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

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

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

“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.

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.

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.

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.

“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.