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Is a strong reaction to the COVID-19 vaccine a sign of a more robust immune response that ultimately brings better protection against infection, hospitalization, and death?

Many are asking that question as they roll up their sleeves for yet another booster.

Science doesn't have a definitive answer, as the literature is generally mixed -- although two papers in the JAMA network of journals suggest that experiencing more side effects does correlate with higher levels of anti-spike antibodies.

Still, nearly all studies agree on one thing -- the vast majority of people develop anti-spike antibodies after they're fully vaccinated.

"Some people get a reaction, some people don't, but everybody gets protected," said William Schaffner, MD, professor of infectious diseases at Vanderbilt University Medical Center in Nashville, Tennessee, and a spokesperson for the Infectious Diseases Society of America (IDSA).

"Some people get more of a reaction than others, and sorry if you got a bad reaction, but you're protected -- and so is your neighbor who was able to go out and play tennis the next day," Schaffner said.

The Evidence to Date

One of the first papers examining the relationship between COVID vaccine reactions and subsequent levels of anti-spike antibodies was an August 2021 by Amanda Debes, PhD, of Johns Hopkins School of Public Health in Baltimore, and colleagues.

They studied 954 healthcare workers at Johns Hopkins who had two doses of either the Pfizer or Moderna COVID-19 vaccine. Patients self-reported their symptoms and had serum samples drawn every 3 to 4 months.

Debes and colleagues found in adjusted analyses that reporting "clinically significant" symptoms -- including fatigue, fever, and chills -- was independently associated with about 5% higher median anti-spike IgG levels.

Still, nearly all participants developed anti-spike IgG antibodies after vaccination, with the exception of one participant who was taking immunosuppressant medications, the team reported.

Last month, Emilia Hermann, MD, MPH, of Columbia University Medical Center in New York City, and colleagues published a looking at the relationship between symptoms and antibody levels among Framingham Heart Study participants.

The researchers found that among 928 participants who completed a questionnaire about symptoms and had a blood spot collected after two doses of either the Pfizer or Moderna COVID vaccine, systemic symptoms were associated with about a 50% greater antibody response in adjusted models.

But once again, nearly all participants made anti-spike antibodies.

"It should give some confidence to people who do have greater reactogenicity that their body is doing some hard work and they're building more antibodies," Debes, author of the Johns Hopkins paper, told 番茄社区app. "But I think both papers highlight that everyone is developing an antibody response."

In contrast to those two studies, published in November 2021 found no relationship between reactogenicity and anti-spike IgG antibody levels after full vaccination with AstraZeneca's or Pfizer's COVID-19 vaccine.

Once again, the paper found that the vast majority of those vaccinated did make anti-spike antibodies.

In addition, a found that while men with more severe reactions to vaccination had higher anti-spike IgG levels (there was no such relationship among women), symptoms didn't correlate with T-cell-mediated immune response in men or women.

Since T-cell response speaks to protection against severe illness, hospitalization, and death, the findings suggest that for this more important form of protection, a severe reaction may not offer any benefit.

Also in this study, all vaccinated patients had anti-spike IgG levels that were within -- but mostly above -- the range seen for convalescent plasma donors at the facility, the authors reported.

No Reaction, Still Uninfected

Kathryn Edwards, MD, an expert in pediatric infectious diseases at Vanderbilt University, and another IDSA spokesperson, interpreted the literature as suggesting a small benefit for people who have severe reactions to the vaccines.

"If you have a little pain, you have a little gain," she told 番茄社区app.

Nonetheless, she said, not having a reaction doesn't mean you're not protected. "By and large, the immune response to COVID vaccines has been quite good," she said. "If you didn't have a reaction, that doesn't mean the vaccine didn't work. We know the vaccine is immunogenic for almost everyone who gets one."

Also, it's difficult to extrapolate the data to any individual patient, she said. Someone without a severe reaction may have developed a lower level of anti-spike antibodies than someone with a strong reaction -- but that level of antibody may be enough to protect them against any outcome, including infection.

There's another data gap: no study has examined whether a more severe reaction to the COVID-19 vaccine brings better protection against infection, hospitalization, and death. While neutralizing antibodies are generally accepted as the best predictor of protection, official correlates of immunity have not been established in COVID-19.

John Moore, PhD, a microbiologist and immunologist at Columbia University, wrote a memo to his email discussion list when the Hermann paper came out 2 weeks ago suggesting that greater reactogenicity indicates higher antibody levels. He said he's "not convinced it's going to turn out to be the definitive story."

While Hermann and colleagues reported that other studies came to similar conclusions, "there have been many others over the past couple of years that find no such association."

"All I can say is that I have no reactions to COVID or flu vaccines, and yet here I [still] am – vaccinated and uninfected," Moore wrote. "The danger here is that people who, like me, have no local response may feel they are not properly vaccinated. And I truly believe that's usually not the case."

Correction: The JAMA Network Open paper by Hermann et al. found that systemic symptoms after vaccination were associated with a 50% greater antibody response in adjusted models.

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