If you feel sick and are able to get a test for the novel coronavirus, it’s most likely to involve a mouth and nose swab. The swabs will be sent to a lab technician, who will search them for the virus’s unique RNA sequence. If they’re present, it means you have an active Covid-19 infection. While counts vary, one estimate suggests 368,000 of these tests have been administered in the US.
But what if you felt sick a couple weeks ago, got over it, and want to know if you may have had Covid-19? For that, the molecular RNA test won’t help. Instead, you need a serologic test: One that searches your blood serum for signs of an immune response to the infection.
Serologic tests for the new coronavirus aren’t yet widely available in the US, even though processing them is simpler and less tech-intensive than molecular tests. A number of serologic tests are in various stages of development by labs and private companies, mostly in China, some of which are modifications of older tests developed for the 2004 SARS outbreak. Now, immunologists are racing to evaluate these tests, develop streamlined alternatives, and decide how best to use them in the current coronavirus response.
“It’s an urgent national priority to develop and distribute such tests,” said Nicholas Christakis, a social scientist and physician who directs Yale University’s Human Nature Lab. “The US has an opportunity not to fumble this kind of testing the way we did with the [molecular] test.”
Serologic tests are about more than satisfying personal curiosity. In the short-term, they could help identify healthcare providers and other essential workers who are immune to the disease and could work safely without protective equipment, or stop social distancing and return to their jobs.
They can also help answer big-picture public health questions, such as how many people actually got infected, and what portion of them died. If recovering patients are tested repeatedly over time, their antibodies can help researchers understand how long the immunity lasts (every pathogen is different; right now Covid-19 immunity is known to last at least 40 days, but it could be a year or more). Duration of immunity is a key issue for vaccine development.
Finally, blood plasma packed with antibodies from recovered Covid-19 patients could be critical to developing treatments and vaccines. The plasma itself could be used to treat the seriously ill: A group of more than 100 researchers from the Mayo Clinic and elsewhere are now working to develop a plasma-based treatment for the highest-risk patients.
Serologic tests do have some drawbacks. The most common technique, called ELISA, involves exposing a blood sample to proteins that mimic the coronavirus’ spiky casing; if antibodies in the blood attack the protein, the sample changes color. But because that casing can be very similar across coronaviruses, serologic tests tend to be less accurate than molecular tests, and could return a positive result if someone had been infected with another coronavirus.
A new serologic test described last week in a preprint paper released by scientists at the Icahn School of Medicine at Mount Sinai Hospital had perfect results in a tiny initial trial, correctly identifying SARS-CoV-2 in four blood samples from recovering patients and returning no false positives in 59 control samples. But Elitza Theel, who researches serologic tests at the Mayo Clinic and is currently evaluating some of the new coronavirus tests, said it’s too soon to say how accurate the new tests are, on average.
Although some serologic tests are being marketed as a quick and easy alternative to molecular tests, Theel said people should be wary of using any blood test to diagnose whether they’re currently infected or not.
Theel and other immunologists are focused on two key antibodies, immunoglobulins G and M, and working to understand how long they take to respond to SARS-CoV-2 infection. Now, she said, it seems that it takes at least eight days after the onset of symptoms for the body’s antibody response to get fired up; any serologic test taken before then could come back negative, even if you feel sick and do indeed have the virus.
For now, Theel said, serologic tests are better suited to hospital and research settings, and not to at-home diagnostic use by the general public.
“The gold standard for acutely ill patients is molecular testing, and it needs to remain that way,” she said. “We have to be very careful about how we use serologic tests.”
The FDA gave the same message last week in its new guidance on how it will regulate coronavirus tests. The agency “does not intend to object to the development and distribution by commercial manufacturers or development and use by laboratories of serology tests” as long as the tests include a disclaimer that the results “should not be used as the sole basis to diagnose or exclude SARS-CoV-2 infection.” The guidance also clarifies that at-home tests are still subject to normal regulatory scrutiny.
In a press conference Monday, Deborah Birx, response coordinator for the White House Coronavirus Task Force, said the FDA is performing its own evaluation of serologic tests and hopes to officially approve one within the next few weeks.
In the meantime, at least 17 companies have notified the FDA that they plan to move ahead with marketing serologic tests to labs and clinics in the US. There’s not yet any data on how many tests are out there or where, said Robert Garry, an immunologist at Tulane University who is also evaluating the tests, or a coordinated effort to carry out a large-scale serologic survey. In one case, the tests are being offered to all 8,000 residents of a small Colorado county where the executives of the manufacturing company United Biomedical like to go on vacation.
One reason the development of serologic tests has lagged behind molecular tests is that the process requires a supply of blood from recovering patients. There’s not much to go around: The overall deficit of molecular testing means most infected people still don’t know they’ve been infected, and even those who get swabbed at a drive-through or outpatient clinic never spend time in a hospital where their blood might be drawn.
The process got a big boost from the Mount Sinai preprint: Significantly, it detailed the steps any lab could follow to make the test on its own, rather than keeping them proprietary as most other labs had done. The paper’s lead author, immunologist Florian Krammer, has already shipped out samples of the specialized protein needed for the test to at least 50 labs.
Serologic tests, and the treatments they might yield, are nothing new or particularly complex, said Gary Miller, vice dean for research strategy at Columbia’s Mailman School of Public Health, who is overseeing the school’s development of coronavirus testing, including a serologic test. Plasma infusions were used as far back as 1934, to fight a measles outbreak. But the deficit of serum samples, constraints on lab work because of social distancing, and frantic nature of the Covid-19 pandemic have made everything more difficult.
“There’s a lot of pressure here,” Miller said. “We’ve been doing this for many years, but the scale and urgency of this is throwing everyone off.”