June 1, 2020 -- Big-name medical testing companies like Quest Diagnostics and LabCorp have expanded access to antibody tests that can tell whether someone was recently infected with the coronavirus a few weeks after they’ve recovered from disease. You can order these tests online or go through your doctor.
Public health experts, however, question the value of antibody testing for individuals given the tests’ limitations and whether results are meaningful.
The CDC said this week that antibody tests are not yet accurate or reliable enough to use to determine whether to reopen workplaces, schools, and other places where people gather.
The accuracy of antibody tests has been mired in controversy. The FDA allowed hundreds of tests onto the market resulting in a Congressional investigation last month.
Reports then surfaced last week that the CDC and states have been combining the number of antibody tests performed with the number of viral tests, further adding to the confusion about interpreting test results.
Researchers do not know yet if the antibodies that result from SARS-CoV-2 infection will provide someone with immunity from reinfection. If antibodies do provide immunity, experts don’t know how much antibody it takes to provide protection or how long protection might last.
“We’ve already measured the antibodies in many people, so we know that an immune response is there. We just have to get better, more nuanced information about what those responses mean and how to interpret them,” Michael Mina, MD, PhD, assistant professor of epidemiology at the Harvard T.H. Chan School of Public Health, said on a May 4 media call.
But the most accurate tests may not be able to correctly identify each person who has antibodies. Even commercial tests that report 100% accuracy may still produce false-positives when enough samples are run, says Andrew Azman, PhD, assistant scientist in the Department of Epidemiology at Johns Hopkins University Bloomberg School of Public Health.
Given the uncertainty, it’s premature to issue “immune passports,” Mina, Azman, and other infectious disease and public health experts wrote in a May 19 editorial in Science Immunology. This concept assumes that when someone tests positive to an antibody test, there is a good chance of avoiding re-infection or transmitting the virus to others. But it can give people a sense of false security, warns Azman.
Some employers are using antibody tests, also known as serological tests, to decide which employees may return to work or work on the frontlines. But “until we have more evidence, serological tests alone should not be used to make decisions such as when staff can return to work, the need for personal protective equipment or the need to discontinue social distancing measures,” the Association of Public Health Laboratories (APHL) said in a joint statement with the Council of State and Territorial Epidemiologists (CSTE) this month.
The CDC said the same thing this week in updated guidance on its website.
The concept of “herd immunity” has also gained traction lately. This is based on the principle that once a certain proportion of the population has developed immunity from previous COVID-19, the spread of the disease will die down. Ideally, the epidemic would eventually die out, explains Azman. For example, it’s believed that a population that achieves 93%-95% immunity to measles through vaccinations would protect the rest of the population from infection.
Preliminary results from widespread antibody testing in Wuhan, China, found that only 2% to 3% of the thousands of people tested developed antibodies. Early results from a nationwide study in Spain found that about 5% of the roughly 90,000 people tested were positive for antibodies. And even in hard-hit regions, such as New York state, preliminary testing of 3,000 people found that 13.9% were positive for antibodies.
“Given the transmissibility of SARS-CoV-2, even 10%-15% is insufficient to bring the outbreak under control. The major component of reducing transmission will have to be behavior change (e.g., social distancing) until a vaccine comes along,” says Azman.
Public Health Uses
Azman, Mina, and their colleagues argue that even perfect tests are not needed at the population level to address critical public health questions, such as the safety of relaxing stay-at-home orders or school closures or evaluations of alternative intervention measures, according to the May 19 editorial In Science Immunology.
But, researchers need to answer more basic population level questions first including test performance, how the development of antibodies relates to infection, and how antibodies impact potential immunity.
“Serologic testing is one of the most powerful tools we have -- not for day-to-day testing, but to understand where the immunity gaps are and where there are a lot of people who are immune,” said Mina on a May 18 media call.
Researchers can use antibody testing to better understand the scale and spread of the disease and estimate the probability and timing of future waves of diseases. Given a lack of widespread diagnostic testing, antibody testing can also capture people without symptoms or with mild symptoms, which may be up to 50% of those infected, according to recent reports.
Understanding how widespread COVID-19 infection has been in a community or population can also help public health officials decide where to use a vaccine once it becomes available and help identify people with an antibody response who could donate blood that may be able to treat COVID-19 in the future, according to the joint APHL/CSTE statement.
FDA Lack of Oversight
Members of Congress have criticized the FDA for its lack of oversight of antibody tests, which resulted in a monthlong investigation in April by the House Subcommittee on Economic and Consumer Policy chaired by Rep. Raja Krishnamoorthi (D-IL).
“As our investigation revealed, FDA’s prior laissez-faire policy let more than 150 tests go to market without any review, flooding the market with inaccurate and falsely marketed tests. Now, FDA must expeditiously conduct its review and clear the market of tests that don’t work or aren’t submitted for review, so that consumers can take confidence that testing services they receive are reliable and trustworthy,” says Krishnamoorthi.
The FDA has since authorized 12 antibody tests for emergency use and is reviewing another 200 antibody tests for potential emergency use authorization.
The FDA acknowledged that its March 16 “maximum flexibility” policy that allowed certified clinical laboratories to validate their own tests and bring them to market had unintended consequences.
“We unfortunately see unscrupulous actors marketing fraudulent test kits and using the pandemic as an opportunity to take advantage of Americans’ anxiety. Some test developers have falsely claimed their serological tests are FDA approved or authorized. Others have falsely claimed that their tests can diagnose COVID-19 or that they are for at-home testing, which would fall outside of the policies outlined in our March 16 guidance, as well as the updated guidance,” Anand Shah, MD, FDA deputy commissioner for Medical and Scientific Affairs, and Jeff Shuren, MD, FDA director, Center for Devices and Radiological Health, said on the agency’s website.
The FDA announced its updated policy May 4 that gives commercial antibody test makers a 10-day deadline to apply for Emergency Use Authorization (EUA) and specific test performance targets to meet for reliability. The companies also have to submit their validation data for an independent federal agency review.
The manufacturers of the 12 antibody tests that the FDA has authorized for emergency include big commercial laboratories and medical device manufacturers like Abbott and Roche as well as Mount Sinai Hospital Clinical Laboratory and Wadsworth Center, New York State Department of Health.
The FDA has posted the expected performance data for every antibody test it authorizes on its website and is adding the results from the independent validation performed by other federal agencies including the National Cancer Institute as they become available, according to an FDA spokesperson.
“There is no such thing as a perfect test -- there will always be false positives or false negatives even in the best designed tests. If you have a poor sample, there is still a chance that it will come out negative even when the patients had it,” says Eric Blank, DrPH, APHL chief program officer.
When public health experts talk about test accuracy, they refer to “sensitivity,” which is how well the tests identify antibodies to SARS-CoV-2 (true positive rate), and "specificity," which is how well the tests identify people without antibodies to SARS-CoV-2 (true negative rate).
Mina says the timing of antibody testing is important. It takes about 1 to 3 weeks after someone becomes infected with SARS-CoV-2 for their body to make antibodies, and some people may take longer.
“If the test is done too soon, the result may be negative but that doesn’t mean the person isn’t positive -- just that the timing was inappropriate.”
The FDA and some health care providers recommend a second test for confirmation. “The result of a single antibody test is not likely to be sufficiently accurate to make an informed decision regarding whether or not an individual has had a prior infection or truly has antibodies to the virus. A second test, typically one assessing for the presence of antibodies to a different viral protein, generally would be needed to increase the accuracy of the overall testing results,” says the FDA.
Researchers in the U.S. and worldwide are setting up studies to better understand how immunity from SARS-CoV-2 antibodies works. “They plan to follow and monitor people who have already been infected and measure antibody levels before and after they are exposed to see which ones actually become re-exposed a second time,” Mina said on the May 4 media call.
“Those studies are beginning now, but they’re going to take some time, in particular because we have to wait to see people who get re-exposed and then be able to measure a sufficient number of people, both at baseline and then as they become re-exposed to the virus the second time or third time,” says Mina.
One way to do this is to track high-risk populations such as health care workers who have a “decent risk of exposure,” says Mina.
Researchers in Belgium are spending 3 months following 300 health care workers who tested positive for COVID-19 with mild symptoms. They want to determine the percentage of health care workers who test positive for antibodies and the percentage who test positive for reinfection. To get those answers, participants are tested for antibodies every 2 weeks and reinfection is monitored by saliva swabs.
“I think that we’ll start to get the information from a lot of the studies that are being set up now within the coming months. And so my anticipation is that we will better understand how to interpret the antibody tests probably many months before we have wide availability of a vaccine,” says Mina.