It’s months into the coronavirus pandemic and public health officials still don’t know how many people have actually contracted the culprit, SARS-CoV-2. In many countries testing capacity has lagged behind the spread of the virus. Large numbers of people have developed COVID-19 symptoms but have not been tested, and the vast majority of people who had the virus but never developed symptoms and therefore were not tested, are not reflected in official statistics.
Federal and state governments, companies, and research groups are now racing to develop antibody tests to shine a light on the true spread of SARS-CoV-2. While PCR tests currently used to diagnose cases detect the virus’s genetic material, antibody tests can screen for virus-attacking antibodies that are formed shortly after an initial infection. Those antibodies usually linger in the blood long after the virus is gone. One such antibody, or serological, test was given emergency use authorization by the Food and Drug Administration in early April, and a number of other groups are making more tests, and in some cases even deploying them.
The National Institutes of Health has launched a study to detect antibodies in order to gather data for epidemiological models. And a recent survey of residents in a German town was one of the first to use an antibody test among the public, reporting that 14 percent of people there were likely to have been infected with SARS-CoV-2 due to the presence of antibodies.
It’s not clear yet whether milder or asymptomatic cases will develop antibodies.
Policymakers have another reason to scramble to deploy antibody tests: they could indicate whether someone is immune to SARS-CoV-2. With around 3 billion people globally under lockdown, pressure is mounting to re-open national economies. In recent weeks, several politicians have proposed the idea of “immunity passports” or “immunity certificates” to identify people who have had the virus and therefore gained immunity to it and could re-enter the workforce again. Officials in Germany, the UK, Italy, and the US are already discussing such proposals.
The success of such a program hinges on whether everyone who has contracted SARS-CoV-2 actually develops antibodies, whether those antibodies protect against secondary infections, and if so, how long the antibodies hang around in the body. So far, scientists don’t have firm answers to any of these questions. Although antibody surveys of communities around the world could yield information that is crucial to understanding the spread of the pathogen, some consider the idea of “immunity passports” premature.
“People understand that [it] would be very powerful, if we could say, ‘you’re immune now, and you can return to work,’ or, ‘you could safely return to your family if you’re a healthcare worker,’” notes Stanford University and Chan Zuckerberg Biohub immunologist Taia Wang. But there are a lot of unknowns, she cautions. “To get to that point where we’ll know with some certainty what the antibody response means, we just have to collect [more] data.”
The antibody response to SARS-CoV-2
There is solid evidence emerging that COVID-19 patients are developing antibodies to the virus, as the human body does for most infectious pathogens. Kara Lynch, a clinical chemist at the University of California, San Francisco, and her colleagues have been testing around 500 serum samples from roughly 100 COVID-19 patients who were treated at the Zuckerberg San Francisco General Hospital, where Lynch co-directs a clinical chemistry laboratory. The team is using an assay that was applied to samples from patients in China and picks out antibodies that target a protein-binding site of the virus’s spike protein.
“What we’re seeing is that patients are [developing antibodies] anywhere from two to about fifteen days” after developing symptoms, Lynch says. In most patients, the antibody response is broadly reminiscent of the typical reaction to many other pathogens: first, a flush of IgM, a generic type of antibody, followed later by the longer-lasting and more-specific IgG antibodies. Other studies have yielded similar results and suggest that antibodies circulate in the blood of COVID-19 patients for at least two weeks.
The data are skewed toward severe cases, however, as most of the subjects that Lynch’s group tested had been hospitalized, and it’s not clear yet whether milder or asymptomatic cases will develop antibodies, Lynch notes. “I’m optimistic [but] I’m still a little bit cautious.”
Recently, researchers at Fudan University in Shanghai examined the plasma from 175 COVID-19 patients who recovered after mild symptoms. The vast majority of patients developed antibodies that targeted the spike protein around 10 to 15 days after symptom onset, the scientists reported in preprint. The report generated some concern on social media because the researchers couldn’t detect antibodies in 10 of the patients. That could have been a fluke, notes Shane Crotty, an immunologist at the La Jolla Institute for Immunology. It’s possible that that the PCR test for SARS-CoV-2 was a false positive, and those people in fact had a different respiratory infection.
It’s also possible that some patients simply don’t develop antibodies.
While years ago, “pretty much everybody infected with SARS made an antibody response,” Crotty says, that did not hold true for MERS. Some studies on MERS have found that PCR-positive mild or asymptomatic infections can cause varied immune responses that are undetectable in antibody assays. Lynch points out that in her cohort, there are three patients who have not yet developed antibodies even though it’s been 17 days or more since their symptoms started. Some of those patients were immunocompromised, “but there are examples of healthy individuals that did not generate antibodies,” she writes in an email to The Scientist.
In many viral infections, “the magnitude of an antibody response correlates well with how big the infection was,” Crotty notes. In other words, severe infections are more memorable to the immune system. Interestingly, the preprint on COVID-19 patients in China also reported a positive correlation between the patients’ antibody levels and their age, which in turn, is known to correlate with the severity of COVID-19 symptoms. If it were the case that milder SARS-CoV-2 infections are less likely to produce a detectable antibody response, that may reduce the usefulness of antibody tests in detecting asymptomatic or mild cases.
Are the antibodies actually protective?
Overall, Crotty says he finds the data from the Chinese study robust and encouraging, noting that the researchers had extracted the patients’ antibodies and conducted in vitro experiments to see if they prevented SARS-CoV-2 from entering human host cells. “They tested 175 people and almost all of them had really nice antibody responses and really nice neutralizing responses,” he says. This is consistent with a recent study in macaques, and some other studies that have extracted antibodies from COVID-19 survivors and also found those antibodies were neutralizing, that is, capable of binding to the virus and its blocking entry into host cells.
Those experiments are important, and the results encouraging, but it’s still a mystery whether neutralizing activity in vitro correlates with protection in vivo for SARS-CoV-2, Wang notes. And even if antibodies aren’t neutralizing—and don’t physically stop the virus from entering host cells—they can still play important roles in immunity by recruiting other components of the immune system. “In vivo, there are many more cells that come into play to clear virus, to clear infected cells,” says Wang. It may well be that other components of the immune system—such as helper T cells or killer T cells—also play important roles in protecting against SARS-CoV-2.
On the whole, Wang finds it too early to say what the role of antibodies is for SARS-CoV-2. “We have no idea if production of antibodies during a primary infection, for example, has any role in clearing virus during that infection, or for that matter, we don’t have any good data on whether antibodies produced during an infection are protective against a second infection,” she says. And even if they were protective, they may not be protective for everyone. “Antibody responses can vary tremendously from person to person.”
How long will antibody levels last?
Ideally, the human antibody response to SARS-CoV-2 would mirror that to measles. A single exposure is enough to generate robust, neutralizing IgG antibodies that circulate in the blood throughout life and provide lifelong protection, Crotty notes.
But immune responses to coronaviruses appear to differ. Studies of survivors of the 2003 SARS epidemic suggest that concentrations of neutralizing antibodies lasted for up to three years. Although, a recent yet-to-be-peer-reviewed preprint reports to have found neutralizing antibodies in SARS survivors 17 years after the epidemic.
At this point, all the antibody tests are really just functioning to help us gather data. And then at a certain point, I think the numbers will be large enough that we’ll be able to do a risk assessment.—Taia Wang, Stanford University and Chan Zuckerberg Biohub
In MERS, the levels of neutralizing antibodies have been observed to fade after three years. For the less deadly, cold-causing coronaviruses, neutralizing antibody levels also fall off in that two-to-three-year range. One 1990 study of fewer than a dozen volunteers found that people exposed twice to the coronavirus 229E developed much milder symptoms compared with people getting exposed the first time, suggesting that re-infection could occur, but with reduced symptoms.
Antibody levels for coronaviruses might be fading over time because the antibody-supplying cells “are not maintained for decades like with other pathogens,” notes Vineet Menachery of the University of Texas Medical Branch in a recent Twitter thread. However, how long those cells or the antibodies they produce persist in the blood is not a surefast indicator of how long someone is immune to secondary infection, he stresses.
That’s because an initial encounter with a pathogen not only prompts the antibody-supplying cells, called plasmablasts, in the blood to turn into plasma cells that generate specific antibodies. It also stimulates memory B cells. These memory B cells can last decades, hiding out in lymph nodes, the spleen, bone marrow, and the lung, while some circulate in the blood. Upon re-infection by the same pathogen, they swing back into action, taking two-to-four days to differentiate into cells that secrete neutralizing antibodies, Menachery explains. He speculates that one might be able to acquire a second SARS-CoV-2 infection once the initial burst of neutralizing antibodies fades—which he reckons might be after one or two years—but the second infection will be milder thanks to immune memory.
Memory B cells could serve as an alternative indicator of immunity, in addition to antibody levels, but memory B cells are harder to isolate. In one 2011 study, researchers did manage to isolate memory B cells from recovered SARS patients six years after the Hong Kong epidemic. Interestingly, the team found that the memory B cells did not react to proteins from the live virus, but memory T cells from 60 percent of the recovered patients did.
“Different parts of the immune system are more important in protection from different diseases,” Crotty says. For many infectious diseases, antibodies as well as T cells can contribute. “If you have a person who makes a lousy antibody response, but they made a good [T helper cell] and [T killer cell] response, they’d probably be okay. And vice versa.”
What this means for immunity passports
Many researchers, including the director of the National Institute of Allergy and Infectious Diseases, Anthony Fauci, say they think that based on what’s known from most other infectious diseases, it’s likely that people will have at least some form of short-term immunity to SARS-CoV-2. Fauci told The Daily Show’s Trevor Noah in March that he’d be “willing to bet anything that people who recover are really protected against reinfection.” It helps matters that SARS-CoV-2’s RNA genome appears to be relatively stable, meaning that the immune system may have a better chance of developing longer-lasting immunity compared to frequently-mutating influenza viruses, for instance, which require researchers to design new vaccines every year.
However, the question is whether antibodies alone will suffice in assessing immunity, and form the basis of “immunity passports” that determine who gets to leave quarantine and go back to work. “There’s nothing perfect about the decisions people are having to make. I’d guess that governments and large organizations are just going to have to make decisions about what is ‘good enough,’ and try and be clear to people [what the tests mean],” Crotty says.
Although it may be true that most first-time exposures to dangerous pathogens will result in protective immunity, it’s scientifically difficult to make the claim that any given person will be immune to the virus if they reach a certain score on an antibody test—not to mention, such predictions carry various legal and ethical issues. It could also encourage dangerous behavior, such as refusal to wear masks or intentionally trying to get sick in order to re-enter normal life, he says.
Regardless of immunity, “with most diseases, if you get exposed to enough virus, you’re going to get sick,” Crotty says—something that is supported by animal studies. And even if someone is immune to the virus, it’s not clear if that means they do or don’t still carry some amount of virus that could be spread to other people, Menachery notes. “In theory, a person could get infected, [and] spread [the] virus before their immune system stops the virus. This is less likely if you have high [neutralizing antibody levels] in your blood,” Menachery writes to The Scientist in an email. “We can’t rule out that immune people might carry virus, but the load of virus would be expected to be lower.”
There are other factors that govern whether the antibody tests will be a reliable proxy of whether someone is immune, such as the accuracy of the tests. It will take some time to get answers. Part of what takes time, Lynch notes, is “monitoring patients long term to see if the people who were previously positive or have antibodies get re-infected or not.”
The results of plasma therapies—which extract antibodies from recovered patients and administer them to patients battling severe forms of COVID-19—may offer some clues as to whether antibodies are protective, at least in the short term. One small study in China has yielded tentatively positive results.
Wang adds that she expects solid answers to come from large-scale epidemiological studies that investigate whether people who carry high levels of neutralizing antibodies in their blood are actually less likely to contract the virus again. “At this point, all the antibody tests are really just functioning to help us gather data. And then at a certain point, I think the numbers will be large enough that we’ll be able to do a risk assessment,” she says. That could then lead to answers for the most pressing questions: “Does the presence of IgG antibodies, for example, change your risk for infection? Does your risk go up, or does it go down? That’s the fundamental question that needs to be answered in order to know whether antibodies are going to be protective.”