Virus World

Several Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) neutralising monoclonal antibodies (mAbs) have received emergency use authorisation by regulatory agencies for treatment and prevention of Coronavirus Disease 2019 (COVID-19), including in patients at risk for progression to severe disease. Here we report the persistence of viable SARS-CoV-2 in patients treated with sotrovimab and the rapid development of spike gene mutations that have been shown to confer high level resistance to sotrovimab in vitro. We highlight the need for SARS-CoV-2 genomic surveillance in at risk individuals to inform stewardship of mAbs use and prevent potential treatment failures.

Preprint available in medRxiv (Dec. 21, 2021):

https://doi.org/10.1101/2021.12.18.21267628 

Glaxo (GSK) and Vir Biotechnology announce promising pre-clinical data from the study of their antibody candidate, sotrovimab, against mutations found in the Omicron variant. The antibody candidate has shown activity against several deadly mutants of coronavirus including Delta, Delta plus and Mu in clinical studies. Amid rising concerns of an Omicron outbreak, the encouraging pre-clinical data against the variant supports its strong potential as an enduring COVID-19 treatment option going forward.  Pre-clinical data included results of testing of sotrovimab against pseudo-viruses with each containing a specific individual mutation found in the Omicron variant. Glaxo and Vir Biotechnology are currently conducting an in-vitro test of their antibody drug against all mutations found in the Omicron variant in a single pseudo-virus. Data from this test will demonstrate the neutralizing ability of sotrovimab against a combination of the Omicron mutations. An update on the data from this in-vitro study is expected by the end of 2021. The companies stated that sotrovimab targets a specific portion of the coronavirus, which makes it more difficult for the variants to develop resistance against the candidate. We note that Glaxo and Vir Biotechnology’s sotrovimab, as an intravenous administration, was granted emergency use authorization (“EUA”) for treating mild-to-moderate COVID-19 in adult and pediatric patients in May. The intravenous drug is available under the tradename of Xevudy.

The approval was based on data from a late-stage study that demonstrated that treatment with sotrovimab achieved 79% reduction in risk of hospitalization or death. Glaxo’s shares have gained 12.7% so far this year compared with the industry’s 12.6% increase. In a separate press release, the companies announced that sotrovimab was granted conditional marketing authorization in the United Kingdom for the treatment of symptomatic adults and adolescents. The drug is authorized for use in patients with acute COVID-19 infection without any requirement of oxygen supplementation with increased risk of progressing to severe infection. The drug needs to be administered within five days of the onset of COVID-19 infection symptoms.  Glaxo and Vir Biotechnology already have a supply agreement in place with the government of the United Kingdom for the supply of sotrovimab. The investigational therapy is also authorized for temporary/conditional use in several other countries including Japan and Canada. It is also under review in Europe. Glaxo and Vir Biotechnology have agreements with several entities across the globe in place for supply of more than 750,000 doses of sotrovimab. The companies also have an agreement with the European Commission for additional doses.

A report released by another COVID-19 drugmaker, Regeneron REGN earlier this week stated that vaccine-induced and monoclonal antibody-conveyed neutralization activity will reduce against the Omicron variant, implying lower effectiveness of available COVID-19 solutions against the new variant of concern, including Regeneron’s antibody cocktail, REGEN-COV. Further tests are being conducted to understand the impact using the actual Omicron variant sequence.  Regeneron’s REGEN-COV comprises two monoclonal antibodies, casirivimab and imdevimab., which have demonstrated strong effectiveness against previous coronavirus strains. Regeneron added $3.5 billion to its top line from sales of REGEN-COV, leading to more than 100% increase in total revenues in the first nine months of 2021...

Vir Biotechnology press release (December 2, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-demonstrate-sotrovimab-retains-activity-against 

See also preprint here (Dec. 1, 2021):

https://doi.org/10.1101/2021.03.09.434607

The U.S. Food and Drug Administration gave an emergency use authorization to the antibody treatment developed by Vir Biotechnology (VIR.O) and GlaxoSmithKline (GSK.L) for treating mild-to-moderate COVID-19 in people aged 12 years and older.  The antibody drug, Sotrovimab, is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy, the health regulator said on Wednesday. (https://bit.ly/3uorQZ8) Sotrovimab belongs to a class of drugs called monoclonal antibodies, which mimic natural antibodies that the body generates to fight off infection. The antibody treatment will be available for COVID-19 patients in the coming weeks, GSK and Vir said, adding that they plan to submit a marketing application to the FDA in the second half of 2021.  Similar COVID-19 therapies by Regeneron Pharmaceuticals (REGN.O) and Eli Lilly (LLY.N) have been authorized for emergency use in the United States. The European Union's drug regulator last week backed the use of Sotrovimab for COVID-19 patients who were at risk of severe disease and do not need supplemental oxygen.

FDA Emergency Use Authorization Letter (May 26, 2021):

https://www.fda.gov/media/149532/download 

Glaxo Press Release (May 26, 2021):

https://www.gsk.com/en-gb/media/press-releases/vir-biotechnology-and-gsk-announce-vir-7831-reduces-hospitalisation-and-risk-of-death-in-early-treatment-of-adults-with-covid-19/ 

SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild-type.

We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

Preprint available in bioRxiv (Nov. 5, 2020):

https://doi.org/10.1101/2020.11.04.355842

SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic that has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 202o. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies.

Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment.

Antibody cocktails including S309 along with other antibodies identified here further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

Published in Nature (May 18, 2020): 

https://doi.org/10.1038/s41586-020-2349-y

The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent individuals.

Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb, retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab, S2X259 and S2H97, neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.

Preprint Available at bioRxiV (Dec. 14, 2021):

https://doi.org/10.1101/2021.12.12.472269

Vir Biotechnology Press Release (Dec. 14, 2021):

https://investors.vir.bio/news-releases/news-release-details/preclinical-data-highlight-significant-antigenic-shift-omicron 

BACKGROUND

Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization or death in older patients and those with underlying conditions. Sotrovimab is a pan-sarbecovirus monoclonal antibody that was designed to prevent progression of Covid-19 in high-risk patients early in the course of disease.

METHODS

In this ongoing, multicenter, double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, nonhospitalized patients with symptomatic Covid-19 (≤5 days after the onset of symptoms) and at least one risk factor for disease progression to receive a single infusion of sotrovimab at a dose of 500 mg or placebo. The primary efficacy outcome was hospitalization (for >24 hours) for any cause or death within 29 days after randomization.

RESULTS

In this prespecified interim analysis, which included an intention-to-treat population of 583 patients (291 in the sotrovimab group and 292 in the placebo group), 3 patients (1%) in the sotrovimab group, as compared with 21 patients (7%) in the placebo group, had disease progression leading to hospitalization or death (relative risk reduction, 85%; 97.24% confidence interval, 44 to 96; P=0.002). In the placebo group, 5 patients were admitted to the intensive care unit, including 1 who died by day 29. Safety was assessed in 868 patients (430 in the sotrovimab group and 438 in the placebo group). Adverse events were reported by 17% of the patients in the sotrovimab group and 19% of those in the placebo group; serious adverse events were less common with sotrovimab than with placebo (in 2% and 6% of the patients, respectively).

CONCLUSIONS

Among high-risk patients with mild-to-moderate Covid-19, sotrovimab reduced the risk of disease progression. No safety signals were identified. (Funded by Vir Biotechnology and GlaxoSmithKline; COMET-ICE ClinicalTrials.gov number, NCT04545060. opens in new tab.)

Published in New England Journal of Medicine (Oct. 27, 2021):

https://doi.org/10.1056/NEJMoa2107934 

Vir Biotechnology and GlaxoSmithKline are stopping a phase 3 clinical trial of their COVID-19 antibody early for efficacy after seeing an 85% reduction in hospitalization or death at an interim review. The trial provided further evidence of the efficacy of anti-SARS-CoV-2 antibodies in ambulatory patients.  As of the interim review, 583 people recently infected with COVID-19 had received VIR-7831, also known as GSK4182136, or placebo. The participants were all at high risk of progression, based on their age or other factors, but were unlikely to require hospitalization in the next 24 hours and had oxygen saturation of 94% or greater at the time of enrollment. In those patients, the anti-SARS-CoV-2 antibody reduced the number of patients who died or needed hospitalizing for more than 24 hours in the 29 days after randomization by 85%. The effect was large enough to prompt the independent data monitoring committee to recommend stopping enrollment.     The study remains blinded while Vir and GSK complete the 24 weeks of follow-up on patients already in the study. Vir and GSK plan to share additional data once the clinical trial is complete but already see enough promise to outline plans to seek emergency use authorization in the U.S. and equivalent approvals in other markets.

A mix of ultrapotent antibodies from recovered COVID-19 patients has been shown to recognize and lock down the infection machinery of the pandemic coronavirus and keep it from entering cells. Each of the antibody types performs these overlapping tasks slightly differently. Low doses of these antibodies, individually or as a cocktail, were also shown to protect hamsters from infection when exposed to the coronavirus by preventing it from replicating in their lungs. An advantage of such cocktails is that they might also prevent the natural mutant forms of the virus that arose during this pandemic to escape treatment. As some variants in the infection machinery have already been discovered during the coronavirus pandemic, using a mix of antibodies allows for neutralization of a broad spectrum of such viral variants. In addition to preventing virus entry into host cells, the presence of the antibodies also seems to set off the infection-fighting actions of other immune cells, which arrive to clear out the virus. "We believe that leveraging multiple, distinct, complementary mechanisms of action could provide additional benefits for clinical applications," the researchers noted.

The researchers determined how the antibodies worked on a molecular level through cryo-electron microscopy studies of the resulting changes in the configuration of the virus infection machinery. Besides directly preventing interactions with the host receptor, one of the two discovered antibodies locks the infection machinery in an inactive conformation, meaning it could not fuse with the host membrane on the surface of the cell. If unable to fuse, the coronavirus cannot break in and deliver its RNA to commandeer the cell.  The findings of this research are reported Sept. 24 in a rapid release paper in Science. Here is the paper. The senior authors were Dr. Katja Fink of Vir Biotechnology and Dr. David Veesler, associate professor of biochemistry at the University of Washington School of Medicine. Veesler has studied the molecular structure and infection mechanisms of a variety of coronaviruses and other viruses. The lead authors were M. Alejandra Tortorici of the UW Department of Biochemistry and the Institut Pasteur in Paris, and Martina Beltramello of Humab BioMed, a subsidiary of Vir Biotechnology in Switzerland. Researchers from Washington University in St Louis, Rega Institute in Belgium, the University of Milan, Italy, and the University of Texas in Dallas also collaborated on the research.

Efficient therapeutic options are needed to control the spread of SARS-CoV-2 that has caused more than 978,000 fatalities worldwide. While the world awaits approved vaccines, pharmaceuticals to prevent or treat infections from the pandemic coronavirus are being sought that might be quicker to develop and test. These might both address the gap until vaccines are widely distributed, and still be needed for use after vaccines are available. "Our results pave the way to implement antibody cocktails for prophylaxis or therapy that might have the advantage of circumventing or limiting the emergence of viral escape mutants," the researchers noted. The antibody cocktail in their study needs to undergo trials in humans to determine safety and effectiveness.

Original study published in Science (Sept. 24, 2020):

https://doi.org/10.1126/science.abe3354

A promising vaccine that clears an HIV-like virus from monkeys is closer to human testing after a new, weakened version of the vaccine has been shown to provide similar protection as its original version.

The vaccine uses a form of the common herpes virus cytomegalovirus, or CMV—was live-attenuated, or weakened so CMV couldn't spread as easily. The new version still managed to eliminate SIV, the monkey version of HIV, in 59 percent of vaccinated rhesus macaques. That result is similar to earlier findings involving the vaccine's original, non-attenuated version. The immunity generated by the attenuated vaccine was also long-lasting, as nine of 12 vaccinated monkeys could still fight off SIV infection three years later.

"These papers are important because they recapitulate the previously reported unique CMV vector efficacy with a genetically modified vector that is highly attenuated and therefore potentially safer for clinical  use" said Louis Picker, M.D., a corresponding author on both papers. "In addition, this new work demonstrates most vaccinated rhesus monkeys that are protected against SIV can also be protected against a second challenge years after initial vaccination. This is a level of durability that would be very important for a human HIV vaccine". The CMV vaccine platform has been licensed by Vir Biotechnology, Inc., of San Francisco, which plans to lead a clinical trial with a human version of the CMV-based HIV vaccine. 

The studies were published on July 17 on Science Translational Medicine:

https://doi.org/10.1126/scitranslmed.aaw2607

https://doi.org/10.1126/scitranslmed.aaw2603