What Does ‘Protection’ against COVID Really Mean?

More than two years into the COVID-19 pandemic, scientists are still scratching their heads over a basic question: is there something they could measure to tell if people are protected?

Measures of protection areindicators that a person is unlikely to get seriously ill if they are exposed to a pathogen such as the one that causes COVID-19.

The data so far has focused on one thing: neutralizing antibodies. White blood cells called B cells help defend against future disease by blocking viral entry into cells.

It is short-lived. A few months later, the levels start dropping again. Wherry of the University of Pennsylvania says that hospitalizations are not going up as fast as they are going down.

He and other experts suggest that memory T cells are a key source of protection. These immune cells keep mild symptoms from getting worse. They accomplish this by recognizing pieces of invaders and using their immune systems to destroy them.

T cell levels can be measured in large numbers of people after an illness. Wherry and dozens of other researchers, physicians and biotech representatives sent a letter to the FDA urging them to better assess immunity.

The need for many doses is not practical at a population level. Ofer Levy, one of the letter's signees, said in a recent Harvard Medical School press briefing that we need vaccines that give broader protection and last longer. Levy is the director of the Precision Vaccines Program at Boston Children's Hospital and serves on the FDA's Vaccines and Related Biologics Products Advisory Committee.

T cells are able to recognize a broad set of targets. T cells detect not only snippets of spike, but a wide range of other things. Each segment is presented on the cell surface by a set of scaffolding molecules that are different for each individual. Hla typing can be used to match patients and donors for blood or marrow transplants.

Brianne Barker, an immunologist at Drew University, says that each person's T cells are different because of their scaffolding. T cells are less vulnerable to viral evolution because of the scaffolding process. Even if some of the viralProtein fragments targeted by T cells have evolved to evade immune attack, others remain unchanged as targets. If the virus tries to evade your T cells and then gets transmitted to me, all that evolution has done is not useful.

Research supports this up. Scientists at the La Jolla Institute for Immunology analyzed blood from 96 adults after they received a COVID vaccine. T cell responses remained strong even after six months after vaccination, but levels of neutralizing antibodies had fallen substantially.

In another study, people showed high-quality T cell memory no matter how many times they had been exposed to the virus. The T cells did not succumb to exhaustion, a state that can arise with chronic stimulation, and that some scientists feared might occur with repeated vaccinations. Nature Immunology published the findings on April 5.

It is very hard to prove that T cells are helping protect against COVID, for all that has been demonstrated so far.

In one study, scientists collected blood from a group of macaques that had been exposed to the disease and found that they were able to resist subsequent infections. The recipients would fare worse if the researchers deplete the T cells before transfer. Small human studies show that cancer patients with impaired immune responses have better survival rates if they have more T cells.

Immunology still needs more answers. How long do memory T cells stay in the bloodstream? Wherry says they don't know how many are needed because they aren't measuring memory T cells at scale.

Wherry's lab has done deep analyses of immune responses in 60 to 80 vaccine recipients for more than a year, even in the absence of large-scale monitoring. The data is intriguing, but there is no statistical power to know if they got infections because their T cells were low or because they were engaging in high-risk behavior.

Wherry says it would take tens of thousands of people to get those answers. The analyses in each person could be simpler with that larger cohort.

T cells are more difficult to study than antibodies. The process of measuring the SARS-CoV-2-specific antibodies can be automated with the help of robots. The process of sterilizing blood samples and culturing the cells requires several hours of work by a lab technician. T cell protocols are more involved than they used to be. Doing the analyses at a large scale would be hard to control and expensive.

The main motivation for measuring T cell responses is to guide decision-making for improving the vaccines. We already have reasonable ideas about what to do, and we should just do them. This could be done by including additional nonspike antigens in future vaccine formulas.

A streamlined T cell testing process is being worked on by researchers. Wherry explained several new approaches to measuring T cells in a March 24 Science Immunology viewpoint article. One is a test that can detect T cells in blood samples by squirting them into tubes with bits of the SARS-CoV-2 proteins. Another approach, which is more expensive but could be scaled up more easily, uses the same technology to detect T cells in whole blood samples as the more cumbersome method of measuring T cells in tubes or dishes.

Wherry says the letter to the FDA got an "enormous response" from many who agreed T cell measurements should be essential for future vaccine studies. I think there is some movement.