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Preventing severe disease in Covid-19 patients

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Written by Raquel Barroso Ferro, University of Aberdeen

In April 2020, Vir Biotechnology and GlaxoSmithKline (GSK) began a partnership that has proven fruitful. As announced on March 10, 2021, patients with mild or moderate Covid-19 at high risk of progression to severe disease who were treated with the human monoclonal antibody VIR-7831 (sotrovimab) in the COMET-ICE study (NCT04545060) had a reduction of 85% in hospitalization or death compared to those who received placebo. Although complete details of the ongoing trial are not yet available, this “artificial immunity” offers hope for patients. In particular, such treatment may be beneficial to those who are unable to receive a vaccine or whose immune system is weakened.

Vir and GSK plan to submit an emergency use authorization application in the US and seek authorizations in other countries.

Originally derived from a patient who survived severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, (1) the antibody binds to a highly conserved epitope on the spike glycoprotein shared by both SARS-CoV and the virus causing the current pandemic, SARS-CoV-2. This shared epitope suggests high conservation and its likely importance for viral infection. Binding this epitope may reduce the likelihood of mutational escape, and allow the antibody to neutralize multiple variants that emerge. In fact, according to a pre-print posted March 10, 2021 on BioRxiv, the epitope of VIR-7831 does not overlap with the mutational sites observed in the circulating variants. (1)

In preclinical studies, VIR-7831 achieved high concentration in the lungs, (1) the principal site of Covid-19 infection, (2) neutralized live virus, and was shown to engage effector functions, such as antibody-dependent cytotoxicity and phagocytosis, to mediate clearance of infected cells. (1)

The announcement of positive results from the COMET-ICE study follows a March 3, 2021, announcement by Vir and GSK that the Data and Safety Monitoring Board for the ACTIV-3 trial (NCT04501978) evaluating VIR-7831 in hospitalized adults with COVID-19 has recommended that the VIR-7831 arm of the trial be closed to enrolment while the data mature. No safety signals were reported, but the sensitivity analysis called into question the magnitude of the potential benefit of VIR-7831 administration to hospitalized patients. The National Institutes of Health is sponsoring the ACTIV-3 master protocol, which is examining the clinical safety and efficacy of numerous investigational agents relative to current standard of care therapy in hospitalized patients with more severe COVID-19.

Overall, the findings from the two clinical studies suggest that VIR-7831 could be of most benefit to patients during early onset of the disease, shortly after a positive test. This treatment has great potential to reduce both the severity of the disease in individuals and the substantial burden COVID-19 has placed on hospital staff and resources.

Another challenge, however, will be instilling confidence in doctors to prescribe anti-SARS-CoV-2 monoclonal therapies to patients. According to Dr. Derek Angus, an intensive-care physician at the University of Pittsburgh who spoke to Nature, (3) the absence of data published in peer-reviewed journals has left doctors wary. Moreover, high costs and more specialized requirements for administering infusion-based therapies will make what seems to be a working therapy and hope for patients a more complicated task. Intramuscular (IM) injection, which may substantially increase patient convenience, is possible. Clinical studies for anti-SARS-CoV-2 antibodies administered via intramuscular (IM) injection, including VIR-7831 (COMET-PEAK) and AZD7442 (PROVENT, STORM CHASER), are ongoing and clinical study results have not yet been announced.

1.       Cathcart et al. The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2. 2021. 
2.       Cevik et al. Virology, transmission, and pathogenesis of SARS-CoV-2. BMJ 2020; 371. BMJ. 2020. 
3.       Ledford H. COVID antibody treatments show promise for preventing severe disease. Nature 2021. 

FDA issues Emergency Use Authorization for bamlanivimab/etesevimab combination

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On February 9, 2021, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for bamlanivimab and etesevimab administered together for the treatment of mild to moderate COVID-19 in adults and pediatric who test positive for SARS-CoV-2 and who are at high risk for progressing to severe COVID-19. Developed by Eli Lilly and Company, bamlanivimab and etesevimab are monoclonal antibodies (mAbs) that target overlapping regions of the SARS-CoV-2 spike protein.

The EUA was based on a randomized, double-blind, placebo-controlled clinical trial in 1,035 non-hospitalized adults with mild to moderate COVID-19 symptoms who were at high risk for progressing to severe COVID-19. Of these patients, 518 received a single infusion of bamlanivimab (2.8 g) and etesevimab (2.8 g) together, and 517 received placebo. The primary endpoint was COVID-19 related hospitalizations or death by any cause during 29 days of follow-up.  Hospitalization or death occurred in 11 (2%) patients treated the mAb combination vs. 36 (7%) patients who received placebo. All 10 deaths (2%) occurred in the placebo group.

The authorized dosage of 700 milligrams bamlanivimab and 1400 milligrams etesevimab administered together is based on analyses of available preclinical, clinical, and virologic data, as well as pharmacokinetic and pharmacodynamic modeling, which, in totality, support that the authorized dosage is expected to have a similar clinical and virologic effect to the dose evaluated in the clinical trial. Use of the mAb combination is not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19.

In November 2020, FDA issued an EUA for a single infusion of 700 mg bamlanivimab for the treatment of mild-to-moderate COVID-19 in adult and certain pediatric patients. Since the monotherapy and the combination treatment are expected to benefit patients at high risk of disease progression, both 700 milligrams bamlanivimab alone and the combination of 700 milligrams bamlanivimab and 1,400 milligrams etesevimab administered together will be available under an EUA.

Ultra-fast development of an anti-COVID-19 antibody

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Thursday February 18, 2021 at 8am PT/11am ET/5pm CET

The SARS-CoV-2 pandemic has spread all over the world in the past year and there is still no efficient treatment available for COVID-19, particularly for patients undergoing severe courses, which often lead to fatal consequences. Antiviral drugs such as virus-neutralizing antibody therapeutics are still urgently needed to save millions of lives.
Corat Therapeutics developed a novel SARS-CoV-2 neutralizing, fully human antibody derived from convalescent patients. Ultra-fast development strategies shortened timelines from discovery to GMP manufactured material to less than 8 months. This was possible by parallelizing discovery and development steps, as well as performing crucial steps on risk. First-in-human studies were recently initiated. This webinar gives an overview of the challenges faced during discovery and development of the lead antibody, COR-101.

Speaker: Dr. André Frenzel, YUMAB/CORAT Therapeutics

Click here to register for this free event!

AIRR Community and PrecisionFDA COVID-19 Precision Immunology App-a-thon

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The AIRR Community is helping to lead the PrecisionFDA COVID-19 Precision Immunology App-a-thon.  

This is part of the “precisionFDA Challenges” program, which is designed to engage and improve software that analyzes NGS (next generation sequencing data) through community challenges. There were 68 bioinformaticians pre-registered for the Precision Immunology Challenge, and more are expected to join as the app-a-thon continues.  These “citizen scientists” will form teams to design software that will make AIRR-seq data more available and accessible for immunologists to realize the promise of immunological big data for improved diagnostics and therapeutics in immunotherapy.

The Precision Immunology Challenge uses AIRR-seq repertoire data from COVID-19 patients downloaded from the AIRR Data Commons (VDJServer and iReceptor Public Archive) through the iReceptor Gateway. These data sets have been carefully chosen to include data on patient demography and clinical outcome in order to illuminate the relationship between personalized adaptive immunity molecular data and COVID-19 disease variables.

The AIRR Community Diagnostics Working Group published a blog post as part of this effort, explaining the possible uses of AIRR-seq data in the clinic in the near future.

The app-a-thon runs through February 2021 at which time the apps will be judged for usability, impact and innovation.

 

Register now for Pre-Meeting “AIRR-seq in the Pandemic!

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AIRR-seq in the Pandemic:
AIRR Community/Tsinghua University Joint Meeting
A pre-meeting to AIRR-C Meeting V: Zooming in to the AIRR Community!

We are pleased to announce a meeting co-organized by the AIRR Community and Tsinghua University, which will mainly focus on Chinese researchers using AIRR-seq data to study the adaptive immune response, especially in COVID-19 patients. This event has been scheduled as a pre-meeting for the regular AIRR Community Meeting V: “Zooming in to the AIRR Community” which will be held virtually December 8-10th, 2020.  Professor Xiao Liu of Tsinghua University is organizing an in-person meeting of Chinese researchers in Shenzen, China on Sunday December 6, 2020, and researchers from North America and Europe will join this group virtually.

The Timeline:
The in-person meeting will convene all day Sunday, December 6th, 2020 in Shenzhen, China.  North American researchers will virtually introduce the AIRR-seq Community approach and present research on COVID-19 during the evening of Saturday, December 5th, including a welcome by the Chair of the AIRR Community Executive Sub-committee, Dr. Nina Luning Prak; Saturday evening in North America will correspond to the morning of Sunday, December 6th in Shenzhen.  In addition, on the morning of Sunday, December 6th in Europe, two members of the AIRR Community will join from Europe, including Victor Greiff; this will correspond to the afternoon of December 6th in Shenzhen. See the draft agenda below for further details on this complicated enterprise!  And please join us if you can, in this international effort to integrate this important sector of the immunogenetics community more closely with the AIRR Community

For complete details and agenda visit the Pre-Meeting web page.

This virtual meeting is free but registration is required.

Please register for this groundbreaking event!