The antibodies target mutations of SARS-CoV-2 spike protein that resist mutation, potentially leading to better treatments and vaccines
A challenge in the fight against COVID-19 is the emergence of SARS-CoV-2 variants, especially the Delta variant, which may be more resistant to neutralizing antibodies compared to the original coronavirus. But now researchers led by researchers at the Fred Hutchinson Cancer Research Center (Fred Hutch) in Seattle say they have identified antibodies that may be largely protective against multiple sarbecoviruses, subgenus containing SARS-CoV-2 and SARS. CoV-1, the virus responsible for the onset of severe acute respiratory syndrome (SARS) in 2002-2004.
In “SARS-CoV-2 RBD Antibodies Maximizing Width and Resistance to Escape”, the researchers described how they compared 12 antibodies obtained from patients infected with either SARS-CoV-2 or SARS-CoV-1. They pointed in particular to an antibody – S2H97 – that could lead to the development of new vaccines and therapies against current and future variants. It may even protect against sarbecovirus that has not yet been identified, they wrote.
Unsolicited in the press release about these research findings is the fact that these particular antibodies may eventually become useful biomarkers for clinical laboratory tests designed to help physicians determine which patients have these antibodies – and the protection against infection they represent – and which who does not.
So far, however, the S2H97 has only been tested in hamsters. But the results are promising.
“This antibody, which binds to a previously unknown site on the coronavirus spike protein, appears to neutralize all known sarbecoviruses – the genus of coronavirus that causes respiratory infections in mammals,” said Jay Nix, Ph.D. Berkeley Lab’s Biosciences Area and Beamline Director of the Molecular Biology Consortium at Berkeley Labs Advanced Light Source (ALS), in a press release from Berkeley Lab. “And because of the unique binding site on the mutation-resistant part of the virus, it may well be more difficult for a new strain to escape,” he added.
The research team led by biochemist Tyler Starr, PhD, a postdoctoral fellow at Fred Hutch, also included researchers from Vir Biotechnology (NASDAQ: VIR), University of Washington in Seattle, Washington University School of Medicine in St. Louis. Louis and Lawrence Berkeley National Laboratory in Berkeley, California.
Researchers have long known that the SARS-CoV-2 virus uses the spike protein to attach to human cells. The Federal Centers for Disease Control and Prevention (CDC) notes that the variants have mutations in their spike proteins that make some of them more transmissible.
The Delta variant, the CDC notes, was the dominant variant in the United States per. August 28, 2021. It “has been shown to have increased transmission, potential reduction in neutralization by some monoclonal antibody treatments, and reduction in neutralization by post-vaccination sera,” the agency states.
The key to S2H97, the researchers wrote, is that it targets a portion of the spike protein that is common among sarbecoviruses and that is likely to be resistant to mutations.
The researchers used a variety of techniques to analyze how the 12 antibodies bind to the virus. They “compiled a list of thousands of mutations in the binding domains of several SARS-CoV-2 variants,” Nature reported. They also cataloged mutations in the binding domain of dozens of SARS-CoV-2-like coronaviruses belonging to a group called sarbecoviruses. Finally, they assessed how all of these mutations affect the ability of the 12 antibodies to adhere to the binding domain. ”
Previous antibody treatment receives an EUA from the FDA
Another antibody studied by the researchers, S309, has already led to a monoclonal antibody treatment approved for use in the United States. On May 26, the FDA issued an Emergency Aid (EUA) for sotrovimab, a therapy developed by GlaxoSmithKline (NYSE: GSK) and Vir Biotechnology, according to SciTechDaily.
When issuing the EUA for sotrovimab, the FDA cited “a preliminary analysis from a phase 1/2/3 randomized, double-blind, placebo-controlled clinical trial in 583 non-hospitalized adults with mild to moderate COVID-19 symptoms and a positive SARS-CoV Of these patients, 291 received sotrovimab and 292 received placebo within five days of the onset of COVID-19 symptoms. ”
Among these patients, 21 in the placebo group were hospitalized or died compared to three who received the treatment, a reduction of 85%.
“Although preventative measures, including vaccines, can reduce the overall number of cases, sotrovimab is an important treatment option for those who become ill with COVID-19 and are at high risk — so they can avoid hospitalization or worse,” said Adrienne E. Shapiro, MD, PhD, from the Fred Hutchinson Cancer Research Center in a GSK press release. Shapiro was an investigator in the clinical trial.
The EUA allows the use of sotrovimab in patients who have tested positive for SARS-CoV-2, have mild to moderate symptoms, and “who are at high risk of progression to severe COVID-19, including hospitalization or death. This includes, for example, people who are 65 years and older or people who have certain medical conditions. “It is not approved for patients who are hospitalized or for those who need oxygen treatment.
The therapy was originally known as VIR-7831. The companies say they have developed a similar treatment, VIR-7832, with modifications designed to improve T-cell function against the disease.
In “Dual-function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2”, published on bioRxiv, researchers from Vir Biotechnology wrote that the S309 antibody was isolated from a survivor of the previous outbreak of SARS-CoV-1.
The antibody, they wrote, targets a region of SARS-CoV-1 spike protein that is “highly conserved” among sarbecoviruses. Clinical laboratory tests, they wrote, also indicated that treatment was likely to be effective against known SARS-CoV-2 variants.
“Our distinctive scientific approach has led to a single monoclonal antibody that, based on a temporary analysis, resulted in a 85% reduction in hospitalizations or death from all causes and in vitro has shown that it retains activity against all known variants of concern,” including the new variant from India, ”said Vir Biotechnology CEO George Scangos, PhD, in the GSK press release. “I believe that sotrovimab is also a critical new treatment option in the fight against the current pandemic and possibly also for future outbreaks of coronavirus.”
Pathologists and clinical laboratory leaders working on rapid molecular and antibody testing for COVID-19 will monitor the development of monoclonal antibody therapies as well as further research studies focusing on these specific antibodies.
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