How protected are we against Covid-19? Scientists search for a test to measure immunity

By Tasnim Ahmed, CNN

In 2010, doctors told Ben Sobieck, now 37, that his kidneys were inexplicably failing. Shortly after, he had a kidney transplant and started on the lifelong medications that weaken his immune system to keep his body from rejecting the donor organ. They never figured out what caused Sobieck’s kidney failure. But a decade later, he confronted another threat to his health: the Covid-19 pandemic.

“I am on immunosuppressants that make me more vulnerable for serious Covid complications,” said Sobieck, 37, who lives in Minnesota. “If you’re immunocompromised, you may not have a very good response to the [Covid-19] vaccine.”

Seeking evidence that his immune system was working the way it should, Sobieck made an unusual request: He asked his nephrologist to do a blood test that gives a rough measure of antibodies, a type of protein the body creates in response to an infection or vaccine. Antibody titers reveal the concentration of a specific antibody found in someone’s blood.

Millions of Americans — not just those with weakened immune systems — are wondering about their protection after a winter of booster shots and Omicron infections. As mask mandates are lifted and restrictions removed in a step toward normalcy, a test to measure immunity would be a powerful tool to measure individual risk.

“The biggest reason I wanted to get my antibody titer checked is because I don’t know how to assess risk,” Sobieck said. “Anyone who is immunocompromised, from the beginning of this pandemic right through today, has very few tools to assess risk: if they’re going to leave the house, when they’re going to leave the house, how to interact with other people, which situations are OK.”

Sobieck had his antibody levels checked after his second, third and fourth doses of the Moderna Covid-19 vaccine. Each result showed that he had more than the maximum number of antibodies the test could detect, indicating a robust immune response.

Although there is no specific guidance on how to interpret these results to figure out the level of protection against infection or disease, Sobieck felt reassured that his immune system was doing its job.

“More than 50% of transplant patients don’t have enough immune response to be protected, even if they get not two but three doses of the vaccine that we use in the general population,” said Dr. Dorry Segev, professor of surgery at New York University Langone Health. “For them, [an antibody titer] is a particularly poignant indicator of whether they have any protection at all.”

Segev, a transplant surgeon, advocates using tests that measure antibodies as a way to check immune protection in people who are immunocompromised.

Sobieck says the test results allowed him to make decisions for himself and his family.

“Knowing that I had the antibody response that I had meant that my son could go to in-person school. That’s huge,” he said.

Correlates of protection

About 95% of Americans 16 and older have antibodies against Covid-19 as of December, the most recent date that data is available, according to US Centers for Disease Control and Prevention estimates that use information from blood donors.

But it’s one thing to measure antibody levels. It’s another to measure how much they protect you against Covid-19.

The US Federal Drug Administration recommends against checking antibody levels at all because there’s no agreed-upon way to calculate how any given antibody level protects you from infection or severe disease. It may also give a false sense of security, the agency says.

“There aren’t good correlates of protection — something that says that this is the measurement that one needs to know how well they are protected,” Emory University virologist Mehul Suthar said.

Scientists are trying to fill the knowledge gap. Studies measure average antibody levels across a population to check vaccine efficacy, often using antibody levels months after vaccination to determine the need for a booster. One study in people who got the Moderna vaccine found that higher antibody levels after vaccination were associated with lower risk of Covid-19 infection.

But not all antibodies are created the same. Of all the antibodies that the body may make after infection or vaccination, only a fraction are considered “neutralizing antibodies,” meaning they can actively prevent infection.

Tests to measure antibodies can be either quantitative or qualitative. Quantitative tests provide a specific number, up to a certain point, of antibodies in the blood. Qualitative tests will indicate only whether certain antibodies were detected. Results of qualitative tests are either positive, negative or indeterminate for neutralizing antibodies.

When it comes to measuring neutralizing antibodies specifically, there is only one type of test that has been given emergency FDA authorization to detect them, and it is qualitative.

Several studies have demonstrated that neutralizing antibodies are a strong correlate for protection against symptomatic infection with Covid-19 and its variants, with boosters enhancing neutralization.

Peter Gilbert, professor of vaccine and infectious diseases at the Fred Hutchinson Cancer Research Center and lead author of the Moderna study, says these correlates are useful to apply to large groups. For example, scientists can use data from larger studies about the correlation between antibody levels and vaccine efficacy in adults to make a prediction about vaccine efficacy in children.

However, reaching conclusions based on one person’s antibody levels is far more limited. Gilbert compares individual antibody titers with a dipstick for oil in a car.

“Is the oil in a particular car low? Therefore, you need to go out and get some new oil,” or in this case, “get another shot of the vaccine,” he said. “For that purpose, the markers aren’t as good.”

This is largely due to how antibody levels vary from person to person. That correlate of protection also changes over time and with different coronavirus variants, which makes it hard to define a cutoff for antibody levels above which scientists can confidently say that someone is protected against Covid-19.

Natural vs. vaccine-acquired immunity

There’s a key difference in how antibody levels compare in people who have been vaccinated against Covid-19 versus those who have been infected with the coronavirus.

“Whereas a vaccine response, you may have all individuals that got the vaccine have high antibodies and sort of wane over time. … With infection, it’s remarkably heterogeneous. You’ll have lots of individuals that have very low and individuals that have very high antibody responses,” Suthar said.

According to Marion Pepper, an associate professor of immunology at the University of Washington, location matters, especially for the immune system.

“There are different immunological environments that make up your body. … When you see an immune response in your arm, it’s going to be a different cast of characters than if you see an immune response in your lungs,” Pepper said.

The immune system “is like lots of different neighborhoods, and each one has a different flavor,” depending on how an individual gets exposed to the coronavirus, whether it’s through a vaccine injected into the upper arm or through an infection to the respiratory system.

The CDC cites one study, which is in preprint and has not been peer-reviewed, that found antibody titers waned more quickly in vaccinated people than in people who had been infected. This may help explain the growing evidence of stronger and more durable vaccine efficacy in people who have immunity through both illness and vaccination, called hybrid immunity.

Although they may not provide the best way to tell how protected someone is, antibodies are useful to understanding how we compare people with natural immunity with those with vaccine-acquired immunity.

“We know that people who have this hybrid immunity are better protected. … So it also really begs the question, ‘which of these parameters is associated with that protection?’ ” said Pepper, who leads a lab that is studying hybrid immunity.

Observing levels of immune cells and antibodies as they change over time in different groups of people can help scientists learn how to create vaccines and time vaccinations to replicate the strength of hybrid immunity without the actual infections.

Just one piece of the immunity puzzle

Antibody levels are only one part of the immunity story. There are also T cells, a type of white blood cell that helps fight infection by killing cells that have been infected with a virus or by helping another type of white blood cell, the B cell, create antibodies.

So why do we focus so much on antibodies? “One aspect is that antibodies are probably one of the easiest to measure in the laboratory,” Suthar said.

“I think when you go to the T-cell-based assays, they’re much more challenging,” he explained. “Each individual has different what are called H.L.A. types that make it a bit more challenging to understand how well one’s T-cell responses are against this virus.”

Unlike antibodies, which are responsible for preventing an infection, T cells are responsible for destroying cells that are already infected. T cells may play a big role in vaccine efficacy against serious disease from more transmissible coronavirus variants, such as Omicron.

One study showed that while the highly mutated Omicron could evade previously neutralizing antibodies, T cells preserved a strong response.

“A memory B cell is a B cell that can get reactivated to make antibodies. It generally doesn’t do that unless a T cell tells it to go, so studying the T cells is going to be really important for understanding this immune protection,” Pepper said.

However, she said that the complexity of measuring T cells means there isn’t going to be a rapid test to measure them any time soon.

The Omicron surge has demonstrated that infection rates can still be high even after a vaccine or a prior infection. With the possibility of more variants forming, Covid-19 has become a moving target requiring a constantly evolving understanding of these correlates of protection.

“The biggest question I have and I think everyone else has is: What level of antibody equals protection from serious complications from Covid?” Sobieck said.

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CNN Chief Medical Correspondent Dr. Sanjay Gupta and Michael Nedelman contributed to this report.