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Coronavirus in the crosshairs, Part 3: Antibodies from human plasma

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Antibodies have extraordinary potential as agents for the treatment of COVID-19 or possible prevention of infection by SARS-CoV-2, the coronavirus that causes the disease. Anti-SARS-CoV-2 antibodies can neutralize the virus, and antibodies that target inflammatory factors such as cytokines can ameliorate symptoms of COVID-19.

The Antibody Society’s series “Coronavirus in the crosshairs” examines the discovery and development of all types of interventions for COVID-19.  In Part 3 of the series, we focus on the use of natural antibodies, i.e., anti-SARS-CoV-2 polyclonal antibodies found in convalescent plasma, in treating COVID-19. In the current emergency when time is of the essence, medical professionals are applying the century-old knowledge that antibody-rich plasma derived from blood donated by people who have recovered from a disease may aid other patients. The efficacy of convalescent plasma was studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. [1, and references therein]

There is, however, no current evidence from randomized controlled trials to recommend any specific anti-SARS-CoV-2 treatment for patients with suspected or confirmed SARS-CoV-2 infection.[2] Anti-SARS-CoV-2 blood products are thus considered investigational drugs that require clinical study and approval by regulatory agencies before they can be administered broadly to treat COVID-19 patients or potentially prevent disease in healthy people, such as health care workers.

FDA response to the need for COVID-19 convalescent plasma

To address the short-term need for treatments, the US Food and Drug Administration (FDA) is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through emergency Investigational New Drug Applications that will enable administration to a single patient. Highly time sensitive requests will receive a response from FDA within 4 to 8 hours.[3]

In the longer-term, FDA is working with other agencies, such as the National Institutes of Health and the Centers for Disease Control and Prevention, to develop master protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.[3]

Ongoing clinical studies of convalescent plasma

Medical professionals in countries greatly affected by COVID-19, such as China and Italy, are evaluating plasma-based treatments for COVID-19. Clinicaltrials.gov lists several clinical studies evaluating the use of convalescent plasma:

  • NCT04292340. In this observational study recruiting patients at the Shanghai Public Health Clinical Center, the investigators collected the clinical information and clinical outcomes of the COVID-19 patients using anti-2019-nCoV inactivated convalescent plasma. The study objective is to evaluate the efficacy and safety of anti-2019-nCoV inactivated convalescent plasma in the treatment of COVID-19 pneumonia. Primary outcome measures are the virological clearance rate of throat swabs, sputum, or lower respiratory tract secretions at day 1, 3 and 7, and the patient outcome at 4 weeks. The actual study start date is February 1, 2020 and the estimated primary completion date is July 31, 2020.
  • NCT04321421. In this study being conducted in Italy, 49 participants are administered plasma from donors recovered from COVID-19 as therapy at day 1 and, based on clinical response, on day 3 and 5., The dose, 250-300 mL of convalescent plasma, was selected based on published literature for this type of therapy. The primary outcome measure is death from any cause within 7 days. The actual study start date is March 17, 2020 and the estimated primary completion date is May 31, 2020.

Similar trials are listed on the Chinese clinical trials registry, e.g.,

  • ChiCTR2000030841, Exploratory study for immunoglobulin from cured COVID-19 patients in the treatment of acute severe novel coronavirus (COVID-19); study registered March 15, 2020.
  • ChiCTR2000030929, A randomized, double-blind, parallel-controlled trial to evaluate the efficacy and safety of anti-SARS-CoV-2 virus inactivated plasma in the treatment of severe novel coronavirus pneumonia (COVID-19); study registered March 17, 2020.

New plasma-derived COVID-10 product candidates in development

On March 4, 2020, Takeda Pharmaceutical Company Limited announced that they are initiating development of an anti-SARS-CoV-2 polyclonal hyperimmune globulin (H-IG) to treat high-risk individuals with COVID-19. Referred to as TAK-888, Takeda plans initially to produce the plasma-derived anti-SARS-CoV-2 polyclonal H-IG in a segregated area within its manufacturing facility in Georgia.

On March 11, 2020, Emergent BioSolutions Inc. announced that it has initiated development of two product candidates for the treatment and prevention of coronavirus disease (COVID-19). COVID-HIG, manufactured from human plasma with antibodies to SARS-CoV-2, will be developed as a potential treatment for severe hospitalized patients as well as protection for at-risk individuals. In parallel, COVID-EIG, manufactured from plasma of immunized horses with antibodies to SARS-CoV-2, will be developed as a potential treatment for severe hospitalized patients. Emergent has initiated plasma collection efforts for both human and equine platforms with a goal of manufacturing clinical material within the next four to five months in anticipation of beginning a clinical study as early as the third quarter of 2020.

Upcoming “Coronavirus in the crosshairs” posts

In Part 4 of “Coronavirus in the crosshairs”, we will discuss recombinant antibodies that may ameliorate symptoms of COVID-19, and examine ongoing efforts to discover and develop recombinant anti-SARS-CoV-2 antibodies.

1. Chen et al. Convalescent plasma as a potential therapy for COVID-19. The Lancet. February 27, 2020. DOI:https://doi.org/10.1016/S1473-3099(20)30141-9
2. World Health Organization. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. Interim guidance. 28 January 2020.
3. US Food and Drug Administration. Investigational COVID-19 Convalescent Plasma – Emergency INDs. March 24, 2020.

Photo by Fusion Medical Animation on Unsplash

Coronavirus in the crosshairs, Part 2: Vaccines in development

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Biopharmaceutical companies, government agencies, academic institutions and non-profits located world-wide have mobilized in an unprecedented effort to develop interventions that are effective against SARS-CoV-2, the virus that causes COVID-19. This global pandemic, however, affects people of all ages and every health status. As a consequence, we need a wide array of medicines, as well as vaccines, to ensure the right intervention is given to the right person. And we need these interventions as quickly as possible.

In Part 1 of ‘Coronavirus in the crosshairs’, we focused on early clinical studies for small molecule drugs that were re-purposed, i.e., drugs that were already approved or in clinical studies for another disease, but were tested for efficacy in COVID-19 patients. In Part 2 of this series, we focus on vaccines currently in clinical study. Part 3 will focus on the use of anti-SARS-CoV-2 polyclonal antibodies found in convalescent plasma as a treatment for COVID-19, and Part 4 will examine efforts to quickly discover anti-SARS-CoV-2 antibody therapeutics.

Vaccines in preclinical and clinical development

The World Health Organization has compiled a list of SARS-CoV-2 vaccine initiatives that, as of March 20, 2020, included 42 vaccines in preclinical development and 2 vaccines in human Phase 1 studies, National Institutes of Health (NIH)/Moderna’s mRNA-1273 vaccine and CanSino Biological Inc./Beijing Institute of Biotechnology’s adenovirus Type 5 vector (Ad5-nCoV) vaccine.

In addition, the Regulatory Affairs Professionals Society is maintaining the Regulatory Focus COVID-19 Tracker, which is a resource for information on COVID-19 vaccine development that is updated weekly.

mRNA-1273 vaccine candidate

mRNA-1273 is a novel lipid nanoparticle-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike protein of SARS-CoV-2. The  vaccine candidate has shown promise in animal models. Manufacturing of mRNA-1273 for the Phase 1 study (NCT04283461) was supported by the Coalition for Epidemic Preparedness Innovations. On March 16, 2020, NIH announced the study, which will assess the safety and immunogenicity of mRNA-1273,  had started. A total of 45 adults between the ages of 18 to 55 years will be enrolled, and the estimated primary completion date of the study is June 1, 2021. According to the protocol, however, the immunogenicity data will start being collected by mid-May 2020. Moderna announced on March 23, 2020 that, under emergency use, a vaccine could be available to some people, possibly including healthcare professionals, in the fall of 2020, although a commercially-available vaccine is not likely to be available for at least 12-18 months.

Enrollment will occur at the Kaiser Permanente Washington Health Research Institute. Forty-five healthy adults will be administered one of three doses (25 microgram [mcg], 100 mcg, 250 mcg). They will receive an intramuscular injection of mRNA-1273 on Days 1 and 29 in the deltoid muscle, and will be followed through 12 months post second vaccination (Day 394). The first four participants will receive one injection with the low dose, and the next four participants will receive the 100 mcg dose. Investigators will review safety data before vaccinating the remaining participants in the 25 and 100 mcg dose groups and before participants receive their second vaccinations. Another safety review will be done before participants are enrolled in the 250 mcg cohort. Follow-up visits will occur 1, 2 and 4 weeks post each vaccination, as well as 3, 6 and 12 months post second vaccination.

The primary objective is to evaluate the safety and reactogenicity and the secondary objective is to evaluate the immunogenicity as measured by IgG ELISA to the 2019-nCoV S protein following a 2-dose vaccination schedule of mRNA-1273 at Day 57.

Ad5-nCoV vaccine candidate

On March 17, 2020, CanSino Biologics Inc. announced that its recombinant novel coronavirus vaccine Ad5-nCoV, co-developed with Beijing Institute of Biotechnology, has been approved to enter into a Phase 1 clinical trial. The Phase 1 ChiCTR2000030906 study was listed as recruiting patients when its record was accessed March 23, 2020; NCT04313127 is assumed to be the same study.

The single-center, open and dose-escalation Phase 1 clinical trial will evaluate Ad5-nCoV in healthy adults aged between 18 and 60 years. Three doses will be evaluated, with a total of 108 patients (36 per study arm) receiving a low (5E10 vp Ad5-nCoV), medium (1E11 vp Ad5-nCoV) or high (1.5E11vp Ad5-nCoV) dose of vaccine. Various types of antibody responses will be measured at Day 14, 28, and months 3 and 6 post injection.

Other vaccine candidates

Clinical studies of two additional vaccine candidates, Covid-19 aAPC Vaccine and Covid-19 Synthetic Minigene Vaccine, are listed on clinicaltrials.gov as recruiting patients (NCT04299724 and NCT04276896, respectively), although the status of these initiatives could not be confirmed as of March 23, 2020. Both vaccine candidates are sponsored by Shenzhen Geno-Immune Medical Institute, Shenzhen Third People’s Hospital, and Shenzhen Second People’s Hospital.

Coronavirus image from: CDC/ Alissa Eckert, MS; Dan Higgins, MAMS

Coronavirus in the crosshairs, Part 1

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Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses that can cause highly lethal respiratory disease in humans, such as Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). The current coronavirus disease (COVID-19) pandemic is caused by the SARS-CoV-2 coronavirus. Infection in humans is initiated through exposure of the respiratory tract to the virus, which enters cells by binding angiotensin-converting enzyme 2 (ACE2) found on the cell surface.[1] Wrapp et al.[2] have shown that the SARS-CoV-2 spike protein binds to ACE2 with ~10- to 20-fold higher affinity than the spike protein of SARS–CoV, which is a coronavirus that caused an epidemic in 2002-2003.

An urgent and immediate need for knowledge about COVID-19 and for drugs to inhibit the virus and treat symptoms has existed since the disease started to spread in December 2019. To address this need, medical professionals have initiated numerous trials to identify key characteristics of the infections and the effects of investigational and approved drugs, including those used during the MERS and SARS outbreaks. As of March 19, 2020, clinicaltrials.gov already included ~115 studies related to COVID-19, with ~40 designed as observational studies or studies of diagnostics or devices, and ~75 designed to evaluate interventions such as antiviral drugs. Of the interventional studies, ~40 are currently recruiting patients, and the rest have not yet started recruiting. The earliest of these studies were started in China in late January 2020; additional studies may be listed on the Chinese clinical trials registry. Many studies are designed to produce results rapidly, which may greatly assist treatment of patients in the near future.

Effective in vitro inhibition of SARS-CoV-2 by remdesivir and chloroquine has been reported,[3] and numerous clinical studies are underway to determine the efficacy of these drugs as COVID-19 treatments.[4] Remdesivir (GS-5734, Gilead Sciences Inc) is an investigational monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families, including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae, through the targeting of the viral RNA-dependent RNA polymerase. It was previously tested in humans with Ebola virus disease, and has demonstrated positive results in animal models of MERS.[5] Numerous clinical studies of the effects are remdesivir are ongoing, including:

  • NCT04257656, started February 6, 2020 in China, with estimated enrollment of 453 patients and a primary completion date of April 3, 2020.
  • NCT04252664, started February 12, 2020 in China, with estimated enrollment of 308 patients and a primary completion date of April 20, 2020.
  • NCT04280705, started February 21, 2020 in the US, South Kora and Singapore, with estimated enrollment of 394 patients and a primary completion date of April 1, 2020.[6]
  • NCT04292899, started March 6, 2020 in the US, South Kora and Singapore, with estimated enrollment of 400 patients and a primary completion date of May 2020.
  • NCT04292730, started on March 15, 2020 in the US, South Kora and Singapore, with estimated enrollment of 600 patients and a primary completion date of May 2020.

The U.S. Army Medical Research and Development Command is sponsoring a study of remdesivir (NCT04302766) with enrollment limited to DoD-affiliated personnel (including active and reserve component service members, US civilian employees, contractors, other US personnel, and dependents of any age, as well as allied military forces and local nationals) who have a COVID-19 diagnosis and have been granted access to the medical facility.

Hydroxychloroquine, which is FDA-approved as a treatment for malaria, lupus and rheumatoid arthritis, appears to interfere with terminal glycosylation of ACE2 and is known to elevate endosomal pH, which may inhibit virus binding and subsequent infection.[7] Preliminary evidence from a small study in humans suggests that the combination of azithromycin and hydroxychloroquine is significantly more efficient for virus elimination.[8] 

At least 3 clinical studies of the effects are hydroxychloroquine are ongoing:

  • NCT04261517, started February 6, 2020 in Shanghai, with estimated enrollment of 30 patients and a primary completion date of August 2020.
  • NCT04307693, started March 11, 2020 in Seoul, South Korea, with estimated enrollment of 150 patients and a primary completion date of May 2020.
  • NCT04308668, started March 2020 in Minneapolis, Minnesota, United States, with estimated enrollment of 1500 patients and a primary completion date of May 2021.

On March 18, 2020, the World Health Organization announced that they are planning a multi-arm clinical trial that will evaluate the following drugs as treatments for COVID-19:

  • Remdesivir;
  • Hydroxychloroquine or chloroquine;
  • Lopinavir-ritonavir (a combination of two HIV drugs marketed as Kaletra or Aluvia); and
  • Lopinavir-ritonavir plus interferon beta.

Argentina, Bahrain, Canada, France, Iran, Norway, South Africa, Spain, Switzerland, and Thailand have offered study sites, and sites in other countries may be added in the future. The study, called SOLIDARITY, will use an adaptive design, which allows study arms to be modified, added or eliminated based on the results of ongoing data collection.[9] The lopinavir-ritonavir arms are included in the SOLIDARITY study despite the negative results of a clinical study of 199 hospitalized adult patients with severe COVID-19 in China, which showed no benefit from adding lopinavir–ritonavir treatment to standard care.[10] Further study is needed to understand whether factors such as the drug dose or patient characteristics (age, severity of disease, underlying medical conditions) affected the possibility of a treatment benefit.

In addition, positive results have been reported for the antiviral agent favipiravir (Avigan), which was evaluated in COVID-19 patients in clinical trials conducted in Wuhan and Shenzhen, China. Favipiravir was approved in 2014 in Japan for treatment of influenza, although use is limited because the drug may cause fetal deaths or deformities. Additional studies in COVID-19 are needed, however, results reported by Japanese health officials suggest the drug is less effective in patients with more severe symptoms.[11]

Other antiviral treatments are currently being evaluated, including anti-SARS-CoV-2 inactivated convalescent plasma (NCT04292340), as are therapies that can ameliorate symptoms of the disease, including anti-IL-6 sarilumab (NCT04315298) and anti-IL-6 receptor tocilizumab (NCT04306705, NCT04310228), which may reduce lung inflammation and improve lung function in COVID-19 patients.

Scientists are searching for new treatments and vaccines, which will be discussed in our upcoming posts.

1. Walls et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. March 09, 2020. DOI:https://doi.org/10.1016/j.cell.2020.02.058
2. Wrapp et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020, 367, 1260-1263.
3. Wang et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 2020, 30, 269–271.
4. Food and Drug Administration, March 19, 2020. Coronavirus (COVID-19) Update: FDA Continues to Facilitate Development of Treatments.
5. National Institutes of Health, February 13, 2020. Remdesivir Prevents MERS Coronavirus Disease in Monkeys.
6. National Institutes of Health, February 25, 2020. NIH clinical trial of remdesivir to treat COVID-19 begins.
7. Vincent et al. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virology Journal 2005, 2, 69.
8. Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of  Antimicrobial Agents – In Press 17 March 2020 – DOI : 10.1016/j.ijantimicag.2020.105949
9. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 18 March 2020.
10. Cao et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19. New England Journal of Medicine. March 18, 2020. DOI: 10.1056/NEJMoa2001282.
11. Watanabe S, Chan M, Suzuki W. China says Japan-developed drug Avigan works against coronavirus. Nikkei Asian Review. March 18, 2020.

Coronavirus image from: CDC/ Alissa Eckert, MS; Dan Higgins, MAMS

FDA issues guidance on conducting clinical trials during the COVID-19 pandemic

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In these challenging times, the biopharmaceutical industry, government agencies, as well as academic and non-profit organizations, are working toward the development of antibody therapeutics and vaccines for the treatment and prevention of infection by SARS-CoV-2, the virus that causes COVID-19. The Antibody Society is currently compiling information on these efforts, which will soon be posted on our website and distributed via email to our members. Many existing antiviral treatments are also being re-purposed in the fight against the virus.

The Society is an authoritative source of information on antibody therapeutics in the clinical pipeline. The COVID-19 pandemic, however, may delay ongoing clinical studies that are evaluating the safety and efficacy of therapeutics for other diseases. In a March 18, 2020 press release, the U.S. Food and Drug Administration (FDA) notes that challenges may arise from quarantines, site closures, travel limitations, interruptions to the supply chain for the investigational product, or other considerations if site personnel or trial subjects become infected with SARS-CoV-2. These challenges may lead to difficulties in conducting the clinical trials. Protocol modifications may be required, and there may be unavoidable protocol deviations due to COVID-19.

Information about FDA’s guidance for industry, investigators and institutional review boards conducting clinical trials during the coronavirus (COVID-19) pandemic can be found here.

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COVID-19 Demands Increased Public Sharing of Biomedical Research Data

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Defeating the coronavirus pandemic will require unprecedented cooperation from the research community. This is especially true for the Adaptive Immune Receptor Repertoire Community (AIRR-C), given the paramount importance of antibodies and T cells for vaccines, diagnostics, and therapeutics in viral infection. Therefore, the AIRR-C hereby calls upon its members, and the wider research community, to share experiences, resources, samples, and data as openly and freely as possible, and to work within their respective systems to break down barriers to achieve this goal, subject to the overarching directives of respect, privacy, and protection for patients and all people. We are in this together.