Next week, blood banks across the Netherlands are set to begin a nationwide experiment. As donations arrive—about 7,000 of them per week is the norm—they’ll be screened with the usual battery of tests that keep the blood supply safe, plus one more: a test for antibodies to SARS-CoV-2, the virus that causes Covid-19. Then, in a few weeks, another batch of samples will get the same test. And after that, depending on the numbers, there could be further rounds. The blood donors should be fairly representative of Dutch adults ages 18 to 75 and, most importantly, they’ll all be healthy enough for blood donation—or at least outwardly so.
Testing thousands of samples from seemingly-healthy people might sound a little wasteful, with all we’ve been hearing about testing shortages around the world. But that’s precisely the point, says Hans Zaaijer, a microbiologist at Amsterdam University Medical Center and Sanquin, the Dutch blood bank. He wants to see how many people have already had the disease and could possibly be immune.
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Nobody knows the true scope of Covid-19 infections: How many people have it and how severe the disease is across different demographics. One reason for that is limited testing, which has made many cases invisible to those keeping count. Was that mystery fever you had a few weeks ago the novel coronavirus? At this point, nobody can say for sure. The other reason is that a still-unknown but sizable percentage of infected people carry on through a Covid-19 infection without symptoms. That stealthiness has been implicated in the virus’s speedy spread.
But a simple blood test, like the kind Zaaijer’s team will perform on the donated blood, can tell whether it carries antibodies to Covid-19, which are produced when a person’s immune system responds after an infection. Identifying what proportion of the population has already been infected is key to making the right decisions about containment. “We hope that this will show us how fast immunity is increasing in the population,” Zaaijer says. The eventual target? When 60 percent of the country’s population has antibodies to the disease. That’s when Zaaijer and other infectious disease experts hope the pandemic shuts down on its own, provided immunity is conferred and lasts.
Tests like the one to be used in the Netherlands are different from the ones typically used for diagnosis. Those look for genetic material collected from throat or nasal swabs, and are analyzed using a technique called PCR, or polymerase chain reaction. That provides a reliable diagnosis, but depends on lab-bound machines.
Blood tests, on the other hand, are comparatively easy to use; they can be performed at a doctor’s office or pharmacy, or even at home. But generally, the point isn’t to give a diagnosis. The tests work by measuring the level of antibodies in a sample of blood serum (hence their other name, serological tests). That means they’re only useful towards the end of a disease’s course, after the body has started putting up a real fight, and after a person has recovered. The sensitivity of a particular test depends on what kinds of antibodies that test is looking for. Because of that lag, and because no Covid-19-specific serological tests have been fully vetted yet, the FDA’s latest guidance is that they shouldn’t be relied upon for diagnoses.
But in epidemiology circles, those tests are a sought-after tool for understanding the scope of the disease. Since February—which was either three weeks or a lifetime ago—epidemiologists have been trying to get the full scope of the number of infections here in the US. Mostly, that’s meant designing mathematical models. Flawed models, as Andrew Lover, an epidemiologist at the University of Massachusetts-Amherst, readily admits. “We were breaking all kinds of rules,” he says of the early efforts. But the need was urgent. So researchers made do with limited data on the virus’s transmission rate in places like China and Singapore, and from just a few identified cases in the US. Lover, for example, extrapolated from a single case at the CPAC conference in late February. Others looked at cases caught after travel abroad, at deviations from the expected death rate, or at the genetic variation of viral samples.
By early March, these various research groups were posting their analyses online, along with heaping caveats of uncertainty. Then came a surprise, given their wildly different approaches. While each model had produced different figures, their conclusions were roughly the same: The actual number of people infected was likely tens of thousands more than the meagre testing results so far had suggested.
Those early models were a good start, and can be credited with awakening local officials to the problems already at our doorstep. But as the disease has continued to spread and a patchwork of local “stay at home” rules begins to bend the course of the disease, projecting who has the disease and where the hotspots are has become more difficult for models to capture. Instead, you need boots-on-the-ground surveillance. In other words, to fill the gap created by a lack of diagnostic tests, you need more testing—but of a different sort. This time, you have to know how many total people have already fought the bug, and how recently they’ve fought it.
“Of all the data out there, if there was a good serological assay that was very specific about individuating recent cases, that would be the best data we could have,” says Alex Perkins, an epidemiologist at the University of Notre Dame. The key, he says, is drawing blood from a representative sample that would show the true scope of unobserved infections.
Normally, to do that, serological testing might be done in the twilight of an outbreak, as a kind of epidemiological post-mortem. Researchers might do a randomized survey, picking 1 percent of people in a particular area for testing, says Martin Hibberd, a professor of infectious diseases at the London School of Hygiene and Tropical Medicine. Then they would gather samples and then run them in big batches. After the 2009 H1N1 outbreak in Mexico, such testing allowed researchers to determine that the mortality was far lower than initially feared.
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But with the severity of the Covid-19 outbreak, researchers around the world are racing to get tests out there quickly. “We haven’t really rolled them out on a very large scale for any other disease,” Hibberd says. The first serological tests for Covid-19 were developed in China and Singapore—partly because both had cases early on, but also because both places were hit hard by SARS and continued to invest in understanding coronavirus-related diseases while funding dried up elsewhere. That gave the countries a head start in developing the tests, due to similarities in the antibodies the two coronaviruses cause our bodies to produce.
Another motivation to develop better blood tests is the potential to develop therapeutics from antibody-rich blood serum. Last week, researchers at the Mount Sinai School of Medicine released the recipe for a serological test with just that purpose in mind; the research is already being used to develop potential therapies in New York State.
And in the thick of the outbreak, especially given the shortage of PCR tests, the right kinds of serological tests could also provide a crucial diagnostic backstop. Hospitals could take advantage of cheap, fast-response tests that can easily be done on site to check front-line health workers, aiming to keep as many of them in commission as possible. “It would allow you to be cleared and come back to work, presumably resistant to infection,” Hibberd says.
But it’s important to tread carefully. “There’s a lot of misunderstandings about what they’re useful for,” says Kristian Andersen, an evolutionary biologist at Scripps Research who has studied the genetic origins of SARS-CoV-2. “A lot of companies out there make it sound as if these can be used for diagnosis, which generally isn’t true.” That requires a test that’s sensitive to the right antibodies and is administered by people who can interpret it properly.
In the Netherlands, researchers are developing a more sensitive test that could be used for diagnoses (and potential therapies). The current test is good enough for an anonymized population study, Zaaijer says. But it isn’t accurate enough to be used to send Dutch health workers back into hospitals with presumed immunity.
In the meantime, some places have started doing this kind of surveillance testing with the existing PCR tests, on a limited scale. Public health officials in Washington on Monday launched the Seattle Coronavirus Assessment Network, which involves randomly selecting households and having the residents ship swabs to the lab by Amazon courier. Iceland’s officials plan to test all their citizens, eventually, though that project still has a long way to go. Most prominent is the city of Vo in Italy, where all 3,000 residents were tested. Those who tested positive were isolated, allowing the town’s leaders to constrain the viral spread, though they acknowledged this would be hard to do in a bigger city.
Serological testing could expand the scope of that testing, and get it done faster. United Biomedical, a New York-based biotech company, decided to offer repeat tests to the roughly 7,000 people in San Miguel County, home to Telluride, Colorado, where the company’s cofounders live. The idea is to develop a model that can be exported elsewhere, cheaply.
The test isn’t rapid-response yet—the company is flying samples to the company’s headquarters in New York, where they’re run in batches. But Sharon Grundy, the San Miguel County medical officer, says the turnaround is quick. To date, they’ve shipped 61 tests to labs for PCR analyses—43 of which are still pending. Since Friday, the county has blood tested 645 people, including all of the county’s first responders. “Any information is better than no information,” Grundy says. “For weeks we’ve been wondering, ‘God, is it this Covid or is it not?’”
Given the test’s limits, the key is getting two data points for everyone, Grundy says. If the first test comes back positive, the county will let the patient know that it still isn’t certain whether they’ve cleared the virus or not, and ask them to isolate as a precaution. A second positive means “they can let their guard down a little,” Grundy says. Negatives are trickier to manage, since they may miss the disease early in its course, but that underlines the importance of everyone adhering to social distancing, she notes. The county will continue sending out swabs for PCR tests, too, for people who qualify under the CDC’s guidelines.
One challenge with distributing serological tests in the midst of a crisis is that they might be a little too easy to get into people’s hands. So easy, in fact, that at-home tests might allow patients to do the whole thing themselves. “That puts me off a bit. I’d worry people would say, ‘Ah, yes, I’m immune,’ and be done with it,” Hibberd says. “The leaflet in your test kit might say it’s lovely, but that may not be accurate.” In addition to inaccurate tests that prey on the worried well, he’s concerned about people interpreting the results incorrectly. He’d prefer to see the tests in the hands of hospital staff first, so that healthcare workers get tested, and then doctors and pharmacies.
San Francisco start-up Scanwell Health is among the companies with plans to do at-home testing, in its case through a partnership with telehealth service Lemonaid. Jack Jeng, Scanwell’s chief medical officer, says the test, made by Chinese biotech company Innovita, is the sole Covid-19 serological test to be approved by China’s equivalent of the FDA. The current plan is to offer the test to those who meet the CDC’s testing guidelines, which he acknowledges comes with challenges. He says the company is working out how best to communicate the limits of the test, including guidance for people who receive a negative result, given the chance that they could be infected but have not yet developed an immune response.
A better use, eventually, might be to expand eligibility for the test to those hoping to determine past exposure. “We’ve gotten a lot of interest from people who think they had it a month ago,” he says. “People who want to go out and help, but want to know if they were exposed first.”
The company, which received its first batch of tests this week, is awaiting word on an emergency use authorization from the FDA to distribute them in-home. Jeng says that in the interim, Scanwell is hoping to get the tests out to hospitals, where they could be used to clear front-line workers. As the cases ramp up across the country, he says he’s had no shortage of people hoping to take them off his hands.
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