, called sotrovimab. It is noteworthy because it doesn't target the RBD in the spike protein. Instead, it acts by "targeting non-RBM epitopes shared across many sarbecoviruses, including SARS-CoV."

The authors then did a test on 36 other monoclonal antibodies. Most of these failed, but three in particular "retained potent neutralizing activity against Omicron." Another two "retained activity against Omicron," they write. 

The key is that all six, including sotrovimab, target parts of the RBD that don't change. "These mAbs recognize four antigenic sites in the RBD that are conserved in Omicron and other sarbecoviruses," they write.

The prospect, the authors write, is that "Collectively, these data may guide future efforts to develop SARS-CoV-2 vaccines and therapies to counteract antigenic shift and future sarbecovirus zoonotic spillovers."

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