His blood carries the memory of every pathogen he has found. If you’ve been infected with the coronavirus, your body probably remembers it, too.
© Frederick Florin / Agence France-Presse – Getty Images
A pharmacist who administered a coronavirus antibody test in France last week.
Antibodies are the legacy of that encounter. Why, then, have so many people affected by the virus found that they don’t seem to have antibodies?
Blame the evidence.
Most commercial antibody tests offer crude yes or no answers. The tests are notorious for delivering false positives, results that indicate someone has antibodies when he or she does not.
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But the volume of antibodies against the coronavirus drops sharply once the acute illness ends. It is now increasingly clear that these tests can also produce false negative results, lacking antibodies to the coronavirus that are present at low levels.
In addition, some tests, including those conducted by Abbott and Roche and offered by Quest Labs and LabCorp, are designed to detect a subtype of antibodies that do not confer immunity and may decrease even faster than the type that can destroy the virus.
What that means is that a decrease in antibodies, as evidenced by commercial tests, does not necessarily mean a decrease in immunity, several experts said. Long-term antibody surveys, aimed at evaluating how widely the coronavirus has spread, may also underestimate the true prevalence.
“We are learning a lot about how antibodies change over time,” said Dr. Fiona Havers, a medical epidemiologist who has conducted such surveys for the Centers for Disease Control and Prevention.
If the narrative about immunity to the coronavirus seems to have constantly changed, it’s partly because the virus was a stranger to scientists. But it is increasingly clear that this virus behaves like any other.
This is how immunity to viruses generally works: The initial encounter with a pathogen, usually in childhood, surprises the body. The resulting disease can be mild or severe, depending on the dose of the virus and the child’s health, access to medical care and genetics.
A mild illness can trigger the production of only a few antibodies, and a severe illness many more. The vast majority of people who become infected with the coronavirus have few or no symptoms, and those people can produce a milder immune response than those who become seriously ill, Dr. Havers said.
But even a minor infection is often enough to teach the body to recognize the intruder.
After the battle is over, the globe-shaped cells that live in the bone marrow constantly pump a small number of specialized killers. The next time, and every time after that, the body meets the virus, those cells can mass-produce antibodies in a matter of hours.
The mnemonic response grows stronger with each encounter. It is one of the great miracles of the human body.
“Whatever your current level is, if you become infected, your antibody titers will go up,” said Dr. Michael Mina, an immunologist at Harvard University, referring to antibody levels in the blood. “The virus will never have a chance the second time.”
A single drop of blood contains billions of antibodies, all on the lookout for their specific goals. Sometimes, as can be the case with antibodies against coronavirus, there are too few to obtain a positive signal in a test, but that does not mean that the person examined does not have immunity to the virus.
“Even if your antibodies drop below the detection limits of our instruments, it doesn’t mean your ‘memory’ is gone,” said Dr. Mina.
A small number of people may not produce antibodies against the coronavirus. But even in that unlikely event, they will have so-called cellular immunity, which includes T cells that learn to identify and destroy the virus. Virtually everyone infected with the coronavirus appears to develop T-cell responses, according to several recent studies.
“This means that even if the antibody titer is low, people who are previously infected can have a T-cell response good enough to provide protection,” said Akiko Iwasaki, an immunologist at Yale University.
However, T cells are more difficult to detect and study, so when it comes to immunity, the antibodies have gotten all the attention. The coronavirus carries various antigens (proteins or parts of a protein) that can cause the body to make antibodies.
The most potent antibodies recognize a portion of the coronavirus spike protein, the receptor binding domain, or RBD. That is the part of the virus that attaches to human cells. Only antibodies that recognize RBD can neutralize the virus and prevent infection.
But the Roche and Abbott tests that are now widely available, and several others authorized by the Food and Drug Administration (FDA), look for antibodies against a protein called nucleocapsid, or N, that is bound to the material virus genetics.
Some scientists were surprised to learn of this choice.
“God, I didn’t realize that, that’s crazy,” said Angela Rasmussen, a virologist at Columbia University in New York. “It’s kind of weird to design a test that doesn’t look for what is believed to be the primary antigen.”
Protein N is abundant in the blood, and the antibody test produces a faster and brighter signal than the spike protein antibody test. However, because antibody tests are used to detect past infections, manufacturers are not required to demonstrate that the antibodies they seek are those that actually confer protection against the virus.
Food and Drug Administration officials did not respond to requests for comment on whether the two tests point to the appropriate antibodies.
There is another wrinkle in the story. Some reports now suggest that antibodies to the viral nucleocapsid may decrease faster than those of RBD or whole-ear, the really effective ones.
“Most people undergo anti-N antibody tests, which tend to decrease more rapidly, and therefore may not be the most appropriate test for observing neutralizing capacity,” said Dr. Iwasaki.
In the United States, millions of people have taken the Roche and Abbott tests. LabCorp has only performed over two million antibody tests performed by the two manufacturers.
Quest is based on tests conducted by Abbott, Ortho Clinical, and Euroimmun. Quest declined to disclose what proportion of the 2.7 million tests it has deployed so far were conducted by Abbott.
Dr. Jonathan Berz, a Boston physician, tested positive for the virus in early April, but felt well, apart from a sore throat. His wife was sicker, and despite various negative diagnostic tests, she remained ill for weeks.
“Initially, we felt like a family that, ‘Oh, wow, we got sick, unfortunately,'” said Dr. Berz. “But the bright side of that is that we are going to have immunity.”
In early June, the couple and their two children took Abbott’s antibody tests processed by Quest. All four were negative. Although Dr. Berz knew that immunity is complex and that T cells also play a role, he was disappointed.
As a doctor at a Covid-19 clinic, he had always acted like he was at risk for infection. But after seeing the antibody results, he said, “My anxiety level just increased.”
An Abbott spokeswoman said the test had 100 percent sensitivity 17 days after symptoms began, but did not provide information on sensitivity beyond that time.
Dr. Beatus Ofenloch-Haehnle, who heads the immunoassay research at Roche, defended the company’s antibody test. His team has tracked N antibodies in 130 people who had mild or symptom-free symptoms and have yet to see a decrease, he said.
“There is some fluctuation, but it doesn’t decrease at all,” he said. “We have a lot of data, and we no longer trust the theory.” Antibody N may be a decent proxy for immunity, added Dr. Ofenloch-Haehnle.
He also noted a study by Public Health England suggesting that the Abbott and Roche tests appeared to work well up to 73 days after symptoms onset. “I think we should be careful to jump to conclusions too soon,” he said.
Other experts also called for caution. Without more information about the significance of the antibody test results, they said, people should do what Dr. Berz did: act as if they had no immunity.
There is still no definitive information on what levels of antibodies are necessary for immunity or how long that protection can last. “I think we are getting closer and closer to that knowledge,” said Dr. Iwasaki.
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