What We Know and What We Don't About Coronavirus Immunity and Antibodies

Medical laboratory scientist, Alicia Bui, runs a clinical test in the Immunology lab at UW Medicine looking for antibodies against SARS-CoV-2, a virus strain that causes coronavirus disease (COVID-19) on April 17, 2020 in Seattle, Washington.  (Karen Ducey/Getty Images)

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.

“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.

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.

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This story was originally published by STAT, an online publication of Boston Globe Media that covers health, medicine, and scientific discovery.