Antibody tests may not paint complete picture, experts say

Your blood carries the memory of every pathogen you’ve ever encountered. If you’ve been infected with the coronavirus, your body most likely remembers that, too.

Antibodies are the legacy of that encounter. Why, then, have so many people stricken by the virus discovered that they don’t seem to have antibodies? Blame the tests. Most commercial antibody tests offer crude yesno answers. The tests are notorious for delivering false positives — results indicating that someone has antibodies when he or she does not.

But the volume of coronavirus antibodies drops sharply once the acute illness ends. Now it is increasingly clear that these tests may also produce false-negative results, missing coronavirus antibodies that are present at low levels.

Moreover, some tests — including those made by Abbott and Roche and offered by Quest Labs and LabCorp — are designed to detect a subtype of antibodies that doesn’t confer immunity and may wane even faster than the kind that can destroy the virus.

What that means is that declining antibodies, as shown by commercial tests, don’t necessarily mean declining immunity, several experts said. Long-term surveys of antibodies, intended to assess how widely the coronavirus has spread, may also underestimate the true prevalence.

“We’re learning a lot about how antibodies change over time,” said Dr. Fiona Havers, a medical epidemiologist who has led such surveys for the Centers for Disease Control and Prevention.

If the narrative on immunity to the coronavirus has seemed to shift constantly, it’s in part because the virus was a stranger to scientists. But it’s increasingly clear that this virus behaves much like any other.

A small number of people may not produce any antibodies to the coronavirus. But even in that unlikely event, they will have socalled cellular immunity, which includes T cells that learn to identify and destroy the virus. Virtually everyone infected with the coronavirus seems to develop Tcell responses, according to several recent studies.

“This means that even if the antibody titer is low, those people who are previously infected may have a good enough T-cell response that can provide protection,” said Akiko Iwasaki, an immunologist at Yale University.

T cells are harder to detect and to study, however, so when it comes to immunity, antibodies have received all of the attention.

The most powerful antibodies recognize a piece of the coronavirus’s spike protein, the receptor binding domain, or RBD. That is the part of the virus that docks onto human cells.

But the Roche and Abbott tests that are now widely available — and several others authorized by the Food and Drug Administration — instead look for antibodies to a protein called the nucleocapsid, or N, that is bound up with the virus’s genetic material.

The N protein is plentiful in the blood, and testing for antibodies to it produces a swifter, brighter signal than testing for antibodies to the spike protein. Because antibody tests are used to detect past infection, however, manufacturers are not required to prove that the antibodies their tests seek are those that actually confer protection against the virus.

Officials at the FDA did not respond to requests for comment on whether the two tests target the appropriate antibodies.

But some reports now suggest that antibodies to the viral nucleocapsid may decline faster than those to the RBD or to the entire spike.

Dr. Beatus OfenlochHaehnle, who heads immunoassay research at Roche, defended the company’s antibody test. His team has tracked N antibodies in 130 people who had mild to no symptoms and has not yet seen a decline, he said.

“There is some fluctuation but no waning at all,” he said. “We have a lot of data, and we do not rely anymore on theory.”

The N antibody can be a decent proxy for immunity, Ofenloch-Haehnle added.

He also pointed to a study by Public Health England that suggested the Abbott and Roche tests seemed to perform well up to 73 days after symptom onset.

“I think we should be careful to jump to conclusions too soon,” he said.