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People who think they’ve been exposed to the novel coronavirus are clamoring for antibody tests — blood screens that can detect who has previously been infected and, the hope is, signal who is protected from another case of Covid-19.

But as the tests roll out, some experts are trying to inject a bit of restraint into the excitement that the results of these tests could, for example, clear people to get back to work. Some antibody tests have not been validated, they warn. Even those that have been can still provide false results. And an accurate positive test may be hard to interpret: the virus is so new that researchers cannot say for sure what sort of results will signal immunity or how long that armor will last.

They caution that policymakers may be making sweeping economic and social decisions — plans to reopen businesses or schools, for example — based on limited data, assumptions, and what’s known about other viruses. President Trump last week unveiled a three-phased approach to reopen the country; he said some states that have seen declining case counts could start easing social distancing requirements immediately. And some authorities have raised the idea of granting “immunity passports” to people who recover from the virus to allow them to return to daily life without restrictions.

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“Before we embark on huge policy decisions, like issuing immunity certificates to get people back to work, I think it’s good that people are saying, ‘Hold up, we don’t know that much about immunity to this virus,’” said Angela Rasmussen, a Columbia University virologist.

To be clear, most experts do think an initial infection from the coronavirus, called SARS-CoV-2, will grant people immunity to the virus for some amount of time. That is generally the case with acute infections from other viruses, including other coronaviruses.

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With data limited, “sometimes you have to act on a historical basis,” Anthony Fauci, the head of the National Institute of Allergy and Infectious Diseases, said in a webcast with JAMA this month. “It’s a reasonable assumption that this virus is not changing very much. If we get infected now and it comes back next February or March we think this person is going to be protected.”

Still, the World Health Organization has stressed that the presumed immunity can only be proven as scientists study those who have recovered for longer periods. The agency is working on guidance for interpreting the results of antibody tests, also called serologic tests.

“Right now, we have no evidence that the use of a serologic test can show that an individual is immune or is protected from reinfection,” the WHO’s Maria Van Kerkhove said at a briefing last week.

Below, STAT looks at the looming questions about antibodies and immunity that scientists are racing to answer.

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What are antibody tests? How widely available are they? And how accurate?

The tests look for antibodies in the blood. Because antibodies are unique to a particular pathogen, their presence is proof the person was infected by the coronavirus and mounted an immune response. The hope is that the presence of the antibodies is an indication that the person is protected from another infection.

These are different from the tests used to diagnose active infections, which look for pieces of the virus’ genome.

Commercial antibody tests are starting to appear on the market, but so far, the Food and Drug Administration has only cleared a few through Emergency Use Authorizations. And already, health regulators are warning that the ones on the market may vary in their accuracy.

“I am concerned that some of the antibody tests that are on the market that haven’t gone through FDA scientific review may not be as accurate as we’d like them to be,” FDA Commissioner Stephen Hahn said on “Meet the Press” earlier this month. He added that “no test is 100% accurate, but what we don’t want are wildly inaccurate tests.”

Even the best tests will generate some false positives (identifying antibodies that don’t actually exist) and some false negatives (missing antibodies that really are there). Countries including the U.K. have run into accuracy issues with antibody tests, slowing down their efforts for widespread surveys.

The fear in this case with imprecise tests is that false positives could errantly lead people to think they’re protected from the virus when they have yet to have an initial infection.

Serology testing “isn’t a panacea,” said Scott Becker, the CEO of the Association of Public Health Laboratories. “When it’s used, we need to ensure there are good quality tests used.”

One specific concern with antibody tests for SARS-CoV-2: they might pick up antibodies to other types of coronaviruses.

Globally, there have only been a few thousand people exposed to the other coronaviruses that have caused outbreak emergencies, SARS and MERS. But there are four other coronaviruses that circulate in people and cause roughly a quarter of all common colds. It’s thought that just about everyone has antibodies to some combination of those coronaviruses, so serological tests for SARS-CoV-2 would need to be able to differentiate among them.

What can be gleaned from serological results?

Detecting antibodies is the first step. Interpreting what they mean is harder.

Typically, a virus that causes an acute infection will prompt the body’s immune system to start churning out specific antibodies. Even after the virus is cleared, these “neutralizing” antibodies float around, ready to rally a response should that virus try to infect again. The virus might infect a few cells, but it can’t really gain a toehold before the immune system banishes it. (This is not the case for viruses that cause chronic infections, like HIV and, in many cases, hepatitis C.)

“The infection is basically stopped in its tracks before it can go anywhere,” said Stephen Goldstein, a University of Utah virologist. But, Goldstein added, “the durability of that protection varies depending on the virus.”

Scientists who have looked at antibodies to other coronaviruses — both the common-cold causing foursome and SARS and MERS — found they persisted for at least a few years, indicating people were protected from reinfection for at least that long. From then, protection might start to wane, not drop off completely.

The experience with other viruses, including the other coronaviruses, has encouraged what Harvard epidemiologist Marc Lipsitch summed up as the “educated guess” in a recent column in the New York Times: “After being infected with SARS-CoV-2, most individuals will have an immune response, some better than others. That response, it may be assumed, will offer some protection over the medium term — at least a year — and then its effectiveness might decline.”

But many serological tests aren’t like pregnancy tests, with a yes or no result. They will reveal the levels (or titer) of antibodies in a person’s blood. And that’s where things can get a bit trickier. At this point, scientists can’t say for sure what level of antibodies might be required for a person to be protected from a second Covid-19 case. They also can’t say how long people are safeguarded, though it’s thought that a higher initial titer will take longer to wane than low levels.

“Further investigation is needed to understand the duration of protective immunity for SARS-CoV-2,” a committee from the National Academies of Sciences, Engineering, and Medicine wrote in a report this month.

It’s not just whether someone is immune themselves. The next assumption is that people who have antibodies cannot spread the virus to others. Again, that hasn’t been shown yet.

“We don’t have nearly the immunological or biological data at this point to say that if someone has a strong enough immune response that they are protected from symptoms, … that they cannot be transmitters,” said Michael Mina, an epidemiologist at Harvard’s T.H. Chan School of Public Health.

The challenge, as the National Academies report highlighted, is that no one knew about this virus until a few months ago. That means they haven’t been able to study what happens to people who recover from Covid-19 — and if and how long they are protected — for more than a short period of time.

“One key uncertainty arises from the fact that we are early in this outbreak and survivors from the first weeks of infection in China are, at most, only three months since recovery,” the report said.

What else can antibody tests show?

In addition to identifying those who have been infected, antibody tests can also suggest at a broader level how widely the virus has spread. These data have implications for how severe future outbreaks of cases might be and what kind of restrictions communities might need to live under. If more people have been infected than known — a strong likelihood, given the number of mild infections that might have been missed and testing limitations in countries including the United States — then more people are thought to be protected going forward.

In the United States, the Centers for Disease Control and Prevention and the National Institutes of Health have both launched “serosurveys” to assess how many people might have contracted the virus. Even employees of Major League Baseball teams have been enlisted in a study enrolling thousands of patients.

What have data from serosurveys shown thus far about antibody generation?

A number of countries have launched large serosurveys, so hopefully we’ll have a better sense soon of the levels of antibodies being generated by individuals who recover from Covid-19 and among the general population. For now, though, there have only been limited data released from a couple small studies.

Scientists in Europe have pointed to strong antibody production in patients within a few weeks of infection. One study found that people were generally quick to form antibodies, which could help explain why the majority of people do not develop severe cases of Covid-19.

But one preprint released this month complicated the landscape. (Preprints have not been peer-reviewed or published yet in a research journal.) Researchers in Shanghai reported that of 175 patients with confirmed Covid-19, about a third had low antibody levels and some had no detectable antibodies. The findings suggest that the strength of the antibody response could correlate to the severity of infection, though that’s not known for sure. They also raised concerns that those with a weaker antibody response might not be immune from reinfection.

But outside researchers have said that conclusions about immunity can’t be drawn from what the study found. For one, there are different kinds of antibodies, so some might exist that the test wasn’t looking for. Secondly, studies in other coronaviruses have shown that antibody responses vary from person to person, without clear implications for how protected someone is from another infection.

And, researchers say, antibodies are not the only trick the body has to protect itself. Immune cells also form memories after an initial infection and can be rallied quickly should that same pathogen try to strike again, even without antibodies or after antibody levels fade.

“People that lose that serum neutralization — it doesn’t mean necessarily that they’re not going to have some level of immunity,” said virologist Vineet Menachery of the University of Texas Medical Branch. “Your immune system hasn’t forgotten. It may just take them a couple of days to generate that immune response and be able to clear a virus.”

He added that it’s likely that if and when protection starts to wane and people contract the coronavirus a second time, it’s likely to cause an even milder illness.

I’ve heard reports of reinfection or “reactivated” virus. What’s going on there?

Health officials in some countries have said they’ve seen examples of people recovering from Covid-19 only to test positive for the virus again — what they’ve taken to calling “reactivation,” to differentiate it from a second infection.

But experts are skeptical that either is occurring.

While no possibility can be eliminated at this early stage of the outbreak, they say that there are more likely explanations for a positive diagnostic test coming after a negative test.

For one: The tests used to diagnose Covid-19 look for snippets of the virus’ genome, its RNA. But what they can’t tell you is if what they’re finding is evidence of “live” virus, meaning infectious virus. Once a person fights off a virus, viral particles tend to linger for some time. These cannot cause infections, but they can trigger a positive test. The levels of these particles can fluctuate, which explains how a test could come back positive after a negative test. But it does not mean the virus has become active, or infectious, again.

And two: the diagnostic tests typically rely on patient samples pulled from way back in their nasal passages. Collecting that specimen is not foolproof. Testing a sample that was improperly collected could lead to a negative test even if the person has the virus. If that patient then gets another test, it might accurately show they have the virus.

As Jana Broadhurst, the director of the Nebraska Biocontainment Unit’s clinical laboratory, said, “garbage in, garbage out.”

Sharon Begley contributed reporting.

  • I’m a complete layman on this subject. So let the criticisms and ridicule begin. But one thought has occurred to me. If recent antibody screening data from Boston (homeless) and Santa Clara are accurate, and show a MUCH higher number of people have already been infected showing little or no symptoms, that makes the fatality rate MUCH lower. Possibly MUCH, MUCH lower, by a factor of 50 or more–if the Santa Clara data can be projected across a wider population. Now, if the fatality rate is that much lower, putting it closer to the range of fatality caused by influenza, why is it critically important to know whether immunity is short-lived or not? Relatively few die even when the virus is new. Any immunity–short or long term–established in the population will only reduce the fatality rate further. But from the start it might already be quite low.

    • I can’t speak to your US datasets but here in UK the total all causes death rate for the whole country for the week to 10 April was almost twice what it was in 2019 and the five year average for that week. It would be quite a coincidence if this almost doubling of the death rate just happened to coincide with a new virus.

    • Layman here too. If I understand well, nature doesn’t jump without cause. So with all respect to Mr. Coburn’s response to this comment, it would still be interesting to figure out IF the virus has been present for some months WHY did it suddenly “flare” in places like NY/NJ? I can imagine some accidentally false reporting on a death certificate but if numbers like those to which Mr. Coburn makes reference are true AND the virus has been present for some time, this really does cause one to wonder how and why.

  • I have a general criticism of all articles dealing with COVID-19 testing. There is a general failure to adequately distinguish the difference in implication between viral testing and antibody testing; as well as a generalized failure to understand that the response to this virus by everyone (from the Federal government organizing a logistical action that exceeds any other action in history in its size and speed, including WWII, and industry) has been beyond awesome.

    There is usually a complete lack of critical examination of an expert’s opinion and how that should or will impact strategies for mass testing. Most of the articles are like a multiple choice test: regurgitate without review or understanding or evaluation.
    Bypassing standard testing protocols prior to formal evaluation by the FDA was mandated by the political hysteria on the one hand, and sage, if not sagacious advice, by experts, who fail to understand the real-life consequences of their decisions.
    We have the tools that we have; it’s as simple as that. If something better comes along, it can be adopted; but as is usually the case, we cannot allow the perfect to be the enemy of the good.
    Of course, if standard testing protocols are bypassed, the tests may not be as robust, sensitive and specific as desired in an ideal situation.
    What is the alternative? Strangling the economy until it is past the point of recovery? Destroying the livelihood of millions?
    Or implementing a rational response with additional care/isolation for those at risk, with some reasonable precautions for everyone else.

    • Do you think this article makes the distinctions you are missing from others? I think this is one of the best I’ve read.

  • A nice round up. Thanks. I suspect a little kin selection is going on also, because viruses are the arch-typical “Black Queen” players, so the mix SAR -CoV-2 particles in individuals and populations may be important. See, for example:
    Domingo-Calap, P., et al. (2019). “Social evolution of innate immunity evasion in a virus.” Nature Microbiology 4(6): 1006-1013.

  • HI,

    I AM TOTALLY AMAZED BY THE ABSOLUTE HYSTERIA ABOUT THIS VIRUS FOR THE FOLLOWING REASONS。

    THE FINANCIAL IMPLICATIONS OF LOCKING PEOPLE UP LIKE ANIMALS IS CAUSING AND WILL CAUSE FAR MORE DAMAGE AND DEATH TO MILLIONS。

    COVID 19 IS NOT THE ONLY THING THAT KILLS PEOPLE。

    MOST PEOPLE DYING ARE OVER EIGHTY OR WITH UNDERLYING HEALTH PROBLEMS。

    MILLIONS ARE DYING FROM HUNGER。

    SUICIDE, DOMESTIC VIOLENCE AND ALCOHOL ABUSE IS RISING。

    HOME DEATHS ARE INCREASING。

    150 000 PEOPLE DIE EVERY SINGLE DAY FROM OTHER CAUSES。

    1.8 PEOPLE DIE EVERY SECOND AND 4.3 BABIES ARE BORN EVERY SECOND。

    MILLIONS WILL DIE FROM CONSEQUENCES BUT NOT THE VIRUS。

    TEN MILLION PEOPLE DIE PER YEAR ON EARTH FROM FAMINE ALONE。

    THE WORLD HAS GONE TOTALLY MAD。

    THE FOLLOWING HAS INCREASED DUE TO BEING LOCKED UP AND FEAR。

    ANXIETY
    DEPRESSION
    VIOLENCE
    THEFT
    SUICIDE
    ALCOHOL ABUSE
    FAMINE
    MENTAL ILLNESS
    MILLIONS HAVE LOST THEIR JOBS
    MILLIONS CANNOT BUY FOOD
    THE LIST IS ENDLESS AND YET YOU CONTINUE WITH THIS STUPID LITTLE VIRUS。

    OLD ANIMALS DIE, STRONG ANIMALS SURVIVE。

    SWEDEN WITH NO LOCKDOWN IS DOING FINE COMPARED TO OTHER NATIONS。

    WHEN IS THIS ABSOLUTE MADNESS GOING TO STOP?

    PEOPLE HAVE BEEN BRAINWASHED AND HAVE ABSOLUTE TUNNEL VISION。

    STUPIDITY AND FEAR FUELED BY THE MEDIA IS OUR BIGGEST THREAT BY FAR。

    WILL IT TAKE ANOTHER REVOLUTION IN AMERICA TO WAKE PEOPLE UP?

    SCIENTISTS AND RESEARCHERS SIT IN THEIR LITTLE LABS CALCULATING ALL KINDS OF SHIT ABOUT SHIT BUT THEY HAVE NO IDEA ABOUT THE REAL WORLD。

    THE WORLD IS HEADING FOR THE BIGGEST CRISIS IN HISTORY NOT BECAUSE OF THE VIRUS BUT ABSOLUTE STUPIDITY。

    NO WORK, NO MONEY, NO FOOD EQUALS MILLIONS OF DEATHS AND DAMAGE LAST SEEN IN WW2.

    IT IS NOT ROCKET SCIENCE。

  • This report reflects the current powerful bias of the coronavirus spread narrative in the U.S. Much of the hand wringing it portrays about the new SARS-CoV-2 antibody test, should be done for the PCR test, too, that is essentially treated as perfect now, with little concern for its undisclosed false-positive rate. Hopefully the scrutiny suggested here will be used to review what we have allowed with the PCR test, too.
    The current spread narrative bias has led to a stampede of premature efforts to develop treatments and vaccines for a virus that, in the U.S., has not shown an increase in morbidity or mortality in the population that is supposedly the most susceptible to it. NY/NJ is the one exception to this assessment presently. However, as the anomaly and not the typical, we must consider that Gov. Cuomo’s intense mandates may play a role in this. Certainly, here in MA, the Globe is also reporting how Baker’s fear-mongering policies have precipitated the understaffing of MA nursing homes enmasse, with certainly deadly consequences.
    The spread narrative bias is further indicated by no attention being given to the importance of using the new (validated!) antibody test to perform an essential epidemiology evaluation that has been ignored much too long. Nothing about testing archival blood and plasma samples to investigate the possible presence of CoV-19 in the U.S. population before the Wuhan event. No matter what the answer, we need to know it yesterday! Needless to say, if it turns out that CoV-19 is a regular element of our common cold virus ecology, and now we are just aware of it for the first time, we can get back to our lives…just as they were before, but with a little more knowledge about them.

    • Thank you for this thoughtful response. I don’t know much about anything. I’m surprised to find myself so critical of professionals on Tuesday about a subject I didn’t know on Morning morning. So I appreciate the humble acknowledgements at the beginning and ending of your comment which recognizes 1) that we treat some things as Gospel (such as PCR tests) until we realize there’s a possibility that it is not and 2) the professionals and the public can stand to learn a lot on the nature of these illnesses and to be glad after all is said and done that a lot is learned. I am certainly not glad this illness has occurred but very many people are most conscious and cautious regarding their environment and hygiene. Many people too are humbled at their vulnerability in this “man-driven” world. Out of this general tragedy, those are still good things to gleam.

  • Given that many of the most serious cases of Covid-19 involve a cytosine storm that overwhelms the body, is it possible that any antibodies to the virus might trigger a similar response when the immune system encounters a future SARS-CoV-2?

  • How comes that in 80 contacts, where there is even direct contact ( those living in the same house ( spouse) and kids got tested negative while one member in the same house was tested positive with complications even

  • I took the covid test kit and it keeps coming up as invalid. What does that mean? I was told that I was positive and I dont have any symptoms of the virus now.

  • What about the folks in S. Korea who recovered, tested negative for the virus, then two weeks later started having symptoms again and tested positive for SARS-Cov-2?

    • “What about the folks in S. Korea who recovered, tested negative for the virus, then two weeks later started having symptoms again and tested positive for SARS-Cov-2?”
      This could be a false positive case: they thought they had the virus initially and recovered, but in fact they didn’t. Or it could be a false negative case: they thought that they had recoverered, but didn’t. Or it could be a false positive on the second time they tested positive.
      in science, it’s always important to keep in mind that experimental measurements have noise: you can see signal when there isn’t one, or you can miss a signal when there is one.

    • I think that’s what the last part of the article, “I’ve heard reports of reinfection or “reactivated” virus. What’s going on there?” is referring to.

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