NEW YORK – In late January, the first cases of COVID-19 were reported in Europe, less than a month after the coronavirus was first detected in China. As countries around the world scrambled to get a handle on what would soon become a pandemic, some looked to the European response as a possible roadmap for what could work and what wouldn't.
If any region was best prepared to endure such a health crisis it was arguably Europe, with its strong healthcare systems, intellectual capital, and biotech backbone. While many countries are EU members, health policy has continued to be set at the national level, meaning that each nation's experience has been different and, therefore, a crisis management experiment in process.
A number of nations turned to serology testing as a possible modality to determine how many people might be infected with SARS-CoV-2, the virus that causes COVID-19, and who they were. But as serious problems with many serology tests – which detect antibodies to the virus, rather than the virus itself – began to appear, countries had to scrap those plans and quickly devise new strategies to battle the pandemic.
In spite of some early setbacks with coronavirus serology tests, clinicians are warming to the use of such assays for surveillance measures and epidemiological studies, even though they continue to favor molecular testing for diagnosing COVID-19.
As the US now tries to figure out what role coronavirus antibody testing may have – and the US Food and Drug Administration continues to grant Emergency Use Authorization to serology tests – the experience in Europe may offer lessons for how the tests may be best considered in a pandemic that is expected to last months, perhaps years.
In Monaco, a principality hemmed in by two countries hard hit by the coronavirus, antibody testing may best be used as a complement to PCR testing, according to one hospital official.
"Combining both serology and PCR are probably a good option to help physicians," said Yann-Erick Claessens, head of emergency medicine at the Princess Grace Hospital Center in Monaco. "PCR can be negative even in patients that suffered from COVID-19," he said. "This can result from the quality of the swab, the cutoff for positive PCR, or the stage of the disorder, Claessens noted. "So, the possibility to combine PCR and serology is a great solution to make a diagnosis properly."
Bordered by France and a stone's throw from the Italian border, Monaco has been deep in the pandemic since it began to accelerate in the region in February and March, treating citizens of both neighboring countries. According to the World Health Organization, Italy currently has had more than 230,000 cases and more than 32,000 deaths, while France has reported nearly 150,000 cases and 29,000 deaths. Monaco itself is aligned with the French healthcare system, while more than half of its residents are Italian citizens.
Yet despite being in one of the hardest hit parts of the continent, Princess Grace Hospital Center actually had to, at first, outsource PCR testing to other regional hospitals in Lyon, Marseille, and later Nice.
"For weeks, it was difficult to have results in due time," said Claessens. "Patients were admitted and we didn't have the tools to diagnose the virus," he said. "It was terrible because we were late for diagnoses and treatment."
Under pressure to provide diagnoses faster, Claessens' team ordered antibody tests from a manufacturer outside Europe from China but quickly discovered they were useless. "We ordered some thousands of tests to help, but they had such poor sensitivity and specificity that we stopped using them to make decisions at bedside."
It was a situation that Spanish health authorities similarly found themselves in when they ordered 640,000 antibody tests from a Chinese firm called BioEasy that they determined could only detect about 30 percent of cases. As a result, Spain returned the entire order to the manufacturer in April. The story in the UK was exactly the same, where the government ordered 17.5 million antibody tests, hoping to use them as a means to ease lockdown restrictions, only to discover they performed abysmally. In the meantime, countries like Germany and Iceland that were arguably successful in mitigating the outbreak began cranking out PCR tests, instead, with activities spearheaded by Charité – Universitätsmedizin Berlin and DeCode Genetics in Reykjavik.
"I think in part, they had limited supplies and were just looking for a test," said Claudia Denkinger, head of the division of tropical medicine at University Hospital Heidelberg in Germany, where she led initial efforts to respond to the pandemic. In Germany, clinical laboratories enjoy a great deal of autonomy and can build and independently validate their own tests, a situation Denkinger said she had been critical of in the past, but actually helped the country respond more quickly to the crisis. "For the coronavirus, it's been a blessing," she said.
Also, Germany didn't fall prey to the supply chain disruptions to the same extent that plagued testing in other countries, because case numbers were not as high and broad portfolios of tests in laboratories were set up early. Because of this, antibody tests were never considered as diagnostic tests there. "There was never a drive to purchase them for the use cases that Spain and the UK considered them for," she said.
Those initial experiences with serology assays in Spain and the UK have since become a warning to others about implementing the tests into routine virus testing, although some have noted that the fact that authorities did not begin relying on those faulty tests was actually a positive thing.
"We need to be mindful that actually it is a sign of a sophisticated health system that can select, independently validate, and reject poor quality diagnostics," said Joe Fitchett, medical director at Mologic, a UK-based developer of rapid and lateral flow tests. "I think it masked a success story, which was to ensure these kits were not deployed at scale causing more harm than benefit."
These have been busy and transformative months for Mologic, as they have been for most test companies, which have had to pivot from initiatives that they originally targeted at the start of the year to meet the public health demands resulting from COVID-19. In April, Mologic announced a manufacturing deal with Omega Diagnostics in the UK to produce enzyme-linked immunosorbent assays for SARS-CoV-2 with an eye to offer them in the UK, as well as through a partner in Africa. Then in May, Mologic partnered with BioSure to produce the BioSure COVID-19 Antibody Self-Test, a lateral flow assay that produces results in 10 minutes and should be available later this month.
Similar to Claessens in Monaco, Fitchett said that UK clinicians have learned during lockdown that patients with symptoms are often presenting late to access healthcare, by which time they are already PCR-negative for the virus but are diagnosed clinically or radiologically as COVID-19 positive. That creates a gap that can be filled by high-quality serology assays.
"This is where an antibody test could be helpful in combination with nucleic acid testing to boost detection rates," said Fitchett. However, he stressed that antibody tests must be independently validated before they can be deployed, especially considering the negative experience some health authorities have had with some tests. "We urgently need diagnostics that are validated independently to a high standard that can be deployed with confidence to address the COVID-19 pandemic," commented Fitchett. He noted that Mologic has partnered with numerous independent validation laboratories worldwide to share data and improve test development.
The manufacturers' view
The kind of breakneck speed at which Mologic has been trying to develop and get SARS-CoV-2 tests on the market is not unique. To meet Europe's need for diagnostics, test makers have been working diligently to fashion a multitude of assays that can be used both to diagnose patients presenting at hospitals, as well as for later surveillance studies and as part of back-to-work measures, all within what have turned out to be complicated local regulatory conditions while experiencing disruptions in supply chains. They also have to grapple with pledges from policy makers to deliver thousands or millions of tests that either don't exist yet or have not yet been validated and approved for clinical use.
Yet they inarguably delivered. Roche, for instance, gained both a CE mark and US Emergency Use Authorization for its real-time PCR Cobas SARS-CoV-2 Test in March, and in May gained similar clearances for its Elecsys Anti-SARS-CoV-2 antibody test. Last month, Roche and Abbott agreed to supply the UK government with up to 10 million tests over the coming months.
"The companies that develop these assays have in my opinion been considerably responsive," said Ranga Sampath, CSO at the Foundation for Innovative New Diagnostics, a Geneva, Switzerland-based nonprofit. Sampath underscored that this has all been taking place against a backdrop of challenges, the poor early experiences with antibody tests just being one part.
"The problem that happened with the antibody tests is exemplary," said Sampath. "There was so much political pressure to get these tests out there, and the agencies didn't have the capability to focus on those, because molecular tests were essential for primary patient care and that's what they focused on," Sampath said.
The regulatory picture was also cloudy. Because there is no overarching European directive that provides a pathway for gaining regulatory clearance for emergency use, companies have had to go to each specific health ministry in each country and seek approval, while working through the process of quickly CE marking their products. In the US, things were more lax at first, with serology test makers merely needing to provide in writing to the US Food and Drug Administration a letter, validation data, and labeling information to sell their tests. That ended in May, though, when the FDA revised its rules, delisted 27 serology assays that had been available under the old system, and began requiring that manufacturers file EUA submissions just like PCR test makers have done.
While the problems with antibody testing in the US never approached the degree seen in Spain and the UK, the FDA toughened its rules for the tests after hearing from various stakeholders about their concerns and confusion about them.
"Antibody tests became sort of the Wild West approach, and people reached for what was available but there are many tests that are subpar," noted FIND's Sampath.
Yet building the serology tests the market needed wasn't easy for even the most weathered diagnostic companies. Across the board, companies have had to deal with a lack of access to samples to validate tests, not to mention a broken supply chain constrained by travel restrictions. Companies also had to compete with one another for access to materials to make the tests the market was clamoring for.
"We are all interconnected globally through our raw materials," noted Mark Miller, BioMérieux's executive vice president and CMO. "Enzymes come from one country, plastics come from another country, and silicon beads come from another country and that is a problem when you get into an epidemic like this," he said. "Everyone is vying for the same raw materials."
Marcy-l'Étoile, France-based bioMérieux has developed four assays for the current crisis, including its SARS-CoV-2 R-Gene test, for open real-time PCR platforms; its BioFire FilmArray Respiratory Panel 2.1 test, which will detect SARS-CoV-2 in addition to 21 other pathogens that cause respiratory infections; its BioFire COVID-19 test, which runs on the FilmArray system and can detect the virus is under 45 minutes from nasopharyngeal swabs; and its Vidas anti-SARS-CoV-2 IgM and anti-SARS-CoV-2 IgG serology assays, which recently received a CE mark. All tests were designed, produced, and submitted for regulatory clearance in Europe and the US within weeks.
Getting so many tests up and ready for clinical use at such a curtailed timeframe was unprecedented, Miller said.
"Just to put it in perspective, normally a molecular biology test will take us one to one-and-a-half years to produce but we did it in seven weeks," said Miller. "Normally a serology test takes about one-and-a-half to two years to produce and it took us eight weeks," Miller said. "At every single point the decision was between speed and quality. How fast can you go and still put out a quality test?"
According to Miller, BioMérieux's approach has been to design a menu of tests that can be used no matter the geography or where a certain country is in its epidemic curve. PCR was rolled out first because molecular biology tests were needed to accomplish diagnosis of the virus. For those countries that have already seen infections rocket and then reduce in volume following lockdown measures, serology assays have now come more seriously into play, despite early negative experiences.
"They are looking at serology [tests] as a tool to help them strategize and structure their back-to-work and back-to-life approaches, and also to get a handle on how many people have been infected," noted Miller. Oftentimes, countries still don't know what percentage of their population was infected during their epidemic curve and serology will allow them to answer that question too, he said. These experiences, in turn, could inform policy in other regions, including the US, as they manage their crises, Miller noted.
"While Europe followed after China, I think that with Europe, people were watching and people were able to take good lessons and bad lessons out of it," Miller said. "When most European countries didn't have enough diagnostic testing, then we started ramping up diagnostic testing," he said. "As confinement worked or didn't work, people were imitating it," he added. "I think Europe served as an example of what to do and what not to do."
Euroimmun, a Lübeck, Germany based provider of laboratory tests, has taken a similar approach by preparing multiple assays for application in different contexts, including a real-time PCR test called EuroRealTime SARS-CoV-2, as well as an ELISA product. The company, which is owned by PerkinElmer, gained a CE mark for its Anti-SARS-CoV-2 ELISA (IgG) serology test in March, followed by a EUA from the US Food and Drug Administration in May, making it one of about 15 serology tests to receive an EUA in the US since the pandemic began.
Johanna Fraune, head of marketing for Euroimmun, said the company has experienced high demand for both assays in Europe since their launch. "While real-time PCR is the method of choice for diagnostics of acute infections, serology is a useful supplement of direct virus detection," Fraune said. Especially in cases where exposure to the virus may have been weeks prior, serology can identify people who have been infected. Yet even if they are determined to be positive, Fraune cautioned that research into what test results mean is still underway.
"Research concerning the question about immunity given by the detected antibodies is still going on," Fraune said.
Big issues remain
While it took weeks for test makers to design, validate, and deliver real-time PCR and serology assays to the hands of European clinicians, the quickly multiplying number of tests out there that have received CE marks, and EUAs in some cases in the US, have also posed some problems for clinicians, who must now wade through reams of validation data to select the best possible assay.
"Trying to ascertain which is the best test for which part of the patient journey is one of the big issues," said Luke Moore, a consultant in infectious diseases and clinical microbiology at Chelsea & Westminister Hospital NHS Foundation Trust, one of the top hospital trusts in the UK. "There is such a multitude of diagnostics out there," said Moore. "Manufacturers say one thing, but you have to do your own independent analysis."
Yet hospitals overseen by the Chelsea & Westminister NHS Trust have also benefited from having multiple platforms at their disposal, which in turn has allowed them to overcome supply chain issues. "In terms of diagnostics in the UK, I think what has been [an apparent problem] is the supply chain for consumables," said Moore. "We have capital platforms for different diagnostics, but the consumables, the cartridges are really hard to get a hold of," he said. "That has been at times a critical shortage for us and for others, and I am not sure how we as a global community address that."
Moore said that the organization he works at has four different molecular PCR platforms installed, not because it needs the equipment, but to ensure continuity in testing. "If we didn't have different ones and relied upon one, and that supply chain for that manufacturer had a delay for a few weeks, we would be without tests, right?" noted Moore. Things become even more problematic in the world of serology assays, where there are even more tests coming online.
"Nightmare is the appropriate word, I think," said Moore. "There is such a huge number of manufacturers of those [serology assays] and they come in variable quality," he said. Each manufacturer also provides its own validation data. Moore stressed the need for head-to-head comparison studies and called on regulatory bodies or other institutions to make recommendations on testing.
"At the European level, it is more organized at a local hospital group level, and there is no central dictate saying Roche or Abbott or Thermo Fisher are the preferred vendor for serology or PCR," Moore said. "There has to be some independent analysis of these tests' function and some kind of oversight," he said. "It's a bit of a hodgepodge market at the moment."
And more work needs to be done in immunology, he stressed, before serology tests can be used outside of seroprevalence studies. "Once the immunologists can tell us if humans produce neutralizing antibodies [to SARS-CoV-2], then it makes the world of diagnostics a lot more palatable, because then the serology side of things becomes useful," said Moore. "For the serology side of diagnostics, until those immunologists tell us whether those antibodies actually protect us, all of those antibody diagnostic tests can tell us, is that we have had it, but they can't tell us if we are immune or will never get it again," he said.
"I think they can only be used as part of a strategy," said Denkinger from University Hospital Heidelberg. She noted that such assays could be used in epidemiological studies, and sequentially, to get an idea of seroprevalence over months or years. She also cautioned about public health authorities touting the idea of such assays being used for individual patients decisions.
"I think they are grossly oversold," said Denkinger. "This is one of the big flaws in communication to the public that these tests could have much value for the individual in settings like in Germany where prevalence is low," she said. "People think they are immune, they don't protect themselves, and it's very counterproductive on a public health level."