“Nocebo” Effect Accounted for Nearly Two-thirds of COVID-19 Vaccine Adverse Events in New Analysis

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A new systematic review and meta-analysis found approximately one-third of placebo recipients in COVID-19 vaccine clinical trials reported at least 1 adverse event (AE) after the first and second dose, with headache and fatigue being the most common.

“Adverse events after placebo treatment are common in randomized controlled trials,” said lead author Julia W. Haas, PhD, Division of Gastroenterology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, in a BIDMC press release. “Collecting systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide, especially because concern about side effects is reported to be a reason for vaccine hesitancy.”

Haas and colleagues analyzed data from 12 clinical trials of COVID-19 vaccines and compared the rates of AEs reported by vaccine recipients to the rates of AEs reported in the placebo groups. The 12 trials included AE reports from 22 578 placebo recipients and 22 802 vaccine recipients, according to the study published in JAMA Network Open.

After the first dose, 35.2% of placebo recipients experienced systemic AEs, with headache (19.3%) and fatigue (16.7%) being the most common, according to the results. Also, 16.2% of placebo recipients reported experiencing at least 1 local AE, such as pain, redness, or swelling.

In comparison, participants in the vaccine group reported higher rates of AEs, with 46.3% who experienced at least 1 systemic AE and 66.7% reported at least 1 local AE. The ratio between placebo and vaccine groups showed that nocebo responses accounted for 76% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose, added researchers.

Although investigators did not identify a potential reason for the decline in nocebo responses after the second dose, the team hypothesized that the higher rate of AEs in the vaccine cohort after the first dose may have led them to anticipate more after the second.

“Nonspecific symptoms like headache and fatigue – which we have shown to be particularly nocebo sensitive – are listed among the most common adverse reactions following COVID-19 vaccination in many information leaflets,” said senior author Ted J. Kaptchuk, director, Program in Placebo Studies and the Therapeutic Encounter, BIDMC, in the same press release. “Evidence suggests that this sort of information may cause people to misattribute common daily background sensations as arising from the vaccine or cause anxiety and worry that make people hyper alert to bodily feelings about adverse events.”

Researchers noted strategies that may help educate individuals about potential AEs from COVID-19 vaccines, including adding simple yet accurate information about nocebo responses to the informed consent procedure and highlighting the probability of not experiencing AEs.

“Although more research on these communication strategies is needed, such honest information adds to full disclosure and is unlikely to cause harm,” concluded authors. “In addition, informing the public about the potential for nocebo responses may help reduce worries about COVID-19 vaccination, which might decrease vaccination hesitancy.”