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Coronavirus in the crosshairs, Part 7: Diagnostic tests

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Post written by Simon L. Goodman, D.Phil.

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).

Classes of virus tests

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.

Viral RNA detection

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).

Viral antigen detection

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:

  • SD Biosensor’s lateral flow system has a well-documented limit of detection of ~2000 tissue culture infective dose / ml with 0/170 false positives specificity, but only 84% sensitivity over PCR (8) (i.e., resulting in 16% false negatives).
  • Coris BioConcept’s acute-phase screening kit uses immunochromatographic colloidal gold-based dip stick technology (analogous to capture ELISA). With a sensitivity of 5000 pfu /ml, the kit has a high positive predictive value (78-100%), but sensitivity over PCR of < 86%.  Both kits are reported to identify both SAR-CoV-2 and SAR-COV (vs other respiratory viruses and bacteria), and target conserved coronavirus nucleoprotein (9, 10).
  • Bioeasy uses time-resolved fluorescence analysis in a similar assay system, but the sensitivity and selectivity data are not reported (11).  Early phase infection was undetectable in a small sample set of urine and blood by VADM, while it could be identified in respiratory test probes (7).

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.

Detecting anti-viral serological responses

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:

  • Immunochromatographic (Coris);
  • Lateral flow (Bioeasy; ElabScience; HighPlusTech; Senova; SD sensor; Premier/Hangzou); and
  • Classical plate-ELISA based for detection of anti-Covid-19 IgA and IgG (EuroImmun) (12).

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.

Deciphering test results

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.

References

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/.

FDA approves sacituzumab govitecan (Trodelvy®) for triple-negative breast cancer

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On April 22, 2020, the US Food and Drug Administration (FDA) granted an accelerated approval to Trodelvy® (sacituzumab govitecan-hziy) for the treatment of patients with metastatic triple-negative breast cancer who received at least two prior treatments for metastatic disease. Sacituzumab govitecan is composed of an anti-TROP-2 humanized IgG1 antibody conjugated to the topoisomerase inhibitor SN38, which is the active metabolite of irinotecan.

The approval was based on the results of a clinical trial of 108 patients with metastatic triple-negative breast cancer who had received at least two prior treatments for metastatic disease. In this study, the overall response rate was 33.3%, with a median duration of response of 7.7 months. Of the patients who responded to treatment, 55.6% maintained their response for 6 or more months and 16.7% maintained their response for 12 or more months.

The accelerated approval program allows FDA to approve drugs for serious conditions to fill an unmet medical need based on a surrogate endpoint, i.e., a result that is reasonably likely to predict a clinical benefit to patients. Additional clinical trials are required to confirm Trodelvy’s clinical benefit, and the FDA can remove the drug from the market if the confirmatory trial does not show that the drug provides clinical benefit.

Antibodies to watch in 2020: Will the pandemic cause delays?

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As regulatory agencies tasked with evaluating and monitoring the development of medicines, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have pivotal roles in the global response to the COVID-19 pandemic. However, these critical activities have been added to an already substantial workload. FDA and EMA are continuing the ongoing marketing application reviews for drugs that are not COVID-19 interventions, and they will need to process new applications submitted throughout 2020. FDA and EMA’s distribution of work is particularly relevant to new antibody therapeutics because a substantial number of license applications for these drugs, none of which relate to COVID-19, are undergoing FDA or EMA review. In a recent statement, FDA offered assurances that their application review teams are focused on their work, but noted that they may not be able to sustain the current level of performance indefinitely.

In total, biologics license applications (BLAs) for 14 new antibody therapeutics (i.e., not previously approved by any agency for any indication) are undergoing FDA review. EMA is reviewing marketing authorization applications (MAAs) for 4 of these 14 antibody therapeutics, and MAAs for 4 antibody therapeutics that are already approved in the US.

New antibody therapeutics undergoing FDA review

The 14 antibody therapeutics undergoing FDA review are treatments for a variety of diseases, including numerous cancers, neuromyelitis optica spectrum disorders, osteoarthritis pain, diabetes, thrombotic microangiopathies, Ebola and HIV infection. The drugs for cancer are:

  • Sacituzumab govitecan, anti-TROP-2 humanized IgG1 antibody-drug conjugate for triple-neg. breast cancer
  • Belantamab mafodotin, anti-B-cell maturation antigen humanized IgG1 antibody-drug conjugate for multiple myeloma
  • Tafasitamab, anti-CD19 humanized IgG1 for diffuse large B-cell lymphoma
  • Naxitamab, anti-GD2 humanized IgG1 for high-risk neuroblastoma and refractory osteomedullary disease
  • Oportuzumab monatox, anti-EpCAM humanized scFv immunotoxin for bladder cancer
  • Margetuximab, anti-HER2 chimeric IgG1 for HER2-positive metastatic breast cancer
  • Dostarlimab, anti-PD-1 humanized IgG4 for endometrial cancer

The drugs for non-cancer indications are:

  • Inebilizumab, anti-CD19 humanized IgG1 for neuromyelitis optica and neuromyelitis optica spectrum disorders
  • Satralizumab, anti-IL-6R humanized IgG2 for neuromyelitis optica spectrum disorders
  • Tanezumab, anti-nerve growth factor humanized IgG2 for pain due to osteoarthritis of the knee or hip
  • Teplizumab, anti-CD3 humanized IgG1 for type 1 diabetes
  • Narsoplimab, anti-MASP-2 human IgG4 for hematopoietic stem cell transplant-associated thrombotic microangiopathies
  • Leronlimab, anti-CCR5 humanized IgG4  for HIV infection
  • REGNEB3, a mixture of 3 human IgG1 targeting the Ebola virus for Ebola disease.

A first review cycle for the BLAs for all 14 should be completed by the end of 2020. Despite the pandemic, 2020 may be a record year for new antibody therapeutics approvals (potentially 17, including the 14 discussed here and the approvals for teprotumumab-trbw (Tepezza®), eptinezumab-jjmr (Vyepti®) and isatuximab-irfc (Sarclisa®) already granted in 2020, or more).

Antibody therapeutics undergoing EMA review

Like FDA, EMA is continuing to process MAAs for antibody therapeutics despite the increase in workload due to COVID-19. EMA provides monthly updates on applications for centralized marketing authorization for human medicines that they have received for evaluation. EMA’s information as of April 6, 2020, indicates that they are evaluating MAAs for 8 antibody therapeutics that, if approved, would be new to the European Union. These 8 are Belantamab mafodotin, Dostarlimab, Satralizumab and Tanezumab, which are also being reviewed by FDA, as well as:

  • Obiltoxaximab (Anthim®), anti-B. anthrasis protective antigen chimeric IgG1 approved by FDA for prevention of inhalational anthrax in 2016
  • Emapalumab (Gamifant®), anti-IFN gamma human IgG1 approved by FDA for primary hemophagocytic lymphohistiocytosis in 2018
  • Moxetumomab pasudotox (Lumoxiti®), anti-CD22 murine IgG1 dsFv immunotoxin approved by FDA for hairy cell leukemia in 2018
  • Crizanlizumab (Adakveo®) anti-P-selectin humanized IgG2 approved by FDA for sickle cell disease in 2019

Other antibodies to watch in 2020

The COVID-19 pandemic might delay the submission of marketing applications for antibody therapeutics that are now in late-stage clinical studies. As documented by Kaplon et al. in ‘Antibodies to watch in 2020’, companies developing 5 antibody therapeutics for cancer (spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) and 5 for non-cancer indications (aducanumab, evinacumab, etrolizumab, sutimlimab, and anifrolumab) had previously announced plans to submit applications to regulatory agencies during 2020. The Antibody Society will continue to monitor the development of these product candidates and report on progress. Discussion of these antibodies can be found in the ‘Antibodies to watch in 2020’ paper.

Coronavirus in the crosshairs, Part 6: Web resources

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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.

Global Distribution of SARS-CoV-2

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.

COVID-19 Clinical Studies

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.

Therapeutics and Vaccines in Development

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.

Scientific and Medical Literature

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.

Coronavirus in the crosshairs, Part 5: Harnessing the human immune system

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Anti- SARS-CoV-2 antibodies produced by the human immune system are key to:

  • Serological tests, which identify past exposure;
  •  Convalescent plasma, which can be used to treat COVID-19 patients;
  •  Protection of healthy individuals, after vaccination.

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.

Serological tests

Detection of anti-SARS-CoV-2 antibodies in the blood of healthy people is critical to determining:

  • Who has previously been exposed to the virus, and may be able to resume work;
  • Who can donate plasma that may be a treatment for COVID-19 patients.

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.

Convalescent plasma

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.

Vaccines

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).