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COVID-19 crisis spurs innovation in rapid diagnostic technologies

A flood of new rapid diagnostic technologies is nearing the market to fight the COVID-19 pandemic

Companies across the world are mobilizing to answer the call for diagnostic innovation brought on by the COVID-19 crisis. The advances made during this time could change the course of this and future outbreaks, but investigators are justifiably concerned that the commitment will fade when the crisis subsides.

The pattern in diagnostics that has played out in the past is that innovation explodes when a public health crisis demands it, then comes to a halt when the emergency passes.

While each passing epidemic nudged the needle forward, they suffered because the lack of continuous innovation left the industry unprepared to respond in time with diagnostics that could influence the global outcome.

Many hope that this time will be different.

The delay in deploying new technologies has contributed to the spread of COVID-19 in many countries, but there’s still a chance for new diagnostic interventions to help shift the course of the pandemic.

First, there’s a platform of progress to build on, made during the recent Zika and Ebola outbreaks.

Second, a flood of novel diagnostics is pouring in for COVID-19 that co-opts technologies created for other indications and even other industries, and the first among these have reached the market.

Much of the innovation so far has homed in on rapid readout technologies that address the problems with testing capacity, speed and accessibility that have plagued healthcare systems during this crisis.

COVID-19 diagnosis has largely relied on standard RT-PCR tests run through reference labs. Under normal circumstances, that protocol has been good enough. The tests have a decades-long track record of high sensitivity and specificity, and the hardware is widely available in labs across the world (see COVID-19 diagnostic tech tableau).

“It’s my hope that we’ve learned our lesson from this experience, that diagnostics are a crucial component of the healthcare system.”

Sylvia Daunert, University of Miami

However, while RT-PCR produces accurate results, it requires shipping patient samples from the point-of-care to testing labs. The backlogs at centralized labs and shipping logistics can add days to turnaround times.

The tests themselves also take between two and six hours to run depending on the lab, leaving large room for improvement.

Dozens of rapid diagnostic tests to detect the virus in the point-of-care setting are now in development; three were granted emergency use authorization (EUA) by FDA this week. Many others are already in use in other countries.

The improvements range from systems to accelerate, miniaturize and automate the standard RT-PCR technology to entirely novel detection methods that haven’t yet been validated in any application. They all aim to advance from the standard RT-PCR testing infrastructure by improving speed and accessibility.

If available in time, these new rapid detection tests may change the course of the pandemic by enabling better tracking and monitoring of patients to control further spread. Thanks to progress made during previous outbreaks, most of the technologies will be deployed in the coming months. Even the more novel technologies could see the market this year.

New diagnostics will also play a key role in the future stages of the pandemic, where they can identify people previously exposed to the virus who can return to work, and track genetic evolution of the virus to adapt countermeasures.

Regardless of whether this crisis effects change in the diagnostics industry that drives continued innovation, or research fizzles out again when the crisis subsides, the advances made for COVID-19 should leave the industry better prepared for future outbreaks.

The first phase in rapid diagnostic innovation

The first wave of next-generation diagnostics to gain authorization are iterations of the classic RT-PCR tests, which have proven accuracy and represent the smallest departure from the norm for regulators.

“Right now, PCR is the gold standard. I think clinicians are just more familiar with it, so I think nucleic acid technologies like PCR are still the tests that will offer confirmatory results that professional healthcare providers are looking for,” said Hong Cai, co-founder and CEO of from molecular diagnostics company Mesa Biotech Inc.

The newer PCR tests require the same RNA extraction and nucleic acid amplification steps as the standard tests, but are scaled down to operate on smaller, automated machines that can be used in physician offices and hospitals without trained technicians.

They also drop the run-time to under an hour by making changes to the reagents, assays and thermocycling steps used in the nucleic acid amplification process

Mario Thomas, co-founder, director and CEO of Precision Biomonitoring Inc. told BioCentury that while rapid PCR tests are unlikely to replace centralized lab-based PCR systems because they can’t compete on capacity and throughput, they’ll serve as an important complement.

“There are so many situations when it’s not possible to send or ship samples, when there’s no hospital close by, and that’s where the rapid test will be most useful,” he said. Precision is developing a portable rapid PCR test for COVID-19.

“I think nucleic acid technologies like PCR are still the tests that will offer confirmatory results that professional healthcare providers are looking for.”

Hong Cai, Mesa

The first rapid PCR test authorized by FDA was the Xpert Xpress SARS-CoV-2 test from the Cepheid unit of Danaher Corp. The test, which takes about 45 minutes to read out, uses individual cartridges for each patient sample and is run on the company’s established GeneXpert system. More than 23,000 GeneXpert systems have been installed worldwide, almost 5,000 of which are in the U.S. (see “FDA Authorizes First COVID-19 Point-of-Care Diagnostic”).

The second test to gain EUA is a palm-sized rapid RT-PCR system from Mesa Biotech that takes about 30 minutes to run. While it can only run one test at a time, the instrumentation is small and inexpensive, according to Cai, so the company believes it can be widely deployed to physicians offices and other point-of-care settings.

Mesa launched tests for influenza and respiratory syncytial virus (RSV) last year using the same hardware and is preparing to ship several thousand COVID-19 test systems before scaling up further.

While the majority of rapid PCR tests follow the same point-of-care format, at least one company is working on a disposable home-based PCR test, which could help curb the spread of the virus by allowing patients to get a result without compromising their or others’ health by leaving the house.

Nuclein LLC is developing a plastic, hand-held, miniaturized PCR system for home use. It hopes to launch the test this fall.

Nuclein’s home-based test stands out from the other at-home testing kids that have come under fire by FDA in recent days for marketing without authorization. Those tests involve at-home sample collection, and the samples are then shipped to labs for testing. Nuclein's test could give patients a result in under an hour. However, no at-home tests have yet been authorized by FDA.

Most of the rapid PCR tests run between 30 and 60 minutes, but some companies are trying to improve on that several-fold with newer technologies.

For example, XCR Diagnostics Inc. claims its PCR technology can read out in seven minutes. The company is using tighter temperature controls to make the amplification step more efficient. It exploits the fact that different sequences of double-stranded DNA open up to be copied at different temperatures.

Next generation amplification

Next generation technologies that don’t rely on standard PCR protocols involving thermocycling are earlier in development, but could offer further cost, accessibility and speed advantages over the rapid RT-PCR tests.

“It’s the amplification step that allows you to detect down to several molecules of the virus,” said Cai.

The problem is that the amplification step is also the factor that slows down the process and requires bulky hardware.

The newer technologies include a crop of nucleic acid detection tests that still require amplification, but either use different detection methods or get around the cumbersome temperature control steps of standard PCR.

Isothermal amplification avoids some problems of thermocycling. Instead of relying on temperature cycling to replicate the DNA, it uses reagents that cut time and complexity of the hardware.

The third test to receive emergency authorization from FDA falls into this category. On Friday, FDA authorized a COVID-19 rapid diagnostic from Abbott Laboratories (NYSE:ABT) that reads out a positive result in five minutes and a negative result in 13. The test uses an isothermal amplification process and fluorescent molecular probes, and is run on the company’s ID NOW hardware.

Heat Biologics Inc. (NASDAQ:HBTX) partnered with the University of Miami to develop another type of nucleic acid test that relies on isothermal amplification.

The technique is similar to PCR in that it selectively amplifies the viral genetic material before detecting it with capture probes that bind to nanoparticles on a paper-based test strip.

Unlike traditional and even rapid PCR tests in development, Heat’s technology doesn’t require any equipment beyond the paper strip and a test tube loaded with reagents.

“It’s the amplification step that allows you to detect down to several molecules of the virus.”

Hong Cai, Mesa

“Our test doesn’t have any instrumentation because the isothermal step means it can be done efficiently at room temperature. It’s a little test tube that can be used anywhere in the world by minimally trained personnel,” said Sylvia Daunert, University of Miami professor and scientific founder of the diagnostic technology in development at Heat.

Daunert said that the portability of the test means it could be used beyond the doctor’s office and emergency rooms. She thinks it would be useful in pharmacies, drive-through testing sites and even TSA locations.

The test reads out in under 30 minutes.

CRISPR-based diagnostics can use either standard non-specific amplification or isothermal amplification to prepare the samples for detection, but involve a different detection technology once the genetic material is amplified.

The CRISPR-based tests involve targeting a CRISPR enzyme with collateral cleavage properties to a specific viral sequence using a guide RNA. When the enzyme encounters its target, it will indiscriminately cleave surrounding nucleic acids including reporters that create visual signals when degraded.

Sherlock Biosciences Inc. is exploring isothermal amplification technologies for its CRISPR-based diagnostics, though its first generation test may involve more traditional thermocycling for amplification. Mammoth Biosciences hasn’t disclosed details about the amplification steps in its platform. (see “CRISPR-Based Diagnostics are Poised to Make an Early Debut”).

Sherlock hopes to have a test on the market this season and Mammoth has not disclosed a timeline.

A third player in the field, Caspr Biotech, was founded last year to create diagnostics using a novel Cas12 family enzyme. The new enzyme, dubbed Caspr, naturally targets DNA rather than RNA, so an extra reverse transcription step is required to convert the RNA into a DNA form that can be detected. Cas13 naturally targets RNA sequence, which makes it a good match for the RNA virus.

Caspr is focused on isothermal amplification protocols for its earliest tests, which could be available in the coming months. The CRISPR tests will be used with hardware in a point-of-care setting but isothermal amplification may eventually enable at-home testing applications.

Amplification-free alternatives

Other technologies take the amplification step out of the equation, allowing for even faster viral detection. But the trade-off is often sensitivity.

The most common are immunoassays, which use antibodies bound to the surface of a test strip to detect proteins rather than nucleic acid.

While most immunoassays are designed to detect antibodies against the virus, some companies are working on immunoassays that detect viral antigens. Both types of tests are on the market in certain regions, but none has been authorized by FDA.

Tests that detect antibodies indicate whether a person has ever been infected with the virus, while tests that detect viral antigens signal an active infection.

With no amplification requirement, the tests are extremely portable and rapid when designed as pregnancy test-like lateral flow stripe. Many read out in ten minutes or less, but it may be difficult to achieve comparable sensitivity to nucleic acid tests.

Another amplification-free method is the electronic test in development at Pinpoint Sciences Inc. Pinpoint and partner Analog Diagnostics are developing bioelectric nanosensors that detect pathogens based on changes in voltage that occur in the test chip when the target protein is present.

Pinpoint is targeting the virus’ nucleocapsid protein with the technology, but CEO Lisa Diamond said it can be adapted to target other proteins, antibodies or even nucleic acids in the future.

The advances made during the Zika epidemic are the reason the technology will be ready to deploy for COVID-19.

The tests involve a handheld reader that costs about $100 and disposable cartridges. They read out in under 30 seconds, and Diamond said the company hopes to have the test available in about six months.

Ativa Medical is taking another approach to COVID-19 detection with a miniaturized flow cytometer programmed to detect changes in immune cells that occur at the start of infection, even before the virus is detectable by PCR.

The test pairs a point-of-care blood analyzer that analyzes a drop of blood on a disposable card with machine learning algorithms that determine the immune cell characteristics associated with early phases of infection to detect patients early in the course of disease.

Innovation into the future

Whether the diagnostic innovation continues after COVID-19 passes will depend on whether issues regarding incentive structure, reimbursement and patentability of tests are addressed.

When previous epidemics have resolved, diagnostic development for infectious diseases came to a halt, said Daunert.

She told BioCentury the technology she’s developing with Heat was first created to diagnose Zika but that crisis resolved before the test was ready.

The advances made during the Zika epidemic are the reason the technology will be ready to deploy for COVID-19.

“In Florida, the governor made money available to develop Zika diagnostics, but three-year grants were pulled and reallocated after less than a year when the tests were no longer needed,” she said.

Most of the companies interviewed by BioCentury shared similar stories about initial development for during other infectious disease outbreaks. In one case, the technology was being developed for an entirely different industry.

Environmental monitoring company Precision Biomonitoring was using its rapid point-of-care PCR technology to detect pathogens in water, but the COVID-19 pandemic led the company to pivot to healthcare applications.

Daunert told BioCentury that the need for diagnostic innovation during this crisis is “a good reminder for the leadership of this country that we cannot forget the importance of science and technology once we get through these hurdles.”

“I do think we’ll see an impact on diagnostic development, in the scalability of medical institutions and in the preparedness of the system in general after this passes by to better manage these kinds of situations in the future,” said Franco Goytia, co-founder and CEO of Caspr.

“It is my hope that we’ve learned our lesson from this experience, that diagnostics and detection are a crucial component of the healthcare system and beyond,” said Daunert.

“People occasionally lift their heads when something breaks out and then they go back to sleep,” said Diamond. However, she said this pandemic has triggered important changes that could impact the course of diagnostic development. For example, the attitude at FDA towards diagnostics has shifted, she said.

At a minimum, the strides made during this crisis period should leave the industry better prepared for the next epidemic.

Targets

Cas12 - CRISPR-associated protein 12

Cas13 - CRISPR-associated protein 13

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