Female doctor taking a throat swab test from a senior man at home for COVID-19 testing

A consensus of experts has agreed that the U.S. needs much more COVID-19. As of today, according to Worldometer, there have been more than 16.3 million COVID-19 tests completed in the U.S.  However, far less agreement exists on how many more tests are needed daily, order for federal, state, and local governments to have the information needed to manage social distancing policies.

In a report published April 20, a group of 23 experts in economics, public health, technology, and ethics recommended that the nation ramp up to at least 5 million tests per day by early June to help ensure a safe social opening—and to 20 million tests per day by mid-summer in order to fully re-mobilize the economy. Those findings appear in “Roadmap to Pandemic Resilience: Massive Scale Testing, Tracing, and Supported Isolation (TTSI) as the Path to Pandemic Resilience for a Free Society,” published by the Edmond J. Safra Center for Ethics at Harvard University, with support from The Rockefeller Foundation.

But according to Paul M. Romer, a co-recipient of the 2018 Nobel Prize in Economic Sciences and professor in economics at New York University, those numbers are not enough,. “To control this pandemic, and any future pandemic, the U.S. should make the investment necessary to test people every two weeks, which would mean 25 million tests per day on an ongoing basis,” Romer wrote in his “Roadmap to Responsibly Reopen America,” published April 23. “It should also have a surge capacity of twice this amount, which would allow us to test every American every week if needed.”

Appearing on CNN, Romer went even further: “Let me be clear. I personally am advocating for 30 million tests a day, not 30 million a week. This nation produces 350 million cans of soda every day. If we can produce 350 million cans worth of soda a day, we can produce 30 million tests a day.”

How robust is the pace of testing in the U.S.? It depends how you measure it. Worldometer, shows that when measured in total number of tests, the U.S. led the 170 nations for which testing data is available (China, significantly, is not among the 170). But when measured in number of tests per 1 million population, the U.S. stood at 49,370 per million as of today—only good enough to rank 34th.

A growing number of diagnostics developers have set out to address the challenge of meeting the nation’s need for more COVID-19 tests. Here we profile five companies that have answered that challenge by working to bring new assays, with new technologies, to patients.

BillionToOne

BillionToOne, a Menlo Park, CA, precision diagnostics developer, says its COVID-19 test is as unique as its name. Instead of using quantitative PCR (qPCR) methods to sequence the SARS-CoV-2 genome, BillionToOne’s assay uses patent-pending qSanger spike-in and proprietary machine learning algorithms, designed to take advantage of 30X higher throughput Sanger sequencing capacity: 1,536 samples at a time on qSanger, vs 48 samples on qPCR.

“The first advantage of our test is that we skip the RNA extraction step, which has been the biggest bottleneck for scaling up testing capacity,” BillionToOne Co-Founder and CEO Oguzhan Atay, Ph.D., told Clinical OMICs. “The second advantage is that it is extremely high throughput, and highly automated. One Sanger device can process 3840 samples per instrument per day, and one or two technicians can process thousands of samples per day.”

The third advantage, Atay said, is its “extreme” accuracy: “Our limit of detection is on par with any qPCR protocol even though we skip the RNA extraction step. Our method is sequencing-based, so it is more specific.”

In April, BillionToOne researchers published a preprint study on bioRxiv showing qSanger to have extremely high sensitivity and specificity for all positive results with a limit of detection of 10 to 20 genome copy equivalents (GCE), equivalent to gold-standard qPCR methods.

“We ran about 100 positive and 100 negative samples with 100% sensitivity and 100% specificity,” Atay said.

Atay co-founded BillionToOne with David Tsao, Ph.D., the company’s chief technology officer. The company says its patent-pending QCT molecular counter platform can accurately count DNA molecules to the single-count level. BillionToOne’s first product, UNITY, is the first and only noninvasive prenatal screening that tests fetal cell-free DNA for cystic fibrosis and spinal muscular atrophy through a single sample of the mother’s blood.

BillionToOne emerged from Y Combinator, among participating investors in both the company’s highly over-subscribed $15 million Series A financing last year, and a follow-on $15 million Series A+ round completed in March. Both rounds were led by Hummingbird Ventures and Neotribe Ventures.

Celltrion

Celltrion says it is adopting a “best of both worlds” approach to detecting COVID-19. The South Korean company in March announced plans to launch a rapid diagnostic kit for the virus this summer.

While designed for speed, aiming to deliver results within 15 to 20 minutes, Celltrion’s test also aims to stand out by using a “best-of-both-worlds” approach, incorporating what is right with both PCR- based testing and rapid diagnostics.

“COVID-19 infection is commonly tested through quantitative reverse transcription PCR. RT-qPCR is widely used—but it takes a few hours to obtain results although it offers a high level of accuracy. In contrast, a rapid diagnostic kit works fast but it often reports inaccurate and inconsistent results,” Ki-Sung Kwon, Head of Celltrion’s R&D Unit, told Clinical OMICs.

Seo Jung-jin, chairman of Celltrion Group, elaborated further in a live YouTube news conference March 23, noting that the accuracy of rapid diagnostics is only about 50% to 70% of standard tests. “In other words, Celltrion is planning to combine the advantages of both methods, ensuring high sensitivity and specificity features as well as providing quick results in just 15 to 20 minutes,” he said.

Another distinction for Celltrion’s test will be how it goes about detecting COVID-19, Kwon said. “Most conventional rapid diagnostic kits detect the nucleocapsid protein (N-protein) commonly shown in various types of coronaviruses. However, Celltrion’s RDT kit specifically detects S-protein in the COVID-19 virus,” Kwon said. “Therefore, our kit will focus on the gene that encodes the surface spike (S) protein; an essential glycoprotein for viral entry into human host cells.”

“As RT-PCR technology remains the gold standard for detecting SARS-CoV-2, we anticipate that our kit will show similar performance as to the standard RT-PCR test,” Kwon added.

Celltrion plans to complete producing prototypes followed by finishing a clinical trial in May, Jung-jin said. The company has since added that it is on track with plans to launch the diagnostic kit this summer, around the time it hopes to start testing an antiviral antibody treatment it is also developing.

CQuentia

CQuentia says it is helping meet the urgent need for COVID-19 tests in multiple ways. CQuentia operates its COVID-19 testing under Roche’s cobas SARS-CoV-2, which received Emergency Use Authorization (EUA) from the FDA on March 12. However, CQuentia is also working to expand its capabilities for COVID testing on its Thermo Fisher Scientific QuantStudio 3 and QuantStudio 5 plat- forms, CQuentia CEO and co-founder D. Alan Meeker told Clinical OMICs.

“By testing at our CLIA lab, CQuentia is effectively adding more capacity to the entire COVID-19 testing system,” Meeker said. “Private labs are doing the majority of testing. There have been challenges with testing, including backlogs and delayed wait times for results, and there is a significant need for more testing. CQuentia is committed to providing a solution to this need.”

The Roche system enables CQuentia to operate at testing approximately 20,000 COVID-19 samples per month. By leveraging the Thermo Fisher platform, CQuentia expects to increase its testing capacity up to another 40,000 samples per month, bringing the company to 70,000 samples per month, Meeker said.

The validation process for the Thermo Fisher platform was expected to be completed by the end of the first week in May. “We are validating several antibody test manufacturers’ kits to determine whether a patient has antibodies in their system, and is possibly immunoprotected, or does not have antibodies in their system and is not immunoprotected,” Meeker said. “In conjunction with this antibody test being developed, we are also working with a major national non-profit and several industry leaders in a coalition to develop a population-based protocol that would assist the entire country to be able to filter inout who can go back to work, job, school, wherever one needs to go. We plan to have this protocol ready very soon.”

CQuentia has also developed the COVID-19 RT-PCR assay, which employs selective amplification of nucleic acid via target-specific primers for ORF 1a, a non-structural region unique to SARS-CoV-2, and a conserved region in the structural protein envelope E-gene. CQuentia says the test’s dual target approach allows for both specific detection of SARS-CoV-2, and for pan-sarbecovirus detection of the sarbecovirus subgenus family, which includes SARS-CoV-2.

“Very soon, our Thermo Fisher-based testing will employ selective nucleic acid amplification and probing of spe- cific SARS-CoV-2 target sequences found in the ORF1 ab, Nucleocapsid (N) Protein, and Spike (S) Protein genes,” Meeker added. “These regions are known to have higher specificity and exhibit a lower risk of mutation.”

Nanomix

When Ebola threatened to become a full-blown global pandemic in 2014, Nanomix responded by develop- ing in eight weeks a test that simultaneously identified and differentiated Ebola from Dengue and Lassa Fever, providing results from whole blood in 10 minutes.

Now, with a full-blown pandemic wreaking havoc on the world, Nanomix is working on a COVID- 19 point-of-care test that will provide results in less than 15 minutes. In April, the company was awarded up to approximately $570,000 in funding from the Biomedical Advanced Research and Development Authority (BARDA).

Nanomix’s test system consists of its handheld Nanomix eLab Analyzer and single-use disposable cartridges that include a microfluidics card and a proprietary nano-electronic sensor.

“The patient sample goes into the cartridge and the sensor performs electrochemical detection that is then read and reported by the analyzer. Specificity is generated by functionalizing each of the electrodes on the sensor for particular biomarkers,” Nanomix President and CEO David Ludvigson said.

The new assays will be designed to distinguish SARS-CoV-2 from other coronaviruses, as well as a common flu strain, to aid in the diagnosis of patients with non-specific respiratory symptoms.

In addition to its speed, Nanomix said, its test offers additional advantages that include the ability to detect SARS-CoV-2 antigens and antibodies to the virus, in order to identify both active infections and previous exposure to the virus.

Nanomix added that its platform’s electrochemical system eliminates the need for ongoing calibration and maintenance, commonly associated with PCR and other optics-based tests.

“This means that tests can reliably be run on the Nano- mix eLab system in a wide range of settings, including hospitals, nursing homes, assisted living facilities, urgent care centers, and emergency medical care,” Ludvigson said.

A wide variety of biomolecules with varying chemistries can be tested on a single Nanomix device in one operation. “The Nanomix COVID-19 tests will be able to distinguish SARS-CoV-2 from other coronaviruses, as well as a common flu strain, to aid in the diagnosis of patients with non-specific respiratory symptoms,” Ludvigson added.

Nanomix said it expects to complete development in early June and file for FDA Emergency Use Authorization soon afterward.

OraSure Technologies

Some COVID-19 test developers target their assays toward healthcare providers. Others aim for consumers who want a test they can use at home. And then there’s OraSure Technologies, which is working to develop and market a COVID-19 test for both types of users.

OraSure said its test will be built on its OraQuick lateral flow platform, the foundation for the company’s current CLIA-waived in-home and professional rapid diagnostics for HIV-1/2 and professional HCV, as well as the 510(k) cleared device designed to detect Ebola. The HIV test can provide results in 20 minutes.

“Oral fluid testing is a proven strategy that, in the case of HIV, has dramatically increased testing capabilities,” OraSure President and CEO Stephen S. Tang, M.D., told Clinical OMICs. “OraSure has the first and only FDA-approved over-the-counter HIV rapid self-test and the first and only WHO-prequalified oral fluid self-test. These oral fluid self-tests for HIV have been used to test millions of people around the world and connect them to life-saving care.”

Users place OraSure’s device into the mouth and swab a porous pad across the gum line. The device is placed into a tube containing a pre-measured amount of solution. Fluid from the surface of the gums enters the device through the flat pad, then flows onto a test strip. A colored line forms in the result window if the COVD-19 antigen is detected.

Tang said OraSure’s rapid coronavirus test will allow for in-home self-testing by lay users as well as by medical professionals. No instrumentation or trained personnel will be needed to administer the test or to read the results.

OraSure won a $710,310 contract from the Biomedical Advanced Research and Development Authority (BARDA) in April to develop its pan-SARS-coronavirus antigen rapid in-home self-test that uses oral fluid samples. OraSure said BARDA’s support will enable the company to pursue FDA Emergency Use Authorization allowing for an in-home self-test to debut in the U.S., following a development cycle it has estimated will take approximately four to six months.

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