Last month Robert Duehmig and Bill Griesar—a married couple in their 50s who live in Astoria, Ore., and Portland, Ore.—were each relieved to get their second shot of the Pfizer-BioNTech vaccine for COVID-19. After the jab, Griesar felt nothing more than a sore arm. But for Duehmig, the effects were more pronounced.

“I woke up during that first night … with the chills and some body aches and just not feeling well by the morning,” Duehmig says. “I really didn’t want to do anything but sleep that day, which is about all I did.”

The unpleasant reaction was reassuring. “I do like to think that it means it’s working, that it’s kicking my system into gear,” Duehmig says. So was Griesar’s vaccine any less effective at protecting him from severe COVID-19?

Absolutely not, according to experts and data from clinical trials of the Pfizer vaccine. The latter indicated that the vaccine was generally 90 to 100 percent effective against COVID-19 in people regardless of their sex, age, race, ethnicity or preexisting conditions. Yet only about half of trial subjects experienced the sort of systemic reactions that Duehmig did.

“The big take-home message is that not having side effects, or [having] not as severe side effects, is no reason to worry,” says John Wherry, an immunologist at the University of Pennsylvania.

So why do some people get side effects and others do not? “It’s a great question, and we don’t know the answer,” Wherry says. But ultimately, the experience probably reflects the quirks of each person’s immune system more than it does the vaccine’s effectiveness.

“If you really feel it, you’re mounting a really vigorous immune response,” says Sujan Shresta, a viral immunologist at the La Jolla Institute for Immunology. “But at the same time, just because a person didn’t feel anything doesn’t mean the immune response wasn’t vigorous. Each one of us makes a different kind of immune response.” Age, sex, genetics, preexisting conditions, environment and even our diet influences how our immune systems might react, she says.

To better understand a vaccine’s side effects, consider what happens when we get vaccinated. First, the innate arm of the immune system—its blunt force tool—rapidly attacks the foreign protein introduced by the vaccine, which can cause effects ranging from inflammation at the injection site to body-wide symptoms such as fatigue, pain or fever. The response activates the adaptive immune system, which takes a slower but more tactical approach: activating and training B cells, which make antibodies, and T cells, which help coordinate future attacks. That process ultimately leads to the formation of memory B cells and T cells, which can live in the body for many months to years.

Viruses infect our cells by fitting like a key into a lock—in this case, a receptor on cells’ surface. To block them, Wherry says, “antibodies act like sticking a piece of gum in the lock so the virus can’t get in.” Those gummy antibodies are crucial, but in order to build lasting protection, the immune system has to remember the specific shape of SARS-CoV-2, the pathogen that causes COVID-19, for its next encounter, which depends on memory B cells.

“Those cells form what we call immunological memory,” Wherry says. “They stick around and form a backup system. If the antibodies fail for some reason, you still have all these other cells working.”

That is why antibodies do not tell the whole story of how well an immune system is protected. For a preprint study recently posted online and not yet evaluated by outside experts, Wherry and his colleagues measured antibody and B cell levels in blood samples from 44 people receiving either the Pfizer or Moderna vaccine, taken at various times over the course of vaccination. The researchers primarily compared vaccine protection in individuals who had recovered from COVID-19 with those who had never been infected. They also found, however, that people who reported systemic side effects had slightly higher levels of antibodies but not higher levels of B cells. The contrast suggests that while these individuals may have mounted a stronger inflammatory response, they were not necessarily better protected against the coronavirus in the long run, Wherry says.

Many people will feel more side effects after the second shot of a two-dose COVID-19 vaccine, providing some reassurance. That shot tends to cause more side effects because the first dose primed the body for it, Shresta says. After the first exposure, the body accumulates a finite pool of memory B cells. With the second dose, she says, “we want to expand that population for later on, so upon real infection, the immune response will be faster, bigger and better.”

Wherry says that second shot may produce bigger side effects in some people because those memory B cells have already been established in response to the first exposure. “The inflammation quickly shifts [B cells] over to these antibody-producing factories,” he adds.

While researchers do not fully understand why only some people have side effects from COVID-19 vaccines, epidemiological data suggest some trends. “Women tend to have more vigorous immune responses than males, and young people tend to respond more than the elderly population,” Shresta says.

And the elderly as a whole report fewer side effects than younger people do, but that could have more to do with the way the immune system ages rather than how well the available COVID-19 vaccines work. “The efficacy in the elderly is great,” Wherry says. “It reflects that these are really good vaccines [that produce] antibody levels that are 100-fold to 1,000-fold more than you need. So even in the elderly, if you lose five- or 10-fold [of that antibody level], it’s like a tree falling in the forest; it doesn’t really matter.”

Our individual reaction to a COVID-19 vaccine could also have to do with the coronaviruses that we encountered in the Before Times. One’s immune system may have a heightened response to viruses similar to those it previously saw, whether that encounter occurred recently or decades ago. “People with young kids who get exposed to seasonal coronaviruses quite a lot may actually have some cross-reactivity that gives them more side effects,” Wherry says. And, he adds, “the elderly may have seen a coronavirus 40 years ago that people in their 30s never saw before.”

Although many questions remain about who gets side effects from a vaccine and why, Shresta says that the millions of people receiving similar vaccines worldwide provide researchers with a unique opportunity. “We’ll really learn some fundamentals about the immune system that we can harness—not just for infectious diseases but for autoimmunity, for cancer, even for neurologic diseases,” she says. And that’s a real shot in the arm.

Read more about the coronavirus outbreak from Scientific American here. And read coverage from our international network of magazines here.


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