What the Vaccine’s Side Effects Feel Like

For a fraction of people, getting these first COVID-19 vaccines could be unpleasant—more than the usual unpleasantness of getting a shot. They might make you feel sick for a day or two, even though they contain no whole viruses to actually infect you. Both the Pfizer/BioNTech and Moderna vaccines are quite “reactogenic”—meaning they stimulate a strong immune response that can cause temporary but uncomfortable sore arms, fevers, chills, and headaches. In other words, getting them might suck a little, but it’s nowhere near as bad as COVID-19 itself.

Reactogenicity happens to some degree with all vaccines and is not in itself a safety concern. Vaccines, after all, work by tricking the body into thinking it has been infected, and these “symptoms” are an indication it has successfully done so. The fever, fatigue, and other signs we associate with colds or flu or even COVID-19 are typically caused by our immune responses, not the virus itself. “A reactogenic vaccine is not the same thing as an unsafe vaccine,” says Saad Omer, a vaccinologist and the director of the Yale Institute for Global Health.

Compared with existing vaccines, the two COVID-19 ones from Pfizer/BioNTech and Moderna are a little more reactogenic than flu vaccines but are roughly on par with the shingles vaccine, which can interfere with daily life for a couple of days in some people. (Moderna’s also seems to be a little more reactogenic than Pfizer’s, possibly because it’s a larger dose.) These vaccines have enough of a kick that the CDC suggested hospitals stagger vaccinations among staff, so an entire unit isn’t out on a given day. Nursing homes as well are concerned about vaccinating all staff and residents at once, which could reduce staff availability at the same time residents need more care.

As the United States embarks on its largest, most complex vaccination campaign in history, experts say vaccine providers need to set expectations for people getting the shots. If someone who gets a vaccine is unpleasantly surprised, they might not come back for a second dose or their experience might sway their friends and family against it. Managing expectations is about making sure that Americans are willing to get the vaccine. “There has to be pretty good transparency about what you’re going to experience,” says Deborah Fuller, a microbiologist and vaccine researcher at the University of Washington.

The sore arms, fevers, and headaches are a result of innate immunity, the first of the immune system’s two main branches. Innate immunity is a blunt tool; it wants to fight anything foreign. When you get a COVID-19 vaccine, the cells in your arm take up mRNA that encodes a version of the coronavirus’s spike protein. The virus uses spike protein as a key to get into our cells, but unattached from the rest of the virus, the spike protein can’t infect anything. Still, the innate immune system recognizes the vaccine materials and the resulting spike protein as foreign.

This signal sets off a reaction that can feel a lot like getting sick. More immune cells get recruited to your arm, which may become inflamed and sore, activating even more immune cells that might cause whole-body symptoms such as fever and fatigue.

Some of those immune cells will belong to the second branch of the immune system, adaptive immunity. These are the targeted assassins of the immune system. They include B cells, which make antibodies that can bind to the spike protein and T cells that can recognize infected cells. Adaptive immunity is what will specifically protect you from COVID-19. And to get there, you first need the innate immune system to recognize the foreign protein and turn on the adaptive immune system. A reactogenic vaccine isn’t necessarily a more effective vaccine, but it is a sign that the first step is working.

Reactogenicity is also distinct from anaphylaxis, a severe allergic reaction that has occurred in a handful of people getting the Pfizer vaccine in the U.S. and the U.K. Anaphylaxis is an immune reaction as well, but it begins within minutes after exposure, with dramatic drops in blood pressure and difficulty breathing. It’s still unclear what in the shots triggered an allergic reaction, though the vaccines contain sugar as a cryoprotectant and salts to get the right acidity, in addition to the active ingredients. The CDC recommends 30 minutes of observation after COVID-19 vaccination for anyone with a history of anaphylaxis and 15 minutes for everyone else. Anaphylaxis is very treatable with epinephrine (a.k.a. an EpiPen) and antihistamines, and the vaccine recipients who experienced it have all recovered. The CDC and FDA have a vaccine adverse-events monitoring network that will scrutinize anaphylaxis as well other possible serious and longer-term side effects. These side effects are all different from normal and common reactogenicity, which should last only a couple of days.

The reactogenicity of the mRNA vaccines from Pfizer/BioNTech and Moderna is likely largely due to the bubble of fat used to package the mRNA. These bubbles, called lipid nanoparticles, seem to stimulate the immune system in animals even when empty. In the past, vaccine makers sometimes have added a second ingredient to a vaccine, called an adjuvant, to enhance the immune response. The lipid nanoparticle, originally designed to protect the mRNA and smuggle it inside cells, just happened to act as an adjuvant as well. “It’s like a three-in-one package,” Fuller says.

Lipid nanoparticles are an active area of innovation for designing future mRNA vaccines, of which Pfizer/BioNTech’s and Moderna’s are the first two. The COVID-19 pandemic finally validated the years of expectations about the technology. When I spoke with Drew Weissman, a mRNA vaccine pioneer at the University of Pennsylvania, not long after the first clinical trial results that proved how well these vaccines worked, he was optimistic about the future of mRNA vaccines. The technology could be applied to improve existing vaccines, such as for the flu, and make new ones against other diseases or even cancer. His one note of caution was on reactogenicity. “We’re working on ways of reducing that,” he told me. “I’m not sure people will tolerate it for influenza vaccines or other vaccines.” For context, less than half of adults in the U.S. got the flu vaccine last year.

But COVID-19 on the whole is much worse than the flu. It’s already killed more than 300,000 Americans this year, compared with the 60,000 who die from the flu in a very bad year. And even for people who recover, illness from the coronavirus can last much longer and feel much worse. A sore arm or fever for a day, in contrast, might not be so bad.