the official website of the antibody society
Sharing is caring. This has become a key phrase during the COVID-19 pandemic. The AIRR Community proudly announces a designated channel in our data discussion forum B-T.CR (www.b-t.cr). This public resource will list all current and upcoming studies with immune repertoire data on COVID-19.
If you happen to stumble upon AIRR-seq or single cell RNA-seq data of COVID-19 research projects, please add them to the list found here!
During public health emergencies, the U.S. Food and Drug Administration (FDA) can allow use of unapproved medical products or unapproved uses of approved medical products to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by threat agents, such as SARS-CoV-2, when there are no adequate, approved, and available alternatives. On March 27, 2020, the Secretary of the Department of Health and Human Services declared that circumstances exist justifying the authorization of emergency use of drugs and biologics during the COVID-19 outbreak, which gave FDA the authority to issue Emergency Use Authorizations (EUA).
It is important to note that FDA’s allowance of an emergency investigational new drug application or compassionate use of a COVID-19 intervention is not equivalent to FDA issuing an EUA, and EUA issuance is not equivalent to FDA approval.
To date (May 12, 2020), although over 90 EUAs have been issued for diagnostic tests of various types, only 3 EUAs have been issued for therapeutics:
Limitations to the scope and duration of the authorizations, as well as specific conditions that apply, are detailed in FDA’s letters of authorization.
Infection with SARS-CoV-2 leads to multiple pathologies, including inflammation, respiratory distress and abnormal coagulation. Existing biological therapies that might ameliorate symptoms, such as monoclonal antibodies (mAbs) that target inflammatory cytokines and proteins involved in clotting, have thus been re-purposed as possible COVID-19 interventions.
Although FDA has not yet issued an EUA for a biologic COVID-19 therapeutic, numerous candidates are in late-stage clinical studies that might yield results that warrant such an authorization in 2020. Of these, 5 (Sarilumab, Emapalumab, Tocilizumab, Siltuximab and Ravulizumab) are already approved as treatments for other diseases, and thus may be available for broad distribution if the sponsoring company chooses to pursue an EUA for COVID-19 and FDA issues the authorization. The logistics of large-scale manufacturing and broad distribution of other candidates may be challenging for the sponsoring companies.
Details of 10 possible biologic candidates for EUAs in 2020 are listed here in chronological order according to the estimated primary completion dates of the relevant studies:
In addition to re-purposing existing biologics for use as treatments for the symptoms of COVID-19, the global biopharmaceutical industry, as well as government, academic and non-profit organizations, are developing therapies that target SARS-CoV-2. Of the biologic candidates that target the virus, the ones most likely to be considered for EUAs in 2020 are those composed of plasma from convalescent patients. SARS-CoV-2- neutralizing antibodies in the plasma are expected to protect patients, and potentially uninfected people such as medical personnel, from the effects of the virus.
The plasma-based products could serve as a critical component of medical care until recombinant anti-viral biologics are available. The first recombinant anti-SARS-CoV-2 antibodies are expected to enter clinical study as early as June 2020. The Antibody Society, in partnership with the Chinese Antibody Society, is maintaining a list of ~60 recombinant biologics that target SARS-CoV-2, including antibodies, a DARPin®, and fusion proteins. We will report on the progress of these candidates in upcoming installments of “Coronavirus in the crosshairs”.
Post written by Simon L. Goodman, D.Phil., Science & Technology Program Manager, The Antibody Society
With no foreseeable safe or effective therapy or vaccine against SARS-CoV-2, extensive population testing and quarantine are amongst the few scientifically rational means of protecting people and monitoring the pandemic. To date (April 26, 2020) only 26.6 million tests for infection have been performed worldwide, with 3 million positives reported (1) by 129 of 195 countries. Cases of infection were confirmed predominantly via nucleic acid amplification tests for viral RNA. Current antibody-based serological tests are qualitative, and poorly validated. But there is little doubt that during epidemic and endemic infection, testing and obligate retesting will likely involve many 100s of millions of samples.
There are currently no validated US Food and Drug Administration (FDA)-approved diagnostic assays for SARS-CoV-2 or anti-SARS-CoV-2 antibodies in patient samples, but tests can receive emergency use authorization (EUA) (2). The lack of certification means that data from these tests is likely to be of lower quality than approved diagnostics, from the point of view of clinical specificity and selectivity. However, in third-world countries, rapid point-of-care tests must become available as soon as possible. To add to the difficulties that governments, the public, and healthcare providers face, there is an amoral escalating grey-market in dysfunctional serological home-test-kits (3).
The coronavirus SARS-CoV-2 triggers a lethal and highly infectious disease, COVID-19, so rapid (minutes-to-hour) point-of-care tests are essential to reduce spread and establish the epidemiology of infection. Classical laboratory culture methods, in any event necessitating rare Biosafety Level-3 facilities, are excluded. The level of anti-SARS-CoV-2 neutralizing antibodies needed for protective immunity, and the degree and duration of protective immunity developed, if any, remain unknown. And there are no well-validated immunohistochemistry-capable anti-virus antibodies, so interstitial tissue distribution and loading remain unknown.
COVID-19 tests currently come in three classes:
1) Viral RNA amplification tests (Nucleic Acid Amplification Tests; NAAT);
2) Viral antigen tests, which are based on affinity detection methods (VADM); and
3) Serological tests, which detect any SARS-CoV-2-reactive antibodies.
Nasal, laryngeal or sputum swabs are currently accepted for tests 1) and 2), while pin-prick or venous blood is used for test 3). Swabbing is uncomfortable and exposes the sampler to virus, so a preprint suggesting detection in saliva of high viral titers by NAAT is of interest (4).
Tests 1) and 2) identify those who carry virus and may be infectious, even if asymptomatic. Test 3) identifies people whose immune systems have responded to SARS-CoV-2 exposure, including those who may have active viremia. Only NAATs and a single VADM are quantitative at present.
A 4th class of test is currently unavailable: a commercial test that accurately detects neutralizing anti-SARS-CoV-2 antibodies, would be valuable because it could identify those likely to mount a strong response to a repeated infection.
Only a combination of such tests, including a serological test in particular, will identify the prevalence and exposure of populations to the virus. However, as described below, current serological tests fall far below diagnostic standards (e.g., > 98% clinical selectivity; > 98% clinical specificity). At present, only predominantly qualitative VADM and serological tests are available. Infectivity is related to the amount of virus emitted by infected people, so routine quantitative tests might allow an accurate assessment of the progression of the pandemic.
Automated commercial PCR and quantitative (Q-PCR) systems can rapidly detect and quantify (Q-PCR) SARS-CoV-2 RNA. However, the high-throughput machinery and expertise needed to perform the test is generally found only in a sophisticated centralized laboratory environment. Q-PCR laboratory-use only kits from 41 companies have received FDA EUAs, including those from:
Use of central laboratory facilities leads to slow readouts (1000-20000 samples per day). In the US, 21 laboratories have independently developed SARS-CoV-2 tests that are permitted for EUA usage as high-complexity molecular-based laboratory developed tests.
An exciting development is the use of isothermal amplification (IA) methods, which need less complex machinery and can be very fast (readout in < 15 mins). On March 27, 2020, the FDA issued an EUA for an IA system, ID NOW COVID-19 (Abbott laboratories), for rapid quantitative point-of-care use in SARS-CoV-2 detection. The system has fast sample analysis time (15 min), but low throughput.
On April 20, 2020, Baek et al. (5) reported a 15 minute, quantitative, one-tube, isothermal reverse transcription-loop-mediated isothermal amplification technique (Q-RT-LAMP) with a visual read out of phenol-red color change, possibly adaptable to microtiter plates. This could prove valuable in those many COVID-19-plagued countries lacking ready access to Q-RT-PCR technology.
Although NAATs are state-of-the-art diagnostics for SARS-CoV-2 infection, it must be noted that “…a significant portion of patients who otherwise fit the diagnosis based on clinical and chest CT findings, including many hospitalized patients, have tested negative for viral RNA.” (italics added) (6). This may include victims whose NAAT sinks below the limit of detection of Q-PCR after day 5 post infection (7).
A number of companies provide point-of-care tests for viral antigen. These tests rely on SARS-CoV-2 antigen in patient samples being trapped by antigen-targeting antibodies on a detectable mobile phase. For a few examples:
The Foundation for Innovative New Diagnostics (FIND), a non-government organization, has identified some 10 (poorly validated) antigen tests marketed under the European CE label, and many tests of very dubious provenance are available on the internet.
Serological tests rely on detecting blood IgM and IgG antibodies, or mucus IgA and IgG, reacting with SAR-CoV-2. The FDA has noted that owing to the urgency of the situation, they “… had not reviewed or authorized (or “approved”) … (these tests)… at least not initially, and … (they)… should not be used for diagnosing or excluding active SARS-CoV-2 infection.” (italics added).
To date (April 28, 2020), 7 serological tests from 6 companies have received EUA. These are based on:
Many more tests have been developed and marketed in Europe, including:
FIND has identified over 60 CE labelled antibody tests (13). Each provider uses immobilized recombinant SARS-CoV-2 proteins to capture antibodies from blood, which are in turn captured on, or recognized by, “anti-human-IgG” and or “anti-IgM” reagents. As yet little detail of the validation of the reagents used in the tests has been published. Whether any tests will ever become FDA-approved diagnostics is still an open question. The sensitivity of these tests is reportedly 1-2 logs below that of viral NAAT, and only the EuroImmun test is semi-quantitative. For many rapid tests, the specificity and sensitivity has been challenged due to the low sample numbers, biased sampling and questionable reagents (14).
As yet only DiaSorin has claimed that their laboratory-based serological assay, detecting both S1 and S2 spike proteins of SARS-CoV-2, can preferentially detect neutralizing antibodies (15). If their claim and methodology can be independently confirmed, the use of such an antibody combination in a rapid test kit may be a valuable step towards disease control.
Though many companies are now offering antibody tests, the World Health Organization has yet to recognize a single appropriate serological SARS-CoV-2 assay, none have been validated sufficiently for clinical approval by the FDA, and they remain as laboratory tests. The quality of the antibodies used is currently unknown, and little data has been published on the conditions used to verify their specificity and selectivity. As we saw in our recent webcast series, such a lack of validation can cause major problems when antibodies are used as a basis to make life and death decisions. In the case of SARS-CoV-2, properly validated tests are urgently needed.
There are 4 clear stages in the progression of SARS-CoV-2 infection, which should have distinct test profiles useful for making decisions on disease spread.
1) The newly infected carry replicating virus, detectable with NAAT.
2) The infected mount a delayed adaptive immune response producing anti-viral IgM 5-10 days after infection.
3) An IgG response begins some 14 days after infection. This response may or may not produce neutralizing antibodies.
4) “Recovered” patients have a low viral titer, and so are NAAT-negative, and may or may not have detectable, and possibly neutralizing anti-SARS-CoV-2 IgG.
Thus, people at stage 1 express only viral RNA, while those at stage 2 express viral RNA and anti-SARS-CoV-2 IgM and, later, IgA. At stage 3, the infected may not express viral RNA and may have SARS-CoV-2 IgG, while those at stage 4 may continue to express anti-SARS-CoV-2 IgG. The duration, strength, and possible neutralizing nature of the primary and any secondary antibody response is currently unknown.
The COVID-19 pandemic has triggered a rapid effective scientific response. Sadly, this has in general been obscured. The demand for “tests” has driven a gold-rush – resulting in a morass of point-of-care lateral-flow kits. These frequently use unvalidated polyclonal antibodies. Given the volume of tests to be performed, this will drastically lower the quality of the resulting data. The Antibody Society welcomes recent ongoing efforts to better define the performance of such kits (16), and we hope for more efforts along these lines in the coming weeks.
1. Foundation for Innovative New Diagnostics. FIND Covid-19 tests. Geneva: FIND; 2020. Available from: https://www.finddx.org/covid-19/test-tracker/.
2. US Food and Drug Administration. Policy for Diagnostic Tests for Coronavirus Disease-2019 during the Public Health Emergency Washington D.C.: FDA; 2020. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/policy-diagnostic-tests-coronavirus-disease-2019-during-public-health-emergency.
3. Hahn SM, McMeekin JA. Coronavirus (COVID-19) Update: FDA Alerts Consumers About Unauthorized Fraudulent COVID-19 Test Kits. March 20, 2020. Available from: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-alerts-consumers-about-unauthorized-fraudulent-covid-19-test-kits
4. Wyllie AL, Fournier J, Casanovas-Massana A, Campbell M, Tokuyama M, Vijayakumar P, et al. Saliva is more sensitive for SARS-CoV-2 detection in COVID-19 patients than nasopharyngeal swabs. medRxiv. 2020:2020.04.16.20067835.
5. Baek YH, Um J, Antigua KJC, Park JH, Kim Y, Oh S, et al. Development of a reverse transcription-loop-mediated isothermal amplification as a rapid early-detection method for novel SARS-CoV-2. Emerg Microbes Infect. 2020:1-31.
6. Xiao SY, Wu Y, Liu H. Evolving status of the 2019 novel coronavirus infection: Proposal of conventional serologic assays for disease diagnosis and infection monitoring. J Med Virol. 2020;92(5):464-7. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/jmv.25702
7. Woelfel R, Corman VM, Guggemos W, Seilmaier M, Zange S, Mueller MA, et al. Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. Available from: medRxiv. 2020:2020.03.05.20030502.
8. SD Biosensor. STANDARD Q COVID-19 Ag 2020. Available from: http://www.sdbiosensor.com/xe/product/7672.
9. BioConcept C. COVID-19 Ag Respi-Strip [Product insert]. B – 5032 Gembloux, Belgium: Coris BioConcepts; 2020 [updated 8th April 2020]. Available from: https://www.corisbio.com/Products/Human-Field/Covid-19.php.
10. Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect. 2020. Available from: https://doi.org/10.1016/j.jmii.2020.03.022
11. Bioeasy. 2019-nCovIgG/IgM GICA rapid test kit 2020. Available from: http://en.bioeasy.com.tr/bioeasy-novel-coronavirus-2019-ncov-test-kits/.
12. EuroImmun. SARS-CoV-2 test systems from EUROIMMUN [Supplier web site]. Lubeck: EuroImmun; 2020. Available from: https://www.coronavirus-diagnostics.com/.
13. European Centre for Disease Prevention and Control. An overview of the rapid test situation for COVID-19 diagnosis in the EU/EEA Stockholm: ECDC; 2020. Available at: https://www.ecdc.europa.eu/sites/default/files/documents/Overview-rapid-test-situation-for-COVID-19-diagnosis-EU-EEA.pdf
14. Vogel G. First antibody surveys draw fire for quality, bias. Science. 2020;368(6489):350-1. Available at: https://science.sciencemag.org/content/368/6489/350.
15. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020;181(2):281-92 e6. Available at: https://www.sciencedirect.com/science/article/pii/S0092867420302622.
16. Whitman JD, Hyatt J, Mowery CT, Shy BS. Test performance evaluation of SARS-CoV-2 serological assays [Assay analysis Lateral flow tests]. UCSF Harvard consortium: University of California, San Francisco; 2020. Available from: https://covidtestingproject.org/.
The extraordinary scope and scale of the COVID-19 pandemic has elicited extraordinary responses world-wide. Companies, government agencies, academic institutions and non-profits located across the globe have mobilized teams to research the SARS-CoV-19 virus and COVID-19, conduct clinical studies of potential interventions that currently exist, and research and develop new interventions, including vaccines. To educate and inform, numerous organizations are also providing news and analysis of the pandemic. Importantly, much of this information has been made available free of charge. In Part 6 of our series “Coronavirus in the crosshairs“, we provide links to a sampling of websites that collectively offer extensive, and free, coverage of the COVID-19 pandemic.
Johns Hopkins University Coronavirus Resource Center
This website is a resource to help advance the understanding of the virus, inform the public, and brief policymakers in order to guide a response, improve care, and save lives. The site includes a global map and a map of the United States
The New York Times
This website includes analysis of recent news and maps of viral distribution.
A new resource for tracking COVID-19 clinical studies has been launched by Cytel. Funded in part by the Bill & Melinda Gates Foundation, the Global COVID-19 Clinical Trial Tracker is designed to identify any active interventional trials investigating treatment of COVID-19, regardless of clinical context.
Clinicaltrials.gov has one-click access to extensive information about hundreds of clinical trials associated with the key words COVID-19, SARS-CoV-2 and 2019-nCoV.
The Milken Institute has launched a COVID-19 Treatment and Vaccine Tracker. Data can be downloaded as a PDF.
BioWorld is offering a list of biopharma products in development for COVID-19, including both therapeutics and vaccines.
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.
The Coalition for Epidemic Preparedness Innovations has published an overview of SARS-CoV-2 vaccines in development. As of April 8, 2020, they had identified 78 confirmed active projects, with 73 currently at exploratory or preclinical stages, and an additional 37 programs that were considered unconfirmed due to limited data available. As the authors note, the range of technology platforms being evaluated, including nucleic acid (DNA and RNA), virus-like particle, peptide, viral vector (replicating and non-replicating), recombinant protein, live attenuated virus and inactivated virus approaches, is striking.
The New England Journal of Medicine is now providing open access to a collection of articles and other resources on the COVID-19 outbreak, including clinical reports, management guidelines, and commentary.
Science has made their coronavirus-related content open access.
Next in Coronavirus in the crosshairs
In upcoming installments of “Coronavirus in the crosshairs“, we will discuss diagnostic tests and preliminary results of clinical studies of small molecule and biologic drugs used to treat COVID-19.
Anti- SARS-CoV-2 antibodies produced by the human immune system are key to:
In this installment of the “Coronavirus in the crosshairs” series, The Antibody Society provides updates on the status of anti-SARS-CoV-2 antibody tests, plasma-based therapeutics, and vaccines.
Detection of anti-SARS-CoV-2 antibodies in the blood of healthy people is critical to determining:
To be useful, however, serological tests must be accurate and reliable, which is typically evaluated by regulatory agencies based on data submitted to them by test developers. In response to the public health emergency caused by SARS-CoV-2 in the US, the Food and Drug Administration (FDA) issued guidance on COVID-19 diagnostic tests and initiated a virtual Town Hall Series on the immediately in effect guidance. Guidance issued February 29, 2020 describes FDA’s policy regarding laboratories immediately using tests they developed and validated while pursuing an emergency use authorization (EUA). Guidance updated March 16, 2020 describes additional policies regarding manufacturers immediately distributing tests they validated while pursuing an EUA and regarding certain serology tests.
To date, one serological test intended for use by clinical laboratories has been granted a EUA by FDA. On April 1, 2020 Cellex Inc. received an EUA for the qSARS-CoV-2 IgG/IgM Rapid Test, which is a qualitative test for the detection of IgM and IgG antibodies against SARSCoV-2 in serum and plasma blood specimens and venipuncture whole blood specimens collected from individuals suspected of COVID-19 by their healthcare provider. According to FDA’s April 7, 2020 update, over 70 test developers have notified the agency that they have serological tests available for use.
Further information about FDA’s Guidance on Coronavirus (COVID-19) Diagnostic Tests, including slides and transcripts from the virtual Town Hall Series can be found here.
Plasma from patients who recover from infectious diseases, including SARS and Ebola, contains antibodies that can used to treat patients with the infections. Preliminary reports (Shen et al. study of 5 patients; Duan et al. study of 10 patients) suggest that plasma from COVID-19 patients who recovered, i.e., convalescent plasma, may benefit patients who are critically ill with the disease.
Early in the pandemic, numerous companies announced initiatives to develop convalescent plasma-based products, also known as hyperimmune therapies, for COVID-19. More recently, however, 6 companies (Biotest AG, Bio Products Laboratory, CSL Behring, LFB, Octapharma and Takeda Pharmaceutical Company Limited) have announced that they are collaborating to accelerate development of potential COVID-19 hyperimmune therapy. The alliance will develop one, unbranded anti-SARS-CoV-2 polyclonal hyperimmune immunoglobulin medicine with the potential to treat patients with serious complications from COVID-19.
Academic organizations and hospitals are also working together to develop convalescent plasma therapy. The National COVID-19 Convalescent Plasma Project comprises a group of physicians and scientists from 57 institutions in 46 states who self-organized to investigate the use of convalescent plasma in the current COVID-19 pandemic. The Mayo Clinic will be the lead institution providing coordinated access to investigational convalescent plasma for hospitalized patients with severe or life-threatening COVID-19, or those at high risk of progression to severe or life-threatening disease.
Regardless of the source of the material, well-controlled clinical trials must be conducted to rigorously evaluate the safety and efficacy of COVID-19 convalescent plasma. Such studies, sponsored by numerous organizations, are now on-going.
FDA’s recommendations for investigational COVID-19 convalescent plasma, including discussion of pathways for its use, can be found here.
Many organizations are conducting research on SARS-CoV-2 vaccines, and their efforts are yielding vaccine candidates that are now entering clinical study. For example, INOVIO Pharmaceuticals, Inc. announced that a clinical study for DNA vaccine candidate INO-4800 will begin this week. The Phase 1 open-label study (NCT04336410) will evaluate the safety, tolerability and immunogenicity of INO-4800 in healthy volunteers. Other vaccines in clinical studies include:
Additional vaccine candidates are expected to enter clinical studies in the next 3-4 months.
Substantial funding for vaccine development is being provided by non-profit organizations such as the Coalition for Epidemic Preparedness Innovations and the Bill & Melinda Gates Foundation. Extraordinary measures have been proposed to accelerate the process so that vaccines are available as quickly as possible. For example, in an interview conducted by Trevor Noah, Bill Gates stated that his Foundation could fund factories for simultaneous production of 7 vaccine candidates (at ~18min 30sec of the 22min interview).
