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We’ve never faced this before, where clinical labs needed to very quickly be able to ramp up a test so fast.[1]
 
- Jennifer Doudna, Executive Director of the Innovative Genomics Institute, University of California, Berkeley

Though the dismantling and fund-cutting (proposed and real) of government programs designed to protect the populace from pandemics—as well as shortfalls in funding overall[2]—have likely hobbled local, national, and global response to COVID-19[3][4][5][6], it should be recognized that this pandemic may arguably represent a once-in-a-century type of event.[7][8] That said, even the most well-prepared governments would still face challenges in quickly learning about, controlling, and developing therapies for a novel disease agent. Shortages in supplies, workers, funding, and other resources are inevitably caused with a pandemic as people across all types of infrastructure fall ill.[2][9] This requires the additional human elements of adaptability, drive, and shared knowledge to find new and alternative solutions to fighting the challenges inherent to fighting against a novel disease.

See for example a non-peer-reviewed paper published on bioRxiv in early April 2020, where Schmid-Burgk et al. pointed out that though RT-PCR methods are the most common for currently testing for SARS-CoV-2, "global capacity for testing using these approaches, however, has been limited by a combination of access and supply issues for reagents and instruments." They proposed "a novel protocol that would allow for population-scale testing using massively parallel RT-LAMP by employing sample-specific barcodes." They claimed that a single heating step, pooled processing, and parallel sequencing with computational analysis would allow for the testing and tacking of "tens of millions of samples." Though the protocol was not validated with clinical samples, and concerns about sensitivity levels of RT-LAMP (an isothermal nucleic acid amplification technique that allows for RNA amplification) have been raised, the authors' work exemplifies the immediacy and ingenuity that has gone into finding workable solutions to a once-a-century problem.[10]

Another example of ingenuity in the face of difficult circumstances can be found at the University of California, Berkeley. At the beginning of the pandemic, its Innovative Genomics Institute (IGI) rapidly repurposed a 2,500-square-foot scientific lab into an automated diagnostic laboratory that could initially process more than 1,000 patient samples per day, with the ability to ramp up to 3,000 per day thanks to robotics and a streamlined workflow. Partnering with dozens of people from Thermo Fisher Scientific, Salesforce, Third Wave Analytics, and Hamilton Corp., the lab focused on not only turnaround time but also accuracy of results through automation. Their continued success, of course, still relies on a steady supply of reagents and related supplies from Thermo Fisher.[1][11]

Since the pandemic's start, others have also expressed concerns about the global supply of reagents necessary to test for SARS-CoV-2. Successful testing using RT-PCR requires two different enzymes: reverse transcriptase, for converting RNA to DNA, and polymerase, for amplifying the converted DNA. These enzymes and other reagent components may be instrument-specific, and at least one component has to be sympathetic to detection of the target virus' RNA. Little of this can be prepared without a proper sequence of the virus in question. Dr. Ronald Leonard, president and medical director of Cytocheck Laboratory and medical director of the Labette Health hospital, expressed the difficulties associated with reagent manufacturing thusly[12]:

With the instant demand for SARS-CoV-2 testing, the manufacturing process had to start from scratch for the SARS-CoV-2 specific components, and this did cause a lag time before reagents were available. The increased demand coupled with the decision to only allocate reagents to two national laboratories, some state health departments, and to "hot spots" has compounded the difficulty for laboratories like ours to obtain the necessary reagents to perform the testing.

Reports of COVID-19 test reagent shortages from various sources have appeared since March 2020.[13][14][15][16][17][18][19][20][21][22][23][24] Over time, those shortages even extended to supplies for non-COVID-19 tests such as those for strep throat, bronchitis, mycobacterial infections, urinary-tract infections, fungal infections, and sexually transmitted infections.[22][23][24] In the face of these supply challenges, some have taken matters into their own hands. Noting Irish laboratories' difficulties sourcing lysis buffer (for isolating molecules of interest and keeping them stable), Cork Institute of Technology's Dr. Brigid Lucey worked with several other virologists and microbiologists early in the pandemic, as well as with pharmaceutical company Eli Lilly, to produce a custom-formulated yet high-quality lysis buffer for not only Irish laboratories but also other countries can take advantage of. "We are happy to share what we found with other countries and it’s important our scientists retain their skills to make this kind of formulation because we may need to do this again in the future if we get other pandemics," she said.[16]

Another challenge lies in the accuracy of serology-based antibody tests, let alone how much they actually tell us about immunity. FierceBiotech's Conor Hale touched upon this in late April 2020[25]:

Compared to molecular tests—which sequence and match the RNA of the novel coronavirus to produce a result—the FDA has described antibody tests that gauge the body’s immune system response as a less-complicated endeavor that could proceed without review, dubbed “regulatory flexibility” by Commissioner Stephen Hahn. This policy shift has led to confusion, with some antibody test developers falsely claiming their tests are FDA-approved or could diagnose COVID-19 at home. Still others have sold outrightly fraudulent tests online.

At least in the U.S., these problems are compounded by company participation in test validation of EUAs being voluntary.[25] As a late April 2020 memorandum from Congress put it: "FDA is unable to validate the accuracy of antibody tests that are already on the market, and companies are ignoring requests from the Department of Health and Human Services (HHS) to voluntarily submit their tests for validation ... FDA has failed to police the coronavirus serological antibody test market, has taken no public enforcement action against any company, and has not conveyed any clear policy on serological tests..."[26] The entire memorandum is revealing in the challenges of attempting to relax social distancing measures under the pretense of the effectiveness of antibody testing. Entities such as the University of California - San Francisco[27] and the University of California - Berkeley[28] early on emphasized the importance of elements such as sensitivity, specificity, proper training, and the unknowns of the predictive ability of the test. Even assays running under trusted platforms such as PCR can reveal issues. For example, Thermo Fisher Scientific's TaqPath COVID019 Combo Kit, approved for EUA in March 2020, received scrutiny and updates to address issues with false-positive and -negative results[29][30], highlighting the difficulty of, at least early on in the pandemic, balancing the need for rapidly approving test kits for emergency use while also maintaining some semblance of oversight regarding their effectiveness and proper use. This has been further hampered by an August 2020 decision that stated the FDA could not require laboratory developed tests (LDTs) to be submitted for an EUA. As the Pew Charitable Trust's Liz Richardson argued in September 2021, reversing this decision "would enable labs to continue bringing innovative and effective new tests to market quickly while empowering FDA to protect the public from faulty products that allow infection to spread."[31]

Finally, while point-of-care testing, including at-home testing, has made strides in 2021[32], their need remains apparent. Dozens of at-home tests remained in development (many of them antigen tests) at the end of 2020, and even now a major barrier is found in making them both accurate and easy for untrained people to understand and use.[33][34] And as more at-home tests continue to receive EUAs in 2021, they are still not without concern, particularly in regards to ensuring that at-home test results get reported properly and rapidly.[33][35] One such early example at the end of 2020 was Lucira Health's LAMP-based Lucira COVID-19 All-In-One Test Kit, which was approved as a prescription-based at-home test, but with the stipulation that the prescribing healthcare provider would be responsible for reporting results.[36] Such a requirement arguably can and should be put in place for at-home antigen-based testing as well.[33]

As the pandemic churns through its second year, it's more important than ever for leaders across government, healthcare, and the media to continue to not spread misinformation and not make decisions based on poor scientific evidence. It will take organized efforts from multiple stakeholders—such as that found with a June 2020 NIH workshop on expanding and improving COVID-19 antibody tests[37]—to continue to find responsible solutions to the challenges we still face with this pandemic.

References

  1. ↑ 1.0 1.1 Terry, M. (30 March 2020). "CRISPR Pioneer Jennifer Doudna Expects Automated COVID-19 Test Lab to Begin Testing Next Week". BioSpace. https://www.biospace.com/article/crispr-discoverer-jennifer-doudna-launches-covid-19-test-lab/. Retrieved 10 April 2020. 
  2. ↑ 2.0 2.1 Sands, P.; Mundaca-Shah, C.; Dzau, V.J. (2016). "The Neglected Dimension of Global Security — A Framework for Countering Infectious-Disease Crises". The New England Journal of Medicine 374 (13): 1281–87. doi:10.1056/NEJMsr1600236. PMID 26761419. 
  3. ↑ Morris, C. (26 February 2020). "Trump administration budget cuts could become a major problem as coronavirus spreads". Fortune. https://fortune.com/2020/02/26/coronavirus-covid-19-cdc-budget-cuts-us-trump/. Retrieved 10 April 2020. 
  4. ↑ Specter, M. (17 March 2020). "The Coronavirus and the Gutting of America’s Public-Health System". The New Yorker. https://www.newyorker.com/news/daily-comment/coronavirus-and-the-gutting-of-americas-public-health-system. Retrieved 10 April 2020. 
  5. ↑ Roos, R. (25 May 2007). "Congress cut pandemic funds before passing spending bill". CIDRAP - News & Perspective. https://www.cidrap.umn.edu/news-perspective/2007/05/congress-cut-pandemic-funds-passing-spending-bill. Retrieved 10 April 2020. 
  6. ↑ Schnirring, L. (20 December 2007). "Congress slashes pandemic preparedness funding". CIDRAP - News & Perspective. https://www.cidrap.umn.edu/news-perspective/2007/12/congress-slashes-pandemic-preparedness-funding. Retrieved 10 April 2020. 
  7. ↑ Gates, B. (2020). "Responding to Covid-19 — A Once-in-a-Century Pandemic?". The New England Journal of Medicine. doi:10.1056/NEJMp2003762. PMID 32109012. 
  8. ↑ Shontell, A. (10 April 2020). "Melinda Gates: This is not a once-in-a-century pandemic. 'We will absolutely have more of these.' The billionaire philanthropist predicts a timeline for going back to normal". Business Insider. https://www.businessinsider.com/melinda-gates-coronavirus-interview-vaccine-timeline-2020-4. Retrieved 10 April 2020. 
  9. ↑ Madhav, N.; Oppenheim, B.; Gallivan, M. et al. (2017). "Chapter 17: Pandemics: Risks, Impacts, and Mitigation". In Jamison, D.T.; Gelband, H.; Horton, S. et al.. Disease Control Priorities: Improving Health and Reducing Poverty (3rd ed.). The World Bank. ISBN 9781464805288. https://www.ncbi.nlm.nih.gov/books/NBK525302/. 
  10. ↑ Schmid-Burgk, J.L.; Li, D.; Feldman, D. et al. (2020). "LAMP-Seq: Population-Scale COVID-19 Diagnostics Using Combinatorial Barcoding". bioRxiv. doi:10.1101/2020.04.06.025635. 
  11. ↑ Sanders, R. (30 March 2020). "UC Berkeley scientists spin up a robotic COVID-19 testing lab". Berkeley News. https://news.berkeley.edu/2020/03/30/uc-berkeley-scientists-spin-up-a-robotic-covid-19-testing-lab/. Retrieved 10 April 2020. 
  12. ↑ Nolting, R. (10 April 2020). "Local testing delayed by lack of reagents". Parsons Sun. https://www.parsonssun.com/news/coronavirus/article_99193646-7aec-11ea-a7c5-b700f82332db.html. Retrieved 10 April 2020. 
  13. ↑ Herper, M.; Branswell, H. (10 March 2020). "Shortage of crucial chemicals creates new obstacle to U.S. coronavirus testing". STAT. https://www.statnews.com/2020/03/10/shortage-crucial-chemicals-us-coronavirus-testing/. Retrieved 10 April 2020. 
  14. ↑ Hale, C. (18 March 2020). "Qiagen aims to more than quadruple its COVID-19 reagent production in 6 weeks". Fierce Biotech. https://www.fiercebiotech.com/medtech/qiagen-aims-to-more-than-quadruple-its-covid-19-reagent-production-6-weeks. Retrieved 10 April 2020. 
  15. ↑ Mehta, A. (3 April 2020). "Mystery surrounds UK claim of Covid-19 test reagent ‘shortage’". Chemistry World. https://www.chemistryworld.com/news/mystery-surrounds-uk-claim-of-covid-19-test-reagent-shortage/4011457.article. Retrieved 07 September 2021. 
  16. ↑ 16.0 16.1 Roche, B. (8 April 2020). "Irish scientists develop reagent in effort to ease Covid-19 testing delays". The Irish Times. https://www.irishtimes.com/news/science/irish-scientists-develop-reagent-in-effort-to-ease-covid-19-testing-delays-1.4223897. Retrieved 10 April 2020. 
  17. ↑ Padma, T.V. (13 May 2020). "Efforts to combat Covid-19 in India hit by imported reagent shortages". Chemistry World. https://www.chemistryworld.com/news/efforts-to-combat-covid-19-in-india-hit-by-imported-reagent-shortages/4011718.article#/. Retrieved 19 May 2020. 
  18. ↑ David, E.; Farber, S.E. (20 June 2020). "Survey shows resources for COVID-19 diagnostic testing still limited months later". ABC News. https://abcnews.go.com/Health/survey-shows-resources-covid-19-diagnostic-testing-limited/story?id=71341885. Retrieved 08 July 2020. 
  19. ↑ Johnson, K. (2 July 2020). "NC Labs Facing Shortages In COVID-19 Testing Chemicals". Patch. https://patch.com/north-carolina/charlotte/nc-labs-facing-shortages-covid-19-testing-chemicals. Retrieved 08 July 2020. 
  20. ↑ Mervosh, S.; Fernandez, M. (4 August 2020). "‘It’s Like Having No Testing’: Coronavirus Test Results Are Still Delayed". The New York Times. https://www.nytimes.com/2020/08/04/us/virus-testing-delays.html. Retrieved 05 August 2020. 
  21. ↑ Courage, K.H. (31 July 2020). "Should we be testing fewer people to stop the spread of Covid-19?". Vox. https://www.vox.com/2020/7/31/21336212/covid-19-test-results-delays. Retrieved 05 August 2020. 
  22. ↑ 22.0 22.1 American Society for Microbiology (9 November 2020). "Supply Shortages Impacting COVID-19 and Non-COVID Testing". American Society for Microbiology. https://asm.org/Articles/2020/September/Clinical-Microbiology-Supply-Shortage-Collecti-1. Retrieved 18 November 2020. 
  23. ↑ 23.0 23.1 Abbott, B.; Krouse, S. (9 November 2020). "Covid-19 Testing Saps Supplies Needed for Other Medical Tests". The Wall Street Journal. https://www.wsj.com/articles/covid-19-testing-saps-supplies-needed-for-other-medical-tests-11604926800. Retrieved 18 November 2020. 
  24. ↑ 24.0 24.1 Williams, S. (21 April 2021). "Supply Shortages Hit Life Science Labs Hard". The Scientist. https://www.the-scientist.com/news-opinion/supply-shortages-hit-life-science-labs-hard-68695. Retrieved 07 September 2021. 
  25. ↑ 25.0 25.1 Hale, C. (27 April 2020). "Congress urges FDA to better police, evaluate COVID-19 antibody tests". Fierce Biotech. https://www.fiercebiotech.com/medtech/congress-urges-fda-to-better-police-evaluate-covid-19-antibody-tests. Retrieved 01 May 2020. 
  26. ↑ Subcommittee on Economic and Consumer Policy (24 April 2020). "Preliminary Findings of the Subcommittee’s Coronavirus Antibody Testing Investigation" (PDF). U.S. House of Representatives. https://oversight.house.gov/sites/democrats.oversight.house.gov/files/ECP%20Staff%20Report%20on%20Preliminary%20Findings%20of%20the%20Subcommittee%E2%80%99s%20Coronavirus%20Antibody%20Testing%20Investigation.pdf. Retrieved 01 May 2020. 
  27. ↑ Farley, P.; Sanders, R. (27 April 2020). "Testing the Tests: COVID-19 Antibody Assays Scrutinized for Accuracy by UCSF, UC Berkeley Researchers". UCSF News. https://www.ucsf.edu/news/2020/04/417276/testing-tests-covid-19-antibody-assays-scrutinized-accuracy-ucsf-uc-berkeley. Retrieved 01 May 2020. 
  28. ↑ Sanders, R. (27 April 2020). "What COVID-19 antibody tests can tell us, and what they can’t". Berkeley News. https://news.berkeley.edu/2020/04/27/what-covid-19-antibody-tests-can-tell-us-and-what-they-cant/. Retrieved 01 May 2020. 
  29. ↑ Whooley, S. (17 August 2020). "FDA warns on false results for Thermo Fisher TaqPath COVID-19 testing kit". + Mass Device. WTWH Media LLC. https://www.massdevice.com/fda-warns-on-false-results-for-thermo-fisher-taqpath-covid-19-testing-kit/. Retrieved 23 August 2020. 
  30. ↑ Taylor, N.P. (18 August 2020). "Thermo Fisher COVID-19 test flagged for false positive and negative results". MedTechDive. https://www.medtechdive.com/news/thermo-fisher-covid-19-test-flagged-for-false-positive-false-negative-resu/583682/. Retrieved 23 August 2020. 
  31. ↑ Richardson, L. (2 September 2021). "With Delta Surging, FDA Needs Authority to Ensure Accuracy of COVID-19 Tests". Pew Charitable Trust. https://www.pewtrusts.org/en/research-and-analysis/articles/2021/09/02/with-delta-surging-fda-needs-authority-to-ensure-accuracy-of-covid19-tests. Retrieved 07 September 2021. 
  32. ↑ "In Vitro Diagnostics EUAs - Antigen Diagnostic Tests for SARS-CoV-2". U.S. Food and Drug Administration. 7 September 2021. https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/in-vitro-diagnostics-euas-antigen-diagnostic-tests-sars-cov-2. Retrieved 07 September 2021. 
  33. ↑ 33.0 33.1 33.2 Wan, W. (24 October 2020). "Home tests could help in the fight against the coronavirus. So where are they?". The Washington Post. https://www.washingtonpost.com/health/2020/10/24/coronavirus-home-tests/. Retrieved 18 November 2020. 
  34. ↑ McDermott, A. (2020). "Inner Workings: Researchers race to develop in-home testing for COVID-19, a potential game changer". PNAS 117 (42): 25956-25959. doi:10.1073/pnas.2019062117. PMC PMC7584891. PMID 32999063. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584891. 
  35. ↑ Crear-Perry, J. (5 November 2020). "The hidden public health hazard of rapid Covid-19 tests". STAT. https://www.statnews.com/2020/11/05/rapid-covid-19-tests-hidden-public-health-hazard/. Retrieved 18 November 2020. 
  36. ↑ Romo, V. (17 November 2020). "FDA Approves 1st At-Home Coronavirus Test". NPR. https://www.npr.org/sections/coronavirus-live-updates/2020/11/17/936055284/fda-approves-first-at-home-coronavirus-test. Retrieved 18 November 2020. 
  37. ↑ National Institutes of Health (23 June 2020). "Experts identify steps to expand and improve antibody tests in COVID-19 response". News Releases. https://www.nih.gov/news-events/news-releases/experts-identify-steps-expand-improve-antibody-tests-covid-19-response. Retrieved 08 July 2020. 

Citation information for this chapter

Chapter: 2. Diagnostic testing of COVID-19 and other coronaviruses

Edition: Fall 2021

Title: COVID-19 Testing, Reporting, and Information Management in the Laboratory

Author for citation: Shawn E. Douglas

License for content: Creative Commons Attribution-ShareAlike 4.0 International

Publication date: September 2021

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