The Second COVID-19 Shot Is a Rude Reawakening for Immune Cells

Side effects are just a sign that protection is kicking in as it should.

a hand holding a syringe
Getty / The Atlantic

At about 2 a.m. on Thursday morning, I woke to find my husband shivering beside me. For hours, he had been tossing in bed, exhausted but unable to sleep, nursing chills, a fever, and an agonizingly sore left arm. His teeth chattered. His forehead was freckled with sweat. And as I lay next to him, cinching blanket after blanket around his arms, I felt an immense sense of relief. All this misery was a sign that the immune cells in his body had been riled up by the second shot of a COVID-19 vaccine, and were well on their way to guarding him from future disease.

Side effects are a natural part of the vaccination process, as my colleague Sarah Zhang has written. Not everyone will experience them. But the two COVID-19 vaccines cleared for emergency use in the United States, made by Pfizer/BioNTech and Moderna, already have reputations for raising the hackles of the immune system: In both companies’ clinical trials, at least a third of the volunteers ended up with symptoms such as headaches and fatigue; fevers like my husband’s were less common.

Dose No. 2 is more likely to pack a punch—in large part because the effects of the second shot build iteratively on the first. My husband, who’s a neurologist at Yale New Haven Hospital, is one of many who had a worse experience with his second shot than his first.

But much like any other learning process, in this one repetition is key. When hit with the second injection, the immune system recognizes the onslaught, and starts to take it even more seriously. The body’s encore act, uncomfortable though it might be, is evidence that the immune system is solidifying its defenses against the virus.

“By the second vaccine, it’s already amped up and ready to go,” Jasmine Marcelin, an infectious-disease physician at the University of Nebraska Medical Center, told me. Fortunately, side effects resolve quickly, whereas COVID-19 can bring on debilitating, months-long symptoms and has killed more than 2 million people.

When the immune system detects a virus, it will dispatch cells and molecules to memorize its features so it can be fought off more swiftly in the future. Vaccines impart these same lessons without involving the disease-causing pathogen itself—the immunological equivalent of training wheels or water wings.

The Pfizer and Moderna vaccines accomplish that pedagogy via a genetic molecule called mRNA that’s naturally found in human cells. Once delivered into the upper arm, the mRNA instructs the body’s own cells to produce a coronavirus protein called spike—a molecule that elicits powerful, infection-fighting antibody responses in people battling COVID-19.

To ensure safe passage of mRNA into cells, the vaccine makers swathed the molecules in greasy bubbles called lipid nanoparticles. These strange, fatty spheres don’t resemble anything naturally present in the body, and they trip the sensors of a cavalry of fast-acting immune cells, called innate immune cells, that patrol the body for foreign matter. Once they spot the nanoparticles, these cells dispatch molecular alarms called cytokines that recruit other immune cells to the site of injection. Marshaling these reinforcements is important, but the influx of cells and molecules makes the upper arm swollen and sore. The congregating cells spew out more cytokines still, flooding the rest of the body with signals that can seed system-wide symptoms such as fever and fatigue.

“It’s the body’s knee-jerk reaction to an infection,” or something that looks like it,  Mark Slifka, a vaccine expert and an immunologist at Oregon Health and Science University, told me. “Let’s spray the area down with antiviral cytokines, which also happen to be inflammatory.”

The mRNA itself might also tickle a reaction out of the immune system, simply because of how unusual it looks. “All of a sudden, you have a lot of new RNA that the cell didn’t make,” says Donna Farber, an immunologist at Columbia University, who got her second shot of Moderna’s vaccine last month, with very few side effects.

The provocative nature of mRNA might help explain why Moderna’s shot, which contains three times as much of the genetic material as Pfizer’s, was linked to more side effects in clinical trials.

The innate immune system acts fast. But its actions aren't very long-lived or discerning: These cells just clobber anything that looks a little weird. Within a day or two of the injection, they start to lose steam. Cytokine production sputters; side effects start to fade. Around this time, innate immune cells start to pass the baton to another division of the immune system, called adaptive immunity, which includes sniperlike molecules and cells, such as antibodies and T cells, that will launch an attack on specific pathogens if they try to infect the body again.

T cells and B cells, the cells that make antibodies, need several days to study the spike’s features before they can respond. But by the time the second injection rolls around, adaptive cells are raring to go, and far faster to react. Some of these cells have even been lingering at the site of injection, out of suspicion that their target would return. Stimulated anew, these sentinel cells will blast out their own cytokines, layering on an extra wave of inflammation. In some people, like my beleaguered neurologist husband, these complex reactions can manifest in fevers, aches, and prolonged exhaustion.

My husband had side effects after his first dose too: a headache, some fatigue, a touch of dizziness—all of which I can safely blame on his innate immune system. Those same innate responses return for another round of inflammation after the second shot. But the ruckus raised after the second injection might be a double whammy: The expected innate cells might be further egged on and amplified by a less sluggish surge of adaptive cells, concentrated near where the needle goes in.

“With the second dose, now everything is responding within that same short time period,” Marion Pepper, an immunologist at the University of Washington, told me.

Pepper described her first shot of Pfizer’s vaccine as “a piece of cake.” The second injection saddled her with flu-like symptoms, tougher to take. But the side effects also signify that both branches of the immune system are being engaged as they should—cementing the memory of the coronavirus’s spike protein in some of the body’s most powerful cells.

That’s a big part of why vaccine boosts are so important, Slifka said. Although the first shot stimulates both innate and adaptive immunity, the second injection reminds B and T cells that the threat of the coronavirus cannot be taken lightly, and ensures that the sharpest and strongest immune players will be used for any subsequent response.

“They’re asking, ‘Why is this happening 21 or 28 days later? I thought we took care of this four weeks ago,’” Slifka said.

Marcelin, the Nebraska infectious-disease physician, also experienced rougher symptoms after her second shot of Pfizer’s vaccine. By the time she went to bed that evening, she was gripped with miserable muscle aches and chills. It took a couple more days before “I felt like myself,” Marcelin recalled.

The side effects didn’t faze her, though. She’s now about three weeks out from her second dose—past the point when the vaccine’s full protective effects are expected to kick in. “I would do it again,” she says. “It was definitely worth it.”

People shouldn’t be perturbed by a lack of vaccine side effects either. As our bodies churn through new information, “some people’s immune systems are louder than others’,” Marcelin said. But the quiet ones are still hard at work.

My husband’s immune system certainly fell into the diva category. The night after his second shot, he pinwheeled between cold and hot, alternately bundling himself in blankets and tossing them away. The flux seemed to bleed a bit into his emotional valence too. After snoozing on the couch for several hours, he perked up and couldn’t stop laughing at a picture of an orange cat curled up next to a box of similarly crescent-shaped croissants.

But within 24 hours of his shot, he was feeling well enough to run (yes, run) to work and finish an 11-hour shift. In a couple of weeks, he’ll join the millions of other Americans who, thanks to a pair of injections, will be cloaked in an extra layer of armor against the coronavirus.

As he told me Wednesday night, shivering through the cushion of two comforters: “This is a million times better than getting COVID.”