How biotechs are racing to develop COVID-19 tests

BY Stella Howard
March 26, 2020

This article is the first in a three-part series covering the response of biotech companies to the COVID-19 crisis. The second article in this series is: How biotechs are racing to develop COVID-19 treatments.

The novel SARS-CoV-2 virus and the disease it causes (COVID-19) are sweeping the world. The US’s ability to rapidly and accurately test patients, not to mention their health care providers, is critical to containing the virus. That said, it has proved to be one of the biggest challenges for our country in recent weeks.

Offering Benchling Pro Bono for COVID-19 Testing

If you are running COVID-19 tests and looking for a better way to run your lab logistics, track samples, and capture results, we’d be interested in helping you manage all of this on Benchling.
Reach out to us at [email protected]

Much has already been written about what initially went wrong with the coronavirus testing in the US and why the US government and CDC lagged behind other developed nations in deploying diagnostics. This article will instead focus on the remarkable companies, institutions, and clinical labs that are rising to the challenge by working around the clock to produce high volumes of accurate and reliable tests.

In addition to the COVID-19 tests that are already in use, companies are prototyping groundbreaking new diagnostics. These new tests have the potential to revolutionize COVID-19 detection now and chart the course for the future of infectious disease diagnostics.

US Diagnostic Labs & the Challenges for COVID-19

Because SARS-CoV-2 is a completely new virus, no diagnostic lab had a method to detect it prior to February. The majority of diagnostic tests run in the US must be approved by the FDA and run in high-complexity CLIA-certified labs. CLIA (Clinical Laboratory Improvement Amendment) was an act set forth in 1988 that regulates laboratory testing on patients and requires all clinical laboratories to be certified by the Center for Medicare and Medicaid Services (CMS) before they can report medical results on human samples.

CLIA-certified diagnostic labs include public health labs, hospitals or reference laboratories. These labs have the necessary equipment to run thousands of automated tests per day. They might use assay methods and instruments from commercial companies (like Abbott and Siemens), or their own methods.

Usually, CLIA-certified labs are trusted to develop what is known by the FDA as “laboratory-developed tests” for in-house use on patients without any FDA approval; they just have to state on the test result that it’s not FDA-approved. However, because of the national public health emergency declared on January 31, a policy kicked in that requires the FDA’s “emergency use approval” (EUA) for any lab-developed tests. This policy essentially stops labs in their tracks from moving forward with a test without an EUA application and FDA approval.

Just before this, the World Health Organization (WHO), in partnership with a German lab, released guidance to diagnostic laboratories who were developing molecular assays to detect the novel SARS-CoV-2 virus. These nucleic acid amplification (NAA) molecular assays can detect the virus in upper/lower respiratory samples/swabs, and even stool or blood. NAA assays include real-time polymerase-chain reaction (RT-PCR) assays, which were invented in 1984. RT-PCR assays are generally considered the gold standard for viral testing. PCR is highly sensitive and detects even a tiny amount of virus in a patient sample by amplifying regions of genetic code that are specific to the virus. Several global labs took RT-PCR testing and ran with it. Labs in South Korea, for example, quickly created and deployed thousands of these tests.

As of late March, several companies have received the EUA for their SARS-CoV-2 tests from the FDA. The majority are the RT-PCR methods, similar to the WHO’s, that need to be run in CLIA-certified labs with special machinery, reagents, and trained staff. Once in the lab, they generally take about 3-4 hours to run on the analyzer. However, it may take upwards of 3-7 days to provide results back to clinicians if you take into account how the sample must be collected at a healthcare provider, shipped to the lab, prepped, analyzed, reviewed, and then finally reported, generally as a qualitative result (positive or negative).

While it’s relieving to see how private companies and labs have been able to develop and distribute accurate tests so quickly, even 3 days for a result is a long time during a rapidly spreading pandemic.

The Current State of COVID-19 Testing in the US

In the US, it’s a long-standing practice for CDC scientists in emergencies to develop the first diagnostic tests, as they have access to the samples before others, specialized biosafety hoods, and experience with novel pathogens. Once they have a working test, they work with state labs, followed lastly by commercial labs that are allowed to produce their own or scale-up the CDC’s test.

When the first COVID-19 cases were reported in the US on January 21, just two labs at the US CDC were permitted to conduct testing. The CDC had set up a similar test to the WHO’s, and as concern around testing grew, the CDC tried to expand testing by sending their kits to other labs beginning February 5. Quickly, an issue arose that negated the CDC’s test, requiring the agency to recall these kits and work to produce and distribute a new set to state labs.

CDC scientist
Although not for COVID-19 testing, this Centers for Disease Control and Prevention (CDC) scientist is shown implementing molecular testing, in order to test for different types of polio. The 6-assay screening can determine which samples are polio, the specific serotype of polio, and whether they are vaccine, or wild strains.

On February 29, in order to meet the increased demand for clinical testing and to respond to the testing crisis, the FDA expanded its EUA policy to start allowing high-complexity CLIA labs to develop and validate their own COVID-19 tests without first getting the agency’s approval. On March 16, the FDA expanded the policy again to allow commercial manufacturers to develop, validate, and distribute tests prior to being granted the EUA. Labs who receive these commercial kits must wait to perform actual testing until the EUA is fully approved.

More than 90 test developers had sought FDA guidance under the EUA process by the week of March 16, and more than 40 laboratories around the country have notified the FDA they will begin testing.

The majority of tests coming to market are for CLIA-certified labs that already have fully automated instruments across the US and EU to run qualitative RT-PCR assays on nasal or oral swabs from the back of the throat.  Although this is not an exhaustive list, these were some of the first to come to market.

Roche AG and Thermo Fisher Scientific were some of the first diagnostic industry giants to complete the EUA process by March 13. Roche designed its test within 6 weeks, and the FDA took less than 24 hours to approve it. Roche will produce 400,000 tests per week to be run on its Cobas 6800/8800 systems. Thermo Fisher is aiming to produce up to 5 million total tests by beginning of April, which will be run on its Applied Biosystems 7500 Fast Dx RT-PCR instrument.

On March 16, the FDA announced additional EUA approvals for COVID-19 detection tests by Hologic, Laboratory Corporation of American (LabCorp). Two days later, Abbott announced its molecular test that can be run on the company’s m2000 RealTime system. Abbott shipped over 150,000 tests the week it was approved with plans to produce 1 million tests per week by the end of March.

Across the globe, several consumer testing kits are also being released, but there have been questions about their accuracy. The FDA put out a warning on March 20 alerting consumers of unauthorized and fraudulent tests.  If concerns about accuracy can be overcome, home tests would be a step in the right direction of reducing exposure to health care workers and the public. Test subjects can mail in their samples from home also saving now-scarce personal-protective equipment (PPE) such as gloves and masks.

Latest Developments in COVID-19 Diagnostics

Certain companies are leveraging CRISPR technology to develop next-generation diagnostics that will eventually allow clinicians to review results of a SARS-CoV-2 test in under a day’s time. Though CRISPR has been widely acknowledged for its potential application to human therapeutics, CRISPR could see its first direct application to human health in diagnostics.

Although not yet FDA/EUA approved, US-based Mammoth Biosciences and Sherlock Biosciences are aiming to manufacture a visual lateral flow strip kit, which would work similar to a  pregnancy test. This technology would be able to test large numbers of samples without specialized instruments or reagents, producing a result read out in under 1 hour (but takes a few hours to prep). The earliest versions of both tests will still need to be run in a centralized lab, as both methods require RNA preampfification on a thermocycler prior to being applied on a lateral flow strip. However, future versions could be done in the field or at the point-of-care.

Mammoth Biosciences, a Benchling client based in South San Francisco, CA, has been developing a CRISPR/Cas12a diagnostic system called DETECTR (DNA endonuclease Targeted CRISPR Trans Reporter), a simple but robust platform that can be used for a variety of applications, including detecting viral and bacterial infections. Mammoth spun out of the laboratory of Dr. Jennifer Doudna, one of the leaders in the CRISPR field. In collaboration with infectious disease expert and University of California San Francisco (UCSF) professor of laboratory medicine, Dr. Charles Chiu, Mammoth has prototyped a rapid COVID-19 detection kit that can also differentiate COVID-19 from other coronaviruses, and detect multiple strains using multiplex methods.

Sherlock Biosciences, based in Cambridge, MA, is releasing an experimental protocol for its own CRISPR/Cas13a diagnostic platform, dubbed SHERLOCK (Specific High Sensitivity Enzymatic Reporter UnLOCKing). The SHERLOCK technology, which can detect single molecule targets, was licensed exclusively from the Broad Institute of MIT and Harvard, and developed by Sherlock’s co-founders, including another CRISPR pioneer, Dr. Feng Zhang. Sherlock is partnering with Cepheid for a prototype SARS-CoV-2 test that can be run on Cepheid’s existing GeneXpert Systems using SHERLOCK technology. If approved, there are over 23,000 GeneXpert instruments around the world that could run up to 80 GeneXpert COVID-19 tests per run. The two companies are looking to provide potential solutions not just for COVID-19, but also for other infectious disease and oncology targets.

Offering Benchling Pro Bono for COVID-19 Testing

If you are running COVID-19 tests and looking for a better way to run your lab logistics, track samples, and capture results, we’d be interested in helping you manage all of this on Benchling.
Reach out to us at [email protected]

There are several other companies around the world developing lateral flow assays for rapid SARS-CoV-2 detection (not necessarily all CRISPR methods), with some in China and Europe already being shipped out. Other companies have developed or are completing serology tests for COVID-19 antibodies, which can help diagnose an acute or convalescent disease state, aid with contact tracing, and assess why some people with the disease may recover more readily than others.

The Road Ahead

As of March 25, many US cities still have a critically low supply of COVID-19 tests, as manufacturing and production rush to catch up to demand, and as many of the EUA approved tests have been reserved to prioritize testing symptomatic patients and health care providers. Testing relief is expected in coming days – a major payoff of the incredible collaboration between public and private labs and commercial biotechs.

While rapid detection methods are still awaiting FDA approval, these types of innovations will bring us closer to being able to evaluate the real-time movements of viruses and infectious diseases before they turn into a global pandemic.

Prior to working at Benchling, Stella Howard was a research assistant and clinical laboratory scientist who worked in CLIA-certified diagnostic labs in Colorado and California hospitals and biotechs. 

Published by Stella Howard
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