Nocebo Effect Might Be Behind Some COVID-19 Vaccine Adverse Effects

Skepticism about the effectiveness of COVID-19 vaccines, as well as apprehension about adverse effects, appears to make the after-vaccine symptom burden worse. That’s according to a new German study finding that the “nocebo effect” could be behind some of the widely-reported effects of the COVID-19 vaccine.

HAMBURG, GERMANY – Concerns about COVID-19 vaccines were linked to a greater symptom burden in recipients, according to a “nocebo” study.

A nocebo effect is when negative expectations cause a medical treatment or procedure to have worse effects than it usually would have. A report in JAMA Network Open suggests that is what occurred when some people received COVID-19 vaccines.

German researchers from University Medical Center Hamburg-Eppendorf sought to investigate whether positive and negative expectations prior to a second dose of COVID-19 vaccination were associated with systemic adverse effects.

The cohort study involving 1,678 participants found that, among recipients who expected low benefit and high adverse effects, their tendency to catastrophize instead of normalize benign bodily sensations, as well as prior negative experiences, were associated with vaccination adverse effects.

“These findings suggest that risk factors for nocebo effects exist that can be assessed prior to vaccination and in some cases (ie, negative expectations) can potentially be changed via expectation management strategies,” the authors advise.

Analyzed in the study were the association of expected benefits and risks of vaccination, adverse effects at first vaccination, and observed adverse effects in close contacts with the severity of systemic adverse effects among adults receiving a second dose of messenger RNA (mRNA)–based vaccines between August 16 and 28, 2021.

Researchers invited 7,771 individuals receiving the second dose at a state vaccination center in Hamburg, Germany, to participate in their study. Of those, 5370 did not respond, 535 provided incomplete information, and 188 were excluded retrospectively. The mobile application m-Path was used for data collection.

Defined as the primary outcome was a composite severity index of systemic adverse effects in 12 symptom areas. Participants used an electronic symptom diary over 7 consecutive days to record information. Ultimately, 10 447 observations from 1678 individuals receiving vaccinations – 77.3% received BNT162b2 [Pfizer BioNTech], with the remainder receiving mRNA-1273 [Moderna] -- were collected. The participants’ median age was 34 (IQR, 27-44) years, and 51.4% of participants were women.

Results indicate that the risk for more severe adverse effects was higher for recipients expecting a lower benefit of vaccination (odds ratio [OR] for higher expectations, 0.72 [95% CI, 0.63-0.83]; P < .001), expecting higher adverse effects of vaccination (OR, 1.39 [95% CI, 1.23-1.58]; P < .001), having experienced higher symptom burden at the first vaccination (OR, 1.60 [95% CI, 1.42-1.82]; P < .001), scoring higher on the Somatosensory Amplification Scale (OR, 1.21 [95% CI, 1.06-1.38]; P = .004), and if the vaccine mRNA-1273 was given rather than BNT162b2 (OR, 2.45 [95% CI, 2.01-2.99]; P < .001). No associations were seen for observed experiences.

“In this cohort study, several nocebo effects occurred in the first week after COVID-19 vaccination,” the authors point out. “The severity of systemic adverse effects was associated not only with vaccine-specific reactogenicity but also more negative prior experiences with adverse effects from the first COVID-19 vaccination, more negative expectations regarding vaccination, and tendency to catastrophize instead of normalize benign bodily sensations. Clinician-patient interactions and public vaccine campaigns may both benefit from these insights by optimizing and contextualizing information provided about COVID-19 vaccines.”

Background information in the article explains that adverse effects following COVID-19 vaccination tend to include systemic reactions such as myalgia and fever. “Psychological factors can contribute to a large extent to symptom burden,” the researchers note. “Nocebo effects are phenomena whereby people taking inert substances experience adverse effects. However, they also influence clinical outcomes in active treatments. For example, in COVID-19 vaccine trials, adverse effects in placebo groups overlapped by 76% (first dose) and 52% (second dose) with those in vaccine groups, while underlying mechanisms were not investigated.”

They suggest, “More knowledge on these factors could aid in strategies to attenuate nocebo-related adverse effects.”