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.
Read: What’s the use of a pretty good vaccine?
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.