The Antibody Society

the official website of the antibody society

An international non-profit supporting antibody-related research and development.

You are here: Home / Archives for SARS-CoV-2

NIH seeks community input on research approaches and priorities related to SARS-CoV-2 serology

by

The National Cancer Institute (NCI) in partnership with the National Institute of Allergy and Infectious Disease is seeking community input on research approaches and priorities related to SARS-CoV-2 serology. In this Request for Information,  NCI seeks comments on any or all of, but not limited to, the following research topics related to serology:

1. Research about the relationship between immunity, recent infection, antibody production, and other immunological markers, including:

  • The role and value of animal models and in vitro assays for determining the relationship between antibody production and immunity to SARS-CoV-2.
  • The types and titers of antibodies that are important for immune protection and the mechanism of such protection.
  • Whether cross-reacting antibodies from prior infection by other coronaviruses confer immunity.
  • Whether antibodies to coronaviridae can cause immunopathogenesis (e.g. ADE).
  • Genetic or other host factors that could predict antibody production and innate or adaptive immunity.
  • Specific virologic factors that mediate the generation of effective host immunity, especially humoral immunity vs. cell-mediated immunity.

2. Clinical utilization of serological testing, including:

  • Design strategies for use in clinical trials and population-based observational studies that are optimal to address the most critical research questions, including biospecimen sampling/biobanking considerations as well as safety and ethical considerations.
  • Characteristics and performance standards needed for serological testing, whether for seroprevalence surveys or point-of-care tests.
  • Approaches to rapidly increase capacity for high-quality serology testing in United States, by leveraging existing infrastructure, especially for underserved communities.
  • How to use and interpret serological testing results safely, effectively, and equitably.

NCI is also specifically interested in the link to cancer across all of these areas, including but not limited to the characteristics of the immune response in patients undergoing treatment and cancer survivors; prediction of susceptibility to infection and outcomes in cancer patients; seroepidemiology in cancer patients.

Your comments could include any of the following:

  • Research approaches for these topics;
  • Innovative strategies to advance research progress;
  • Challenges to progress in these areas;
  • Emerging trends, advances, technologies, analytic strategies, and perspectives that NCI should consider in this planning process;
  • Potential approaches to gauge research progress and success.

Please comment on any other topic that you find relevant. Responses to the notice are due on May 26, 2020. 

NCI has posted a Notice of Intent to Publish a Funding Opportunity Announcement for components of the new Serological Sciences Network on May 15. The RFA is expected to be announced in June with expected application due dates in July. Awards are anticipated to be made in September 2020.

Coronavirus in the crosshairs, Part 8: FDA’s Emergency Use Authorization of Therapeutics

by

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.

Letters of authorization issued for therapeutics

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:

  • Fresenius Propoven 2% emulsion to maintain sedation via continuous infusion in patients greater than 16 years old who require mechanical ventilation in an Intensive Care Unit setting during the COVID-19 pandemic. The EUA was issued to Fresenius Kabi USA, LLC on May 8, 2020.
  • Remdesivir to treat adults and children with suspected or laboratory confirmed COVID-19 and severe disease defined as SpO2 ≤ 94% on room air, requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation. The EUA was issued to Gilead Sciences, Inc. on May 1, 2020.
  • Chloroquine phosphate and hydroxychloroquine sulfate supplied from the Strategic National Stockpile for treatment of COVID-19. The EUA was issued to the Biomedical Advanced Research and Development Authority on March 28, 2020.

Limitations to the scope and duration of the authorizations, as well as specific conditions that apply, are detailed in FDA’s letters of authorization.

Possible biologic candidates for EUAs in 2020

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:

July – August 2020

  • Sarilumab (Kevara®; Sanofi, Regeneron), a human IgG1 mAb targeting the interleukin-6 receptor (IL-6R), is approved for rheumatoid arthritis in adults. Sanofi and Regeneron are sponsoring an adaptive Phase 3, randomized, double-blind, placebo-controlled study assessing the efficacy and safety of sarilumab for hospitalized patients with COVID-19 (NCT04327388). The primary outcome measure of the study is time to improvement of 2 points in clinical status assessment from baseline to Day 29 using the 7-point ordinal scale, and the estimated primary completion date is July 2020.
  • Emapalumab (Gamifant®; Swedish Orphan Biovitrum) is a human IgG1 mAb targeting interferon gamma  approved for treatment of pediatric (newborn and older) and adult patients with primary hemophagocytic lymphohistiocytosis (HLH) with refractory, recurrent or progressive disease or intolerance to conventional HLH therapy. Sponsored by Swedish Orphan Biovitrum, NCT04324021 is a Phase 2/3, randomized, open-label, parallel group, 3-arm, multicenter study investigating the efficacy and safety of intravenous administrations of emapalumab and anakinra (IL-1R antagonist) versus standard of care in reducing hyper-inflammation and respiratory distress in patients with SARS-CoV-2 infection. The primary outcome measure is treatment success, defined as the proportion of patients not requiring invasive mechanical ventilation or extracorporeal membrane oxygenation, up to Day 15. The estimated primary completion date of this study is July 2020.
  • Tocilizumab (Actemra®; Hoffmann-LaRoche), a humanized IG1 mAb targeting IL-6R, is approved for rheumatoid arthritis in adults, juvenile rheumatoid arthritis, as well as treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome in patients two years of age and older. Clinicaltrials.gov currently lists 42 studies of tocilizumab in COVID-19 patients, with 12 of these Phase 3 studies. Only one Phase 3 study sponsored by the drug’s co-developer, Hoffmann-LaRoche, is now recruiting patients. The NCT04320615 Phase 3 study is evaluating the safety and efficacy of tocilizumab in patients with severe COVID-19 pneumonia. The primary outcome measure is clinical status assessed using a 7-category ordinal scale, and the estimated primary completion date of this study is August 31, 2020.

September – October 2020

  • Lenzilumab (Humanigen, Inc.) is a Humaneered® mAb targeting granulocyte-macrophage colony-stimulating factor. Humanigen, Inc. is sponsoring the NCT04351152 Phase 3 randomized, placebo-controlled study of lenzilumab in hospitalized patients with COVID-19 pneumonia. The primary outcome measure is the incidence of invasive mechanical ventilation and/or mortality up to 28 days. the estimated primary completion date of this study is September 2020.
  • Siltuximab (SYLVANT®; EUSA Pharma, BeiGene, Ltd.) is an anti-Il-6 chimeric IgG1 mAb marketed for treatment of patients with multicentric Castleman’s disease. University Hospital, Ghent is sponsoring the NCT04330638 Phase 3 study  evaluating siltuximab, anakinra and tocilizumab in improving oxygenation and the short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure and systemic cytokine release syndrome. The primary outcome measure is time to clinical improvement evaluated up to Day 15. The estimated primary completion date of this study is September 2020. Preliminary results of a compassionate-use program (SISCO study; NCT04322188) sponsored by the Papa Giovanni XXIII Hospital have been reported. EUSA Pharma has exclusive rights to SYLVANT® globally. EUSA Pharma has granted BeiGene, Ltd., exclusive development and commercialization rights to SYLVANT® in Greater China.
  • Olokizumab and RPH-104 (R-Pharm International, LLC, Cromos Pharma) are being evaluated in a Phase 2/3 study of COVID-19 patients. Olokizumab is a humanized anti-Il-6 mAb and RPH-104 is a fusion protein that selectively binds and inactivates IL-1ß. R-Pharm International is sponsoring the NCT04380519 international, multicenter, randomized, double-blind, adaptive placebo-controlled study of the efficacy and safety of a single administration of olokizumab and RPH-104 with standard therapy in patients with severe SARS-CoV-2 infection. The primary outcome measure is the proportion of patients that responded to the study therapy in each of the treatment groups at Day 15. The estimated primary completion date of this study is October 15, 2020.
  • IFX-1 (InflaRx GmbH) is an IgG4 mAb targeting complement 5a, which is a component of the complement system that can trigger inflammation. InflaRx GmbH is sponsoring a pragmatic adaptive open label, randomized Phase 2/3 multicenter study of IFX-1 in patients with severe COVID-19 pneumonia (NCT04333420). The primary outcome measure is the relative change (%) from baseline in Oxygenation Index (PaO2 / FiO2) to Day 5. The estimated primary completion date of this study is October 31, 2020.

November – December 2020

  • Ravulizumab (ULTOMIRIS®, Alexion Pharmaceuticals) is a humanized IgG2/4 mAb targeting C5 that is approved for treatment of adult patients with paroxysmal nocturnal hemoglobinuria. Due to start in May 2020, NCT04369469 is a Phase 3 open-label, randomized, controlled study to evaluate the efficacy and safety of intravenously administered ravulizumab compared with best supportive care in patients with COVID-19 severe pneumonia, acute lung injury, or acute respiratory distress syndrome. The primary outcome measure is survival based on all-cause mortality at Day 29, and the estimated primary completion date of this study is November 2020.
  • Leronlimab (CytoDyn, Inc.) is an anti-CCR5 IgG4 mAb undergoing evaluation in two Phase 2 studies of COVID-19 patients. The NCT04343651 study to evaluate the efficacy and safety of leronlimab for mild to moderate COVID-19 and the NCT04347239 study to evaluate the efficacy and safety of leronlimab for patients with severe or critical COVID-19 have estimated primary completion dates of December 4 and December 31, 2020, respectively. Based on results from 10 critical COVID-19 patients who received leronlimab, disrupting the CCL5-CCR5 axis leads to rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia.

Biologic candidates targeting SARS-CoV-2

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”.

Coronavirus in the crosshairs, Part 7: Diagnostic tests

by

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).

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/.

Coronavirus in the crosshairs, Part 6: Web resources

by

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 2: Vaccines in development

by

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