The ever-expanding and increasingly diverse COVID-19 testing landscape can be confusing to navigate and comprehend. In this article, FirstWord MedTech aims to get some insights into the commonly asked whats and whys of COVID-19 testing.
While the world waits for the pharma industry to come up with a vaccine for COVID-19, the key strategy in curbing the spread of this particularly contagious virus continues to be - in the words of World Health Organization Director-General, Tedros Adhanom Ghebreyesus - “test, test, test”.
Testing is critical not only for treatment decision-making and tracking the spread of the pandemic; it also helps to reduce any unnecessary use of healthcare resources that are already under enormous strain.
Regulators and industry have collectively responded to the call to meet soaring demand for COVID-19 tests. IVD companies have been quick off the mark in developing tests specific to the new coronavirus and the emergency relaxation of rules by regulators have helped to fast-track these new diagnostics into the field.
From this, an increasingly diverse COVID-19 test landscape has emerged. Both established and smaller IVD players equally contribute to this landscape and the breadth of diagnostics - initially dominated by nucleic acid tests but antibody tests are now coming onto the scene - is ever-expanding. The speed at which this space is evolving could make it confusing to navigate and understand how one class of test differ from another, the impact these IVDs could have on controlling the pandemic, how innovative approaches beyond traditional PCR or antibody testing could help, and also why, in spite of companies’ efforts to ramp up production, demand for tests continue to outstrip supply.
In this article, FirstWord MedTech aims to get some insights into the commonly asked whats and whys of COVID-19 testing.
Nucleic acid tests: gold standard but what are its limits
As of April 3, the FDA has granted Emergency Use Authorization to a total of 28 tests, although this number would be bigger if we include tests that have been launched in the US but are still awaiting final authorisation from the FDA as well as in-house lab-developed tests offered by non-commercial, research labs. Outside the US, myriad COVID-19 tests have now been CE-marked and sanctioned for use in Europe, and/or are approved in specific jurisdictions in Asia and the Middle East.
The vast majority of these tests currently deployed in the pandemic response efforts are molecular diagnostics that use polymerase chain reaction (PCR) methods to detect nucleic acid from the SARS-CoV-2 virus.
The key advantage of PCR is that it is widely recognised as a highly sensitive and specific technique for nucleic acid testing and it works well when the viral load is high in active infection cases. At the start of an outbreak, when new infections are rising, identifying active infections would not only ensure these patients are given the care they need as soon as possible but also enable these cases to be quarantined to stop them spreading the virus.
Another advantage of PCR is it lends itself to high-end automation, which allows large numbers of samples to be processed with minimal technical handling. Leading IVD companies like Roche, Thermo Fisher, Abbott, have the largest installed base of these high-throughput PCR systems and these players were among the early entrants to the COVID-19 testing landscape.
However, these instruments that carry out "gold standard PCR tests really limit how flexibly they can be deployed," pointed out Harry Lamble, CEO of Sense Biodetection, a UK start-up developing an instrument-free, molecular diagnostic. "They always end up in central labs and this highly centralised system automatically leads to sample queues, contamination risk and slow turnaround time," he told FirstWord MedTech.
Why speed is good, but capacity better
There are nucleic acid tests available that can produce results in minutes, rather than hours, although these are still in the minority. Cepheid’s Xpert Xpress SARS-CoV-2 was the first FDA authorised nucleic acid test with a result turnaround time of under an hour (~45 minutes), but this was shortly trumped by Abbott’s ID NOW test which narrows the turnaround time to under 15 minutes - "as little as five minutes" for detecting positive cases, and around 13 minutes for negative results.
There will likely be more nucleic acid tests with equivalent turnaround times to Cepheid’s and Abbott’s coming into the market very soon, with some like Menarini’s VitaPCR SARS-CoV-2 assay (results in 20 minutes) which are CE marked but not yet available in the US, and others that are still in development, such as Mesa Biotech’s molecular point of care test (results in around 30 minutes).
Speed however isn’t everything. The benefits of a faster turnaround time are only realised if the instruments on which these tests are run are widely available. The tests from Cepheid and Abbott run on point-of-care systems designed for use in smaller labs and in less centralised settings, which makes them more accessible. However, their installed base looks to be limited to mainly the US. Cepheid’s GeneXpert systems on which the Xpert Xpress tests are analysed are believed to be in "90% of hospitals in New York"; Abbott claims ID NOW "is the most widely available molecular point-of-care testing platform in the US today" and the tests have so far only been launched in that country.
Achilleas Neophytou, Group Marketing Manager of Novacyt, argued that when it comes to testing during a global pandemic such as COVID-19, the bigger challenge is about testing capacity and quantity, rather than speed of delivery.
Novacyt was one of the early arrivals on the COVID-19 testing scene with its SARS-CoV-2 PCR test from its molecular diagnostics subsidiary Primerdesign. The CE-marked and FDA-authorised test produces results in around two hours, and it is currently available in over 80 countries across Europe, the US, Latin America, Asia and the Middle East. "Even if you are able to get a result much, much quicker, it's obviously better to be able to process a higher volume of patient samples within a specified time window," he told FirstWord MedTech. "That couldn't be more true than with regards to this outbreak situation where the quantity of people that need testing is extremely high. So, we're looking to support, as best as we can, greater capacity of testing. We're looking at running our tests on bigger capacity instrumentation and we're supporting the processes for people that are doing that work as well." The Primerdesign COVID-19 test not only runs on the company’s genesig systems, but also on open instruments. "There are small exceptions here and there, but for the majority of commonly used open instrumentation, our product will run [on those platforms too."
What’s limiting testing capacity
While IVD manufacturers are pulling out all stops to try and meet the pandemic’s testing needs, the gap between supply and demand does not look to be narrowing any time soon.
What’s limiting capacity? As identified above, the sheer volume of test orders and turnaround times are causing bottlenecks to occur in labs and hospitals. Point-of-care platforms could expand access to testing beyond centralised settings to more localised ones, like the doctors’ office and smaller ambulatory centres, but the readers tend to be lower throughput than the central lab-based systems and many of these molecular point-of-care systems involve more complex manufacturing processes, according to Nicolas Vergauwe, CEO of miDiagnostics, an early-stage start-up that is developing a silicon chip-based point-of-care test platform designed to be easy-to-use, highly portable and, more importantly, allows for cost-effective, high-volume mass manufacturing.
"Most point-of-care solutions focus on a level of miniaturisation, but still use relatively complex cartridges, plastics, that are assembled together and rely on some mechanical and electronic interfaces between the instrument and the consumable. As a consequence, these devices are pretty costly [to manufacture and to buy]," commented Vergauwe.
For Novacyt, the company has been enlisting the help of manufacturing partners in and outside the UK to scale up production of its Primerdesign tests, for which CEO Graham Mullis said there is "unprecedented demand." "[The] rate of growth in orders for [our COVID-19 tests] increases each week and continues to exceed our expectations. As a result, and despite our best efforts to ensure we are fully prepared to meet demand, the rate of sales growth is beginning to be restricted by our ability to scale-up manufacturing as quickly as we would like," Mullis stated recently.
"When you're working with a molecular product, it's not a simple case of just surveying the outside packaging to make sure that it meets standards," Nephytou commented. "You need to perform tests [for validation and quality assurance]. These are microscopic components, you can't see them to know what their quality is like. So, you need to go through a robust process of quality control, internally, to make sure that they meet standards and that they're fit for purpose. That is as much part of the challenge as manufacturing the products.”
The other antibody test: why exercise caution
In addition to PCR-based nucleic acid tests, there is another class of rapid diagnostics being deployed in certain countries. These tests are designed to detect the virus indirectly by using antibodies in their chemistry to bind to the protein surface of the virus, unlike nucleic acid tests that use PCR to detect the virus directly by identifying its genetic signature.
This class of antigen tests has recently come under fire in terms of their level of performance, in spite of their relative ease of use and fast result turnaround time of a few minutes.
Shanghai Fosun Pharmaceutical has reportedly warned about the accuracy of these rapid tests, saying that they have yet to match conventional PCR nucleic acid tests, which might take a couple of hours but results are significantly more robust. Fosun’s comments come after fellow Chinese firm Shenzhen Bioeasy Biotechnology had been accused of selling sub-quality tests to several European countries. Bioeasy’s test is said to produce results in 10 minutes, and uses fluorescence immunuochromatography to detect the virus. While this approach has been used for detecting other influenza viruses, it is also recognised for having low sensitivity and specificity levels.
The reason, explained Lamble,
is that these rapid antigen tests like Bioeasy’s do not amplify the signal like PCR. So they always have a lower sensitivity, which means you miss a lot of cases. The trouble with that in the current climate is every case missed is a potential new outbreak; the impact of a false negative that you would get from these immunoassay tests is extremely significant as this pandemic continues. The other issue with this class of tests is specificity
These viruses evolve and the surface proteins of the virus, that’s the region that evolves most rapidly because they are trying to evade the immune system. Yet you’re using the same binding antibodies in your test, so when you are validating your test, you never know whether it really still has the same performance. That's the underlying challenge of this class of products.
Immunity testing: what’s the buzz
A class of diagnostics that are hitting the headlines with increased frequency are tests for antibodies to the SARS-CoV-2. To recap, these tests (typically requiring a fingerprick blood sample and having much faster turnaround times of a few minutes compared to the few hours of standard molecular diagnostics) are used to identify which individuals already have had the virus and developed immunity to COVID-19; in contrast, the aforementioned antigen tests that use antibodies are designed to detect active infections, not immunity.
The policy on the use of antibody tests for managing the pandemic differs from country to country. Countries like the UK are starting to embrace antibody tests, primarily to allow individuals who test positive for immunity to COVID-19 to go back to work or return to the community safely without spreading or acquiring the infection. This is particularly useful for healthcare and other key workers, whose services are in great need, and also to potentially loosen the lockdown that is having a significant impact on economies. Furthermore, Vergauwe added that immunity testing is helpful at a later stage when it comes to rolling out vaccine programmes and prioritising which individuals have not developed immunity yet and require vaccination.
In contrast to the UK, Belgium is one country that is skeptical about the utility of antibody testing at this juncture of the pandemic. In mid-March, the country’s federal agency for medicines and health products (FAMHP) announced that they were banning the use of rapid tests that measure COVID-19-related antibodies, such as the immunoglobulins IgG, IgM, and IgA, for six months, citing the lack of proof of the tests' specificity which puts people at risk of misinterpreting the results.
Specificity is one of the major issues of these antibody tests, especially as it relates to a novel virus, according to Lamble.
While he said he sees a lot of value in these antibody tests as a screening tool to allow people to get back to work, he believes it will be technically challenging to get rapidly to certainty on the [test’s] performance and be sure you weren't getting a lot of false negatives, where people are actually immune but the test says they aren't."
"It's very difficult particularly with a new disease and new pathogen that very little is known about in terms of how it leads to an immune reaction," said Lamble. "People could easily be immune to something but yet not give a positive result in such a test because of the complexity of the human immune system and how immunity is derived. I could see how you would struggle to really validate those tests."
In the US, the FDA has also taken a cautious approach towards antibody tests. To achieve more rapid testing capacity, the regulator has updated its guidance around COVID-19 testing to include a special emergency policy that allows companies to develop and distribute a serology/antibody test without getting an EUA, as long as they have validated the tests, notify the FDA that they are offering the product for clinical use and that the labelling clearly states the test has not been authorised by the regulator. Additionally, the FDA stipulated that companies need to indicate that the results of the antibody test should not be used on its own for diagnosis and follow-up testing with a molecular diagnostic should be considered.
Under this policy, a number of companies have recently announced the launch of their antibody tests in the US, including Aytu Biosciences, Bodysphere (who jumped the gun and said they had an EUA then had to retract their statement), as well as Ortho Clinical Diagnostics - the former IVD business of Johnson & Johnson - which has just introduced its VITROS SARS-CoV-2 antibody test to the market.
As of the writing of this article, the FDA has granted EUA to only one antibody test, Cellex’s qSARS-CoV-2 IgG/IgM rapid test.
What other testing innovations ahead
Among the things that this pandemic highlighted are the pain points of different testing approaches, such as long turnaround times, overly complex and costly manufacturing processes, and the compromise between the speed of test and performance, among other things.
However, several innovations are in development to address the limitations of these current models. For example, the silicon chip-based testing platform that is being developed by Vergauwe’s miDiagnostics, as well as the instrument-free molecular test by Lamble’s Sense Biodetection, aim to really shift the needle when it comes to providing lab-equivalent testing in decentralised settings, such as in pharmacies or at border control centers, and play a role in pandemic control.
Another start-up FBB Biomed, headed by RNA virologist and a veteran in the IVD industry Howard Urnovitz, is aiming to bring out a molecular diagnostic test for COVID-19 that requires a fingerprick of blood to not only identify patients with COVID-19, but to monitor the progression of the disease - the severity and other co-infections that might exist.
COVID-19 infection follows multi-phasic patterns not detected by current tests which focus either on the virus or on antibodies. Respiratory viral diseases, like COVID-19, comprise multi-microbial co-infections, so FBB Biomed’s test is designed to measure viral load count, co-infectants count, plus inflammation-associated RNA, according to Urnovitz. "This test is based on my 1992 proposal that many viral pandemics are based on ‘interactive infections’", he told FirstWord MedTech. However, the hypothesis can only be put to the test now, with the power of today’s computers and sequencers as well as bioinformatic pipelines, he said. "Adding the measurement of inflammation-associated RNA should deliver the most clinically useful [COVID-19] test, with the objective of better patient outcomes."
What’s proprietary to the company are the primers for the test to allow the detection of the sentinel biomarkers for the disease, and the bioinformatics algorithm that ranks the biomarkers on their importance.
The firm is in the process of collecting COVID-19 samples from asymptomatic and symptomatic patients to run pre-clinical trials followed by a formal clinical trial. "Our target is to have the product on the market by this fall," said Urnovitz. The firm is looking to partner with larger IVD companies with established distribution channels to launch the test.
As with many IVD experts, Urnovitz agrees that the COVID-19 outbreak could last for 12 to 18 months. Should this be true, there will definitely be scope for more tests, using different approaches, to come on board to tackle this health crisis.