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Placebo Recipients in COVID-19 Vaccine Trials Often Report Adverse Events

New data show "nocebo responses" are frequent in COVID-19 vaccine studies—which may drive recipients' expectation of side effects.

Adverse events are not confined to only vaccine recipients in COVID-19 clinical trials.

A new systematic review and meta-analysis showed approximately one-third of all placebo dose recipients in COVID-19 vaccine trials reported a systemic adverse event (AE) such as headache or fatigue.

The significant prevalence of adverse events elicited by placebos, called “nocebo responses,” may perpetuate an expectation of common nonspecific symptoms including headache and fatigue in new vaccine recipients—thereby leading to greater likelihood of nocebo responses versus actual events associated with COVID-19 vaccines.

“Emerging research has shown that informing patients about nocebo responses and providing a positive framing of potential AEs may be associated with reduced AE-related anxiety and nocebo responses,” investigators wrote. “Although nocebo phenomena have been investigated in many contexts involving medication, evidence of their influence in vaccination remains scarce.”

A team of multinational investigators conducted a systematic review and meta-analysis of 2 major clinical trial databases to compare the frequency of adverse events reported by placebo-controlled participants of COVID-19 vaccine trials versus those reported by actual vaccine recipients.

Led by Julia W. Haas, PhD, of the Program in Placebo Studies at Beth Israel Deaconess Medical Center, investigators noted a global survey from January 2021 showing that 47% of respondents were worried about adverse events from a COVID-19 vaccine. Even before the pandemic, the World Health Organization (WHO) defined vaccination hesitancy as a global health threat; it has since been a burden in reducing the spread and effect of COVID-19.

“Counteracting the underlying motivations for vaccination hesitancy is therefore crucial to overcome this worldwide crisis,” they wrote.

Haas and colleagues used relevant published data on COVID-19 vaccine trials up to July 14, 2021. Eligible trials featured randomization, adults aged ≥16 years old, a placebo arm, data for solicited adverse events within 7 days of injection and a report of adverse events for both vaccine and placebo groups separately.

Their analysis included 12 articles with adverse event reports for 45,380 participants (22,578 placebo). Investigators observed adverse event reporting outcomes for both first- and second-dose experiences in patients.

After the first dose, 35.2% (95%, 26.7 - 43.7) of placebo recipients reported systemic adverse events; headaches (19.3%; 95% CI, 13.6 - 25.1) and fatigue (16.7%; 95% CI, 9.8 - 23.8) were the most commonly reported events, followed by muscle pain (9.1%; 95% CI, 6.0 - 12.1).

Even after the second dose, 31.8% (95% CI, 28.7 - 35.0) of placebo recipients reported systemic adverse events—again primarily either headache, fatigue or muscle pain.

Though significantly more COVID-19 vaccine recipients in the analyzed trials reported systemic events, investigators noted that given the ratio between placebo and vaccine arms, nocebo responses accounted for more than three-fourths (76%) of systemic adverse events after the first COVID-19 vaccine dose and more than half (51.8%) after the second dose.

Noting that adverse event frequency dropped among placebo recipients on the second dose, investigators hypothesized that participants in the control arm had lesser expectation of adverse events than vaccine recipients.

“Headache, fatigue, malaise, and joint pain were common in both groups and seem to have been particularly associated with nocebo,” Haas and colleagues wrote. “Furthermore, exploratory analyses suggested that nocebo responses may produce adverse events of severity grades similar to those of active vaccines after the first dose.”

The team pointed to various strategies that could help to inform the public about nocebo responses and reduce the likelihood of misperceived adverse events, including information added to informed consent procedure documents. Even highlighting the probability of not experiencing adverse events in a controlled clinical trial may eventually provide the public a more clear understanding of risks and benefits.

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

The study, “Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials,” was published online in JAMA Network Open.