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About six to 10 days after viral exposure,the body begins to develop antibodies that bind and react specifically to the proteins found on SARS-CoV-2. The first antibody produced is called immunoglobulin m (IgM), which is short-lived and only stays in the bloodstream for a few weeks. The immune system refines the antibodies and just a few days later will start producing immunoglobulins G (IgG) and A (IgA), which are much more specific. IgG stays in the blood and can confer immunity for months, years, or a lifetime, depending on the disease its protecting against.

In someone who has survived infection with covid-19, the blood should, presumably, possess these antibodies, which will then protect against subsequent infection by the SARS-CoV-2 virus. Knowing whether someone is immune (and eligible for potential future certification) hinges onserological testing,drawing blood to look for signs of these antibodies. Get a positive test and, in theory, that person is now safe to walk the street again and get the economy moving. Simple.

Except its not. There are some serious problems with trying to use the tests to determine immunity status. For example, we still know very little about what human immunity to the disease looks like, how long it lasts,whether an immune response prevents reinfection, and whether you might still be contagious even after symptoms have dissipated and youve developed IgG antibodies. Immune responses vary greatly between patients, and we still dont know why. Genetics could play a role.

Weve only known about this virus for four months, says Donald Thea, a professor of global health at Boston University. Theres a real paucity of data out there."

SARS-CoV-1, the virus that causes SARS and whose genome is about 76% similar to that of SARS-CoV-2, seems toelicit an immunity that lasts up to three years. Other coronaviruses that cause the common cold seem to elicit a far shorter immunity, although the data on that is limitedperhaps, says Thea, because there has been far less urgency to study them in such detail. Its too early to tell right now where SARS-CoV-2 will fall in that time range.

Even without that data, dozens of groups in the US and around the world are developing covid-19 tests for antibodies. Many of these are rapid tests that can be taken at the point of care or even at home, and deliver results in just a matter of minutes. One US company, Scanwell Health, has licensed a covid-19 antibody test from the Chinese company Innovita that can look for SARS-CoV-2 IgM and IgG antibodies through just a finger-prick blood sample and give results in 13 minutes.

There are two key criteria we look for when were evaluating the accuracy of an antibody test. One is sensitivity, the ability to detect what its supposed to detect (in this case antibodies). The other is specificity, the ability to detect the particular antibodies it is looking for. Scanwells chief medical officer, Jack Jeng, says clinical trials in China showed that the Innovita testachieved 87.3% sensitivity and 100% specificity(these results are unpublished). That means it will not target the wrong kind of antibodies and wont deliver any false positives (people incorrectly deemed immune), but it will not be able to tag any antibodies in 12.7% of all the samples it analyzesthose samples would come up as false negatives (people incorrectly deemed not immune).

By comparison, Cellex, which is the first company to get a rapid covid-19 antibody test approved by the FDA, has a sensitivity of 93.8% and a specificity of 95.6%. Others are also trumpeting their own tests vital stats. Jacky Zhang, chairman and CEO of Beroni Group, says his companys antibody test has a sensitivity of 88.57%, for example. Allan Barbieri of Biomerica says his companys test is over 90% sensitive. The Mayo Clinic is making available its own covid-19 serological test to look for IgG antibodies, which Elitza Theel, the clinics director of clinical microbiology, says has 95% specificity.

The specificity and sensitivity rates work a bit like opposing dials. Increased sensitivity can reduce specificity by a bit, because the test is better able to react withanyantibodies in the sample, even ones you arent trying to look for. Increasing specificity can lower sensitivity, because the slightest differences in the molecular structure of the antibodies (which is normal) could prevent the test from finding those targets.

It really depends on what your purpose is, says Robert Garry, a virologist at Tulane University. Sensitivity and specificity rates of 95% or higher, he says, are considered a high benchmark, but those numbers are difficult to hit; 90% is considered clinically useful, and 80 to 85% is epidemiologically useful. Higher rates are difficult to achieve for home testing kits.

But the truth is, a test that is 95% accurate isnt much use at all. Even the smallest errors can blow up over a large population. Lets say coronavirus has infected 5% of the population. If you test a million people at random, you ought to find 50,000 positive results and 950,000 negative results. But if the test is 95% sensitive and specific, it test will correctly identify only 47,500 positive results and 902,500 negative results. That leaves 50,000 people who have a false result. Thats 2,500 people who are actually positiveimmunebut are not getting an immunity passport and must stay home. Thats bad enough. But even worse is that a whopping 47,500 people who are actually negativenot immunecould incorrectly test positive. Half of the 95,000 people who are told they are immune and free to go about their business might never have been infected yet.

Because we dont know what the real infection rate is1%, 3%, 5%, etc.we dont know how to truly predict what proportion of the immunity passports would be issued incorrectly. The lower the infection rate, the more devastating the effects of the antibody tests inaccuracies.The higher the infection rate, the more confident we can be that a positive result is real.

And people with false positive results would unwittingly be walking hazards who could become infected and spread the virus, whether they developed symptoms or not. A certification system would have to test people repeatedly for several weeks before they could be issued a passport to return to workand even then, this would only reduce the risk, not eliminate it outright.

As mentioned, cross-reactivity with other antibodies, especially ones that target other coronaviruses, is another concern. There are six different coronaviruses known to infect humans, says Thea. And its entirely possible if you got a garden-variety coronavirus infection in November, and you did not get covid-19, you could still test positive for the SARS-CoV-2 antibodies.

Lee Gehrke, a virologist and biotechnology researcher at Harvard and MIT, whose company E25Bio is also developing serological tests for covid-19, raises another issue. It's not yet immediately clear, he says, that the antibodies these tests pick up are neutralizing. In other words, the antibodies detected in the test may not necessarily actagainstthe virus to stop it and protect the bodythey simply react to it, probably to tag the pathogen for destruction by other parts of the immune system.

Gehrke says he favors starting with a smaller-scale, in-depth study of serum samples from confirmed patients that defines more closely what the neutralizing antibodies are. This would be an arduous trial, but I think it would be much more reassuring to have this done in the US before we take serological testing to massive scale, he says.

Alan Wells, the medical director of clinical laboratories at the University of Pittsburgh Medical Center, raises a similar point. He says that some patients who survive infection and are immune may simply not generate the antibodies youre looking for. Or they may generate them at low levels that do not actually confer immunity,as some Chinese researchers claim to have found.

I would shudder to use IgM and IgG testing to figure out whos immune and whos not, says Wells. These tests are not ready for that.

Even if the technology is more accurate, it might still simply be too early to start certifying immunity just to open up the economy. Chris Murray from the University of Washingtons Institute for Health Metrics and Evaluationtold NPRhis groups models predict that come June, at least 95% of the US will still be susceptible to the virus, leaving them vulnerable to infection by the time a possible second wave comes around in the winter. Granting immunity passports to less than 5% of the workforce may not be all that worthwhile.

Theel says that instead of being used to issue individual immunity passports, serology tests could be deployed en masse, over a long period of time, to see ifherd immunity has set inlifting or easing restrictions wholesale after 60 to 70% of a communitys population tests positive for immunity. There are a few case studies that hold promise. San Miguel County in Colorado has partnered with biotech company United Biomedical in an attempt to serologically test everyone in the county. The community is small and isolated, and therefore easier to test comprehensively. Iceland has been doing the same thing across the country.

This would require a massively organized effort to pull off well in highly populated areas, and its not clear whether the decentralized American health-care system could do it. But its probably worth thinking about if we hope to reopen whole economies, and not just give a few individuals a get-out-of-jail-free card.

Not everyone is so skeptical about using serological testing on a case-by-case basis. Thea thinks the data right now suggests SARS-CoV-2 should behave like its close cousin SARS-CoV-1, resulting in an immunity that lasts for a maybe a couple of years. With that in mind, its not unreasonable to identify individuals who are immune from reinfection, he says. We can have our cake and eat it too. We can begin to repopulate the workforcemost importantly the health-care workers. For instance, in hard-hit cities like New York that are suffering from a shortage of health-care workers, a serological test could help nurses and doctors figure out who might be immune, and therefore better equipped to work in the ICU or conduct procedures that put them at a high risk of exposure to the virus, until a vaccine comes along.

And at the very least, serological testing is potentially useful because many covid-19 cases present, at most, only mild symptoms that dont require any kind of medical intervention. About 18% of infected passengers on theDiamond Princesscruise shipshowed no symptoms whatsoever, suggesting there may be a huge number of asymptomatic cases. These people almost certainly arent being tested (CDC guidelines for covid-19 testing specifically exclude those without symptoms). But their bodies are still producing antibodies that should be detectable long after the infection is cleared. If they develop immunity to covid-19 thats provable, then in theory, they could freely leave the house once again.

For now, however, there are too many problems and unknowns to use antibody testing to decide who gets an immunity passport and who doesnt. Countries now considering it might find out they will either have to accept enormous risks or simply sit tight for longer than initially hoped.

Correction: The initial version of the story incorrectly stated: "The higher the infection rate, the more devastating the effects of the antibody tests inaccuracies." A higher infection would actually produce more confident antibody test results. We regret the error.

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Why its too early to start giving out immunity passports - MIT Technology Review

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