Even before their rollout, a clear feature of safe and effective COVID-19 vaccines has been their "reactogenicity" - that is, their tendency to cause mild symptoms that signal that immune responses start after one shot, especially the second. When vaccine supplies were released in the United States last year, families, friends and colleagues exchanged stories of their shaky days after jab, often reminiscent of fever, chills, fatigue and general curvature.
While these experiences are undoubtedly real, their connection to the vaccines may not be. As more and more results from randomized controlled vaccine trials hit scientific journals, researchers kept noticing that while trial participants often reported mild symptoms after shots, so did participants who received placebo - and not at trivial levels.
Many people are familiar with the "placebo effects" that occur when an inert intervention causes people to report health benefits that could not possibly be caused by the fake treatment. Placebo effects are well documented and real - as people can actually experience some degree of psychosomatic benefits. A placebo will not treat serious medical conditions, such as cancer, but it can make people feel, for example, that they have more energy or less general discomfort.
But placebo also has a dark side. The harmless interventions can just as easily cause people to report harmful side effects, especially when people expect such side effects. Researchers have invented these phantom side effects "nocebo reactions." Nocebo reactions are thought to stem from expectations of side effects, anxiety-induced effects, and the erroneous attribution of common, nonspecific disorders, such as headaches, to placebo.
COVID vaccine nocebos
Nocebo reactions were surprisingly common in trials with COVID-19 vaccines, and a new study quantified the role they played. The meta-analysis, led by Harvard researchers and published Tuesday at the JAMA Network Open, looked at adverse reaction data from 12 high-quality randomized clinical trials testing various COVID-19 vaccines against inert placebo control groups. The analysis concluded that nocebo reactions accounted for 76 percent of the systemic side effects - such as headaches, fever and chills - after the first vaccine dose and 52 percent of the systemic reactions after the second vaccine dose.
The number of side effects in the placebo groups was "significant," the researchers concluded, led by Harvard researcher Julia Haas. While common, nonspecific symptoms, such as fatigue and headaches, are among the most common side effects associated with the vaccines, the study found that they are "particularly associated with nocebo."
Of course, the point of this analysis is not just to make you question your reason (though, seriously, your mind might be messing with you). The bottom line is that these nocebo reactions are likely to make safe, life-saving vaccines seem significantly less pleasant than they actually are - and fear of such unpleasant side effects is a known reason why some people choose not to be vaccinated.
"Informing the public about the potential for nocebo reactions can help reduce concerns about COVID-19 vaccination, which may reduce the hesitation of vaccination," Haas and her colleagues wrote. In addition, some clinical evidence suggests that making people aware of nocebo reactions may also lower their expectations of side effects and thereby actually lead to fewer side effects experienced.
Of course, not all side effects are nocebo reactions; some are clearly real, especially local reactions and side effects after the second dose of a COVID-19 vaccine.
In the meta-analysis, Haas and her colleagues found that about 35 percent of placebo recipients reported at least one systemic side effect after their first faux dose. Meanwhile, 46 percent of vaccine recipients reported at least one systemic side effect after receiving their first correct dose. When the researchers looked at the severity of all these systemic side effects, they found similar proportions of severity between the placebo and vaccine groups. In other words, the vaccine group did not collectively report more serious adverse events than the placebo group. But there was a clear difference in the local side effects. Only 16 percent of placebo recipients reported local side effects, such as pain or swelling at the injection site, while 67 percent of the vaccine group reported such effects.
After the second dose, there were even more differences. About 32 percent of the placebo group reported at least one systemic effect, while 61 percent of the vaccine group reported systemic effects. And in this case, the vaccine group tended to report more moderate to severe systemic effects than the placebo group. As in the first shot, the vaccine group had several local side effects, with about 73 percent reporting local effects, while only about 12 percent of the people in the placebo group reported them.
Overall, it seems clear that the nocebo responses distort our experience with COVID-19 vaccines, which are used worldwide. As such, the researchers argue that highlighting the potential for nocebo responses may reduce side effects and help improve vaccine uptake.