Many people who've received two-dose Covid-19 vaccines say the second dose spurs much more significant side effects than the first, Katherine Wu reports for The Atlantic—but that just means the vaccines are doing what they're designed to do, experts say.

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Why the second dose might cause more significant side effects

As Wu reports, the two-dose vaccines developed by Pfizer and BioNTech and Moderna use mRNA wrapped in lipid nanoparticles to instruct the body's cells to create the spike protein found on the new coronavirus.

That protein elicits a strong antibody response, which in turn allows the immune system to learn the features of the protein so it can better fight the virus in the future.

At the same time, the lipid nanoparticles—which, Wu writes, are "unlike anything naturally present in the body"—trigger a swarm of immune cells to the injection site, causing the area to become inflamed and sore. This reaction also can trigger temporary, short-lived symptoms in the rest of the body, such fever and fatigue.

"It's the body's knee-jerk reaction to an infection" or anything that looks similar to an infection, Mark Slifka, a vaccine expert and immunologist at Oregon Health and Science University, said. "Let's spray the area down with antiviral cytokines, which also happen to be inflammatory."

That initial reaction explains the relatively mild effects many people feel after a first vaccine dose. In the days afterward, however, the body start to corral additional defenses—namely, antibody-making T cells and B cells, Wu writes.

As a result, when the patient receives a second vaccine dose, the body is prepared to spring into action much more quickly.

In fact, some T and B cells remain "lingering at the site of the [first] injection, out of suspicion their target would return," Wu writes. Further, these cells send out their own cytokines, adding another layer of inflammation and spurring other defensive reactions, such as fevers, aches, and fatigue.

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

In essence, Wu writes, it's the second shot that instructs T and B cells to take the novel coronavirus seriously, ensuring the body will mount a strong response to any further attack.

"[The cells are] asking, 'Why is this happening 21 or 28 days later? I thought we took care of this four weeks ago," Slifka explained.

Even so, not everyone will experience side effects after their second dose—but that doesn't mean their immune system isn't working properly, Wu reports.

"[S]ome people's immune systems are louder than others," Jasmine Marcelin, an infectious disease physician at the University of Nebraska Medical Center, explained—but the quieter ones are working just as hard.

Do people who have already had Covid-19 need a second dose?

While most patients have only mild reactions to their first mRNA vaccine dose, some Covid-19 survivors say even the first dose spurred "unexpectedly intense reactions," the New York Times reports—prompting a new idea among experts: Maybe people who've already been infected, and whose immune systems have thus already had experience with the coronavirus, need only one dose.

In a study that has yet to be peer-reviewed, researchers examined the symptoms of 231 people after vaccination, 83 of whom had previously recovered from Covid-19. They found that those who had previously been infected were more likely to report side effects such as fatigue, headache, and chills.

The researchers also measured the immune response to the vaccine in 109 people, 41 of whom had previously been infected with the new coronavirus. They found that those previously infected showed a stronger antibody response after their first dose of the vaccine.

Based on these results, the researchers suggested patients who have recovered from Covid-19 may need only one dose of the vaccine.

A second pre-print study offers similar findings, the Times reports. In that study, researchers found that of 59 health care providers, 42 of whom had had Covid-19, those who reported prior infection generated antibody levels after the first dose that were comparable to the levels generated by people without prior infection after the second dose. Further, lab experiments demonstrated that the antibodies produced by previously infected participants successfully prevented the virus from entering cells.

"I think one vaccination should be sufficient" for people who've already had Covid-19, Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai and an author on the first study, said. "This would also spare individuals from unnecessary pain when getting the second dose and it would free up additional vaccine doses."

However, E. John Wherry, director of the University of Pennsylvania's Institute for Immunology, said that before supporting any policy changes, he'd like to see data showing that antibodies in recovered Covid-19 patients successfully prevent the virus from replicating after just one vaccine dose.

"Just because an antibody binds to a part of the virus does not mean it's going to protect you from being infected," he said.

Furthermore, Wherry pointed out that people who've had relatively mild cases of Covid-19 appear to have lower levels of antibodies, which could mean they don't have sufficient protection against more transmissible coronavirus variants.

Further, it would be challenging to correctly identify which people have previously been infected by the virus, he added, noting, "Documenting that becomes a really potentially messy public health issue" (Wu, The Atlantic, 2/2; Willyard, New York Times, 2/2; Willyard, New York Times, 2/1).