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How the body’s immune system tries to fight COVID-19

Vaccines have proven to be the best defense against a serious case of COVID-19: According to the Centers for Disease Control and Prevention, unvaccinated adults were about 13 times more likely to be hospitalized with the disease than vaccinated adults in late November.

But vaccines and the antibodies they generate are only one piece in the puzzle when it comes to fighting coronavirus. The immune system has other sets of defenders that find and kill infected cells and then maintain a live record of the virus, bacteria or other infectious agents so that the body can react faster the next time it is under attack.

And speed is crucial, said E. John Wherry, director of the University of Pennsylvania's Institute of Immunology.

"During an infection, it's a race," where the immune system presses on to stop the virus before it has multiplied to a disabling level, Wherry explained. This is especially true of the Omicron variant, which replicates at an alarming rate.

Here is an overview of how the body's immune system works and how it has been tested by Omicron:

B cells, T cells, NKs and DCs

Think of the immune system as having three layers of defense. One tries to keep enemy molecules - pathogens - on the outside and look inside. That work is done by the skin, the body's largest organ, whose cells can defeat invaders and warn the rest of the immune system that problems are on the way.

The second layer tries to stop the invaders once they have entered the body but before they have infected cells. This is where the bone marrow comes in. It produces "natural kills" - or NK cells as well as B cells, those that generate antibodies. Both are types of white blood cells or lymphocytes.

A colored electron micrograph of a natural killer cell.

We have "natural killer" or NK cells in the tonsils, lymph nodes and spleen, ready to fight any attacker.

(National Institute of Allergy and Infectious Diseases)

NKs got their name because they are not produced in response to an attacker; they are already present and ready to kill cells that do not belong in the body, such as tumor cells. NKs are part of what researchers call the innate immune system. According to researchers at Rockefeller University, NKs hang out in the tonsils, lymph nodes and spleen and then rush to confront the attackers where they appear.

Antibodies, on the other hand, are generated after an attacker is detected, making them part of what is known as the adaptive immune system. They bind to specific pathogens, which are then ingested and destroyed by other members of the immune system team.

In the case of SARS-CoV-2, the coronavirus that causes COVID-19, different antibodies bind to different parts of the virus, including the tip protein that the virus uses to penetrate a healthy cell and replicate itself over and over again. . If the tip protein is chewed up by an antibody, the virus cannot infect a cell.

It is conceivable that if you are newly vaccinated or boosted, you may have so many antibodies ready to attack that you will not be infected, said Trudy U. Rey, a virologist and science communicator. This is called "sterilizing immunity", although in the case of COVID-19 it would be only temporary. But that is not the goal of a COVID-19 vaccination. (More on that later.)

A more common scenario is that a certain amount of invading coronavirus gets past the antibodies. Cells have some innate defenses that can defeat the invaders, but SARS-CoV-2 has been shown to be able to avoid them. Fortunately, there is a third line of defense: T cells.

A color image of a T cell seen with a scanning electron microscope.

T cells in the upper thymus gland of the breast can detect pathogens after entering a cell where antibodies cannot find them.

(National Institute of Allergy and Infectious Diseases)

Like B cells and NKs, T cells are white blood cells that originate from the bone marrow, but they develop in and emanate from the thymus gland in the upper part of the breast. Their special power is their ability to detect viruses and other bacteria after they enter a cell where they are hidden from antibodies.

T cells come in two basic flavors: killers and messengers. The lethal version detects cells that have been infected with a virus and then kills them (by releasing a toxic version of a granulate called a cytokine) to prevent the virus from replicating. Wherry called this "destroying the village to save the nation." The messengers warn B cells of the new threat, and they respond by making antibodies designed to counter this threat.

It is a complex molecular dance with many other vital parts, including dendritic cells or DCs, that act as sentinels and cure the immune system. The DCs tell the T cells, among other things, what specific threat they must hunt and kill.

Once an infection is overcome, the immune system unwinds naturally and releases some antibodies and T cells. However, some T cells survive as memory T cells, ready to respond by killing infected cells and stimulating the production of new antibodies if the same attacker returns. And some B cells remain as memory cells to handle antibody production.

How vaccines primer the pump

Daniela Weiskopf, an immunologist at the La Jolla Institute for Immunology, said the body's adaptive immune system is very specific. That's good, she said, for "otherwise you would be in a constant state of inflammation." But it also means that antibodies and T cells are limited in what they can bind to or recognize. They must get to know their enemy before they can defend themselves against it.

A pharmacist prepares a syringe with the Pfizer-BioNTech COVID-19 vaccine.

Vaccines help us create antibodies and T-memory cells that recognize a virus and infected cells, so our immune system responds faster. Booster shots amplify this process.

(Gary Coronado / Los Angeles Times)

Vaccination, Weiskopf said, "is nothing but training the immune system without getting sick." COVID-19 vaccines generate antibodies that recognize the tip protein and other properties of SARS-CoV-2, along with memory T cells that can recognize cells that have been infected with the virus.

The more often your immune system sees a threat, Weiskopf said, "the more detailed it makes the answer." The faster too - once your system has these memory cells, she said, it can respond "much, much, much faster" the next time the same pathogen knocks. Hence the value of booster shots.

As viruses mutate, the parts to which antibodies bind may change. If they change too much, the antibodies will not be as good at binding to them and preventing them from entering the cells. This appears to be the case with the Omicron variant, which has several mutations affecting its tip protein.

But Omicron's mutations have not attenuated the response from T-memory cells, Weiskopf, Rey and Wherry said. This is because the mutations have not had much effect on the parts of the virus that T cells recognize.

In addition to that, Weiskopf said, each person has several different T cells, and their T cells are different from everyone else's. If a new variant by a rare accident managed to dodge all your T-memory cells, she said, it would still encounter plenty of efficient T-cells in the rest of the population.

Rey added that much of the talk of "declining immunity" is based on the declining presence of what are known as neutralizing antibodies, which can block the virus from binding to a cell and replicating. But other types of antibodies remain in the system.

"There have even been studies that have shown that just because an antibody does not neutralize does not mean it can do nothing," Rey said. For example, she said that by binding to only some parts of the tip protein, it can cause other immune cells to participate in the fight.

COVID-19 and unvaccinated

If you have never been exposed to SARS-CoV-2 or COVID-19 vaccines, coronavirus will not encounter any custom antibodies or T cells on the way to your respiratory system. Although your immune system is healthy, it takes a week to 10 days to turn undifferentiated T cells into killers and get them in place to confront infected cells, Wherry said. During that time, the virus replicates exponentially and spreads throughout the body.

But if you've been immunized, you can have killer T cells ready in four days or less, Wherry said. That lead makes a huge difference in preventing an infection from raging out of control.

Non-vaccinated people may still have some T cells ready to defend at the first sign of an infection, Weiskopf said. Researchers found some T cells that responded to SARS-CoV-2 in samples taken from humans who had never been exposed to the virus, she said. These cells - created in response to the common cold, which can be caused by other forms of coronavirus - helped speed up and strengthen the immune response, she said.

Not everyone who has had a cold will want T cells with this kind of versatility, she added. However, the discovery suggests to some researchers that researchers may be able to devise a vaccine that is capable of attacking any variant of the coronavirus by causing the immune system to make T cells like these. (Dr. Patrick Soon-Shiong, owner of The Times, has another company investigating this possibility.)

In any case, the more a virus replicates in the body, the greater the response from killing T cells. That raises another issue, Wherry said: T cells can not keep killing tissue forever; at some point, the system must switch to repair mode. That's why there are regulatory T cells to "act as a counterweight to this whole system" that help rein in the killer cells, he said.

Sometimes, however, the system does not turn the "off" switch fast enough. Wherry said that for some severely ill COVID-19 patients, the virus spreads to many places inside their bodies, and a large number of killer T cells flood their systems with "very harmful" cytokines. Clinicians are helping these patients by suppressing their immune system to dampen this response, he said.

Unvaccinated people recovering from COVID-19 will need antibodies and memory cells to protect against the next encounter with SARS-CoV-2. But Rey said a person's immune response is much better after vaccination than with the "natural immunity" that an infection provides. The re-infection rate for unvaccinated people who have only natural immunity is twice as high as the infection rate for people who have been vaccinated, she said.

Immunological age

During the pandemic, older people have tended to suffer far more severe consequences of COVID-19 than children have. There seem to be at least a few reasons for this.

Rey pointed to a study led by researchers at the Charité-Universitätsmedizin Berlin, who found certain innate defenses in children's nasal passages that can help them stop the virus before it can replicate wildly.

"This type of congenital immune response appears to be delayed in older adults, and in an attempt to 'catch up', it can result in excessive inflammation and thereby ultimately cause more serious damage," she wrote in a blog post.

Wherry said the immune system is susceptible to the effects of aging, just like the rest of the body.

"One of the most important things is that you lose the production of these new, what we call 'naive' T cells," he said. These act as blank boards, ready to learn new threats. Late in life, Wherry said, "they become a much smaller part of the cells you can call to action."

As we get older, problems also appear in other elements of the immune system, he said. All in all, he said, "these problems make it harder for the immune system to get out of the gate."

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