The Truth About Antibody Testing For COVID-19 Immunity

I am asked almost on a daily basis if I would recommend antibody testing to see if one has antibodies against the COVID-19 virus. This week in JAMA, a lengthy article about antibody testing was published. I think it is important to present the true facts as there continues to be misinformation and falsehoods published daily that only causes confusion.

Early in the COVID-19 pandemic, developers designed SARS-CoV-2 antibody tests to detect whether people had been infected. Some experts thought the blood tests eventually would help to ease lockdowns. One idea was that those with antibodies likely would be immune to reinfection at least temporarily, allowing them to reenter society without putting themselves or others at risk. But as the pandemic unfolded, the concept of an immunity passport based on having antibodies didn’t pan out. The early consumer tests’ accuracy was unproven, making the results somewhat dubious. More fundamentally, the so-called correlates of protection were unknown. Which specific antibodies guarded against SARS-CoV-2 reinfection? How high did their levels need to be? And how long would they provide a reliable defense?

As the assays’ usefulness for individual patients became less clear and testing for active infections expanded, the public’s clamor for antibody testing waned. But for some, the arrival of COVID-19 vaccines revived their interest in serology. Could a simple blood test reveal whether the vaccine was working or, later, if it was time for a booster shot?

No, says the US Food and Drug Administration (FDA), which discouraged antibody testing as a do-it-yourself immunity check in a communication to the public and clinicians this past spring. A spokesperson for the agency reiterated the position in an email to JAMA in September. Yet many aren’t heeding the advice. A recent New York Times article described concierge clinicians who regularly test their clients for SARS-CoV-2 antibodies. And Florida-based Epitome Risk Solutions promises that the direct-to-consumer SARS-CoV-2 serology assay it sells for $170 “correctly identifies the number of neutralizing antibodies you have with 100% specificity” so that in “24-48 hours you’ll know if your immune system is still protecting you from COVID” after vaccination or infection.

The SARS-CoV-2 serology tests that eventually received FDA Emergency Use Authorization (EUA) have demonstrated high sensitivity and specificity, but that accuracy is for detecting antibodies. Their ability to predict protection against the virus based on those antibodies hasn’t been proven. Plus, the FDA cautioned that some tests detect antibodies the immune system likely produces only after natural infection with the virus. Depending on the assay, people who weren’t previously infected could test negative for antibodies despite having vaccine–induced immunity.

Therefore, the agency in its May 19 communication stated that “results from currently authorized SARS-CoV-2 antibody tests should not be used to evaluate a person’s level of immunity or protection from COVID-19 at any time, and especially after the person received a COVID-19 vaccination.” The problem isn’t simply that the tests weren’t designed to assess immunity, experts told JAMA. It’s also that the protective antibodies and their thresholds still haven’t been fully worked out.

In an email, Nicole Doria-Rose, PhD, a staff scientist and chief of the Humoral Immunology Core at the National Institutes of Health’s Vaccine Research Center, noted that antibodies that bind to the SARS-CoV-2 spike protein—particularly neutralizing antibodies—“do correlate with protection.” For example, higher titers were associated with increased protection in 2 phase 3 studies: one not yet peer-reviewed of the mRNA-1273 (Moderna) vaccine and another of the ChAdOx1 nCoV-19 (Oxford/AstraZeneca) vaccine. Still, she wrote, “it’s not a simple relationship—there is no clear titer at which you can say whether a particular person is protected.” What’s more, different neutralizing antibody thresholds, or even different immune responses altogether, may correlate with protection against asymptomatic, symptomatic, or severe disease.

Theel pointed to a recent study of breakthrough infections among 1497 fully vaccinated health care workers in Israel. The 39 workers who became infected after receiving their second dose of the BNT162b2 (Pfizer-BioNTech) vaccine had lower neutralizing antibody levels than their uninfected colleagues. Although antibody levels were associated with protection, the researchers were unable to pinpoint a threshold. None of the cases was severe, but antibodies obviously weren’t foolproof against the virus. “Individuals can have neutralizing antibodies and still get infected,” Theel said in an interview. “We know that higher antibody levels, specifically higher neutralizing antibody levels, are better. But we don’t know how high is high enough.”

Meanwhile, the laboratory tests haven’t been standardized. “That’s a problem when people say, ‘Okay, I want to go see if I should get a booster or not,’” Theel said. Some SARS-CoV-2 serology assays simply give a positive or negative result, without antibody values. Those that are quantitative use varying methods, detect different antibody classes, and report values using different units of measurement. According to Theel, if and when correlates and thresholds of protection are determined, the tests will need to be standardized and calibrated, as has been done with antibody tests for other vaccine-preventable diseases, including tetanus, diphtheria, and measles. So far, only one commercially available SARS-CoV-2 antibody test, from Ortho-Clinical Diagnostics, has been calibrated to the World Health Organization’s reference standard, she said.

What’s more, all antibodies bind but only some neutralize, and almost none of the authorized clinical tests distinguish between them. Although some studies have shown a correlation between levels of binding and neutralizing antibodies, they’re still an imperfect match.

Doria-Rose noted that measuring neutralizing antibodies requires a complex test that is run in only a few laboratories and hasn’t been scaled up for diagnostic use. The test sold through Epitome Risk Solutions’ subsidiary, FourthWall Testing, appeared to be an at-home version of the FDA-authorized GenScript cPass SARS-CoV-2 Neutralization Antibody Detection Kit, a surrogate assay that indirectly measures neutralizing antibodies. According to an FDA spokesperson, the cPass test does not have authorization for sample collection at home. And despite Epitome’s marketing hype, GenScript states that customers “should not interpret the results of this test as an indication or degree of immunity or protection from reinfection.”

For Paul Offit, MD, director of the Vaccine Education Center at Children’s Hospital of Philadelphia, there’s another strong argu