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How the Nocebo Effect Influences COVID-19 Vaccine Safety Data

Julia Haas, PhD, discusses her team's recent findings that one-third of patients in COVID-19 vaccine trials reported side effects after receiving a placebo dose.

New data from a multinational assessment of COVID-19 vaccine clinical trials showed a significant rate of systemic side effects, such as headaches and fatigue, being reported by patients who were randomized to a placebo dose.

The findings, presented by a team from Beth Israel Deaconess Medical Center led by Julia W. Haas, PhD, show the significant prevalence of the “nocebo effect” in placebo-controlled trials—and how the public’s understanding of adverse events associated with COVID-19 vaccines may be skewed.

In an interview with HCPLive, Haas discussed the nocebo effect, the impact of her team’s findings, how clinicians need to address COVID-19 vaccine safety data with hesitant patients, and more.

HCPLive: Could you explain the current understanding of nocebo effect and its impact on clinical trial results, as well as patient buy-in?

Haas: Many people treated with placebo report side effects, and this phenomenon is often called the nocebo effect. The nocebo effect probably occurs because of anxiety and negative expectations, which can be caused by negative information (e.g., via the internet) or by prior negative experiences with other drugs. The nocebo effect can also be influenced by other factors, such as the clinician’s behavior (e.g., does the clinician show empathy, warmth, and competence?).

Regarding the COVID-19 vaccine trials, this suggests that the vaccines may actually cause fewer side effects than one might infer from looking only at those who got a vaccine, without also making the comparison to those who got a placebo.

What are the unique factors of COVID-19 vaccine research that made this systematic review and meta-analysis of interest to your team?

There are so many people worldwide who have received or will receive a COVID-19 vaccine, and many of them are worried about potential side effects of the vaccines. These worries can enhance nocebo effects and lead to worse unpleasant side effects. Therefore, we thought it is important to investigate nocebo effects in the context of the vaccines systematically. Hopefully, this can help to reduce side effect worries.

What stands out to you as the most surprising outcome of your assessment?

That 76% of systemic adverse events (i.e., symptoms like headache or fatigue) may actually be nocebo responses. We did not expect such a high percentage.

Frontline physicians and caregivers are generally at the greatest opportunity to discuss vaccine efficacy and safety with hesitant patients. What recommendations would your team give to such colleagues on the basis of these findings?

I would recommend explaining the nocebo effect to patients. This includes informing them that many people experience symptoms after placebo treatment, and that these effects are probably caused by worries, negative expectations or misattribution of symptoms that may have occurred anyway (e.g., people may routinely have headaches, but when they got the placebo shot they attributed the headache to the injection). There is evidence to suggest that such honest information may help to reduce adverse events.

What would a greater public understanding of the nocebo effect provide us in our ongoing efforts to improve COVID-19 vaccination rates?

A greater public understanding of the nocebo effect may help to reduce worries about the vaccines. Hopefully, this may even help to improve COVID-19 vaccination rates.