Key points What was the frequency of adverse events (AEs) in the placebo groups of the COVID-19 vaccine trials? Findings In this systematic review and meta-analysis of 12 articles including reports of AEs for 45,380 trial participants, 35% of placebo recipients experienced systemic AEs after the first dose and 32% after the second. Significantly more AEs were reported in the vaccine groups, but AEs in the placebo arms ("nocebo responses") accounted for 76% of systemic AEs after the first dose of the COVID-19 vaccine and 52% after the second dose. Meaning This study found that the rate of nocebo responses in the placebo arms of the COVID-19 vaccine trials was substantial; This finding should be considered in public vaccination programs. |
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The placebo effect is the well-known phenomenon of improvement in a person’s physical or mental health after taking a treatment without pharmacological therapeutic benefit, for example, a sugar pill or a syringe filled with saline solution.
While the exact biological, psychological, and genetic underpinnings of the placebo effect are not well understood, some theories point to expectations as the primary cause and others argue that nonconscious factors embedded in the doctor-patient relationship automatically reduce the volume of symptoms. .
Sometimes placebo effects can also cause harm: the so-called “nocebo effect” occurs when a person experiences unpleasant side effects after taking a treatment without pharmacological effects. That same sugar pill that causes nausea, or that syringe full of saline solution that causes fatigue.
In a new meta-analysis of randomized, placebo-controlled COVID-19 vaccine trials, researchers at Beth Israel Deaconess Medical Center (BIDMC) compared the rates of adverse events reported by participants who received the vaccines with the rates of adverse events reported by those who received a placebo injection that contained no vaccine.
While the scientists found that significantly more trial participants who received the vaccine reported adverse events, nearly a third of participants who received the placebo also reported at least one adverse event, with headache and fatigue being the most common. The team’s findings are published in JAMA Network Open .
"Adverse events after placebo treatment are common in randomized controlled trials," said lead author Julia W. Haas, PhD, an investigator in the Placebo Studies Program at BIDMC. “Gathering systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination around the world, especially as concerns about side effects are reported to be a reason for vaccine hesitancy.” ”.
Haas and his colleagues analyzed data from 12 COVID-19 vaccine clinical trials. The 12 trials included adverse event reports from 22,578 placebo recipients and 22,802 vaccine recipients.
After the first injection, more than 35 percent of those receiving the placebo experienced systemic adverse events (symptoms that affect the entire body, such as fever), with headache and fatigue being the most common at 19.6 percent and 16.7 percent, respectively. Sixteen percent of placebo recipients reported at least one local event, such as injection site pain, redness, or swelling.
In comparison, after the first injection, 46 percent of those who received the vaccine experienced at least one systemic adverse event and two-thirds of them reported at least one local event. Although this group received pharmacologically active treatment, at least some of their adverse events are attributable to the placebo, or in this case, nocebo, effect, since many of these effects also occurred in the placebo group.
Haas and colleagues’ analysis suggested that nocebo accounted for 76 percent of all adverse events in the vaccine group and nearly a quarter of all reported local effects.
After the second dose, adverse events among the placebo group were reduced to 32 percent reporting systemic events and 12 percent reporting local effects. In contrast, participants who received the vaccine reported more side effects, with 61 percent reporting systemic adverse events and 73 percent reporting local adverse events.
The researchers estimated that nocebo accounted for nearly 52 percent of the side effects reported after the second dose. While the reason for this relative decrease in nocebo effects cannot be confirmed, the researchers believe that the higher rate of adverse events in the first-time vaccine group may have led participants to anticipate more the second time.
“Nonspecific symptoms such as headache and fatigue, which we have shown to be particularly sensitive to nocebo, are listed among the most common adverse reactions after COVID-19 vaccination in many information leaflets,” said lead author Ted J. Kaptchuk, director of the Program in Placebo Studies and the Therapeutic Encounter at BIDMC and professor of medicine at Harvard Medical School. "Evidence suggests that this type of information may cause people to misattribute common daily background sensations as arising from the vaccine or cause anxiety and worry that make people highly alert to bodily feelings about adverse events." .
Kaptchuk and his colleagues are known for a large and growing body of evidence showing that full disclosure of placebo treatment, what he calls "open-label placebo," can actually improve common chronic conditions without any nocebo effects. While some researchers believe that informing patients about adverse effects can cause harm, Kaptchuk believes it is ethically necessary to fully inform participants about possible adverse reactions from vaccines.
“Medicine is based on trust,” Kaptchuk said. “Our findings lead us to suggest that informing the public about the potential for nocebo responses could help reduce concerns about COVID-19 vaccination, which could decrease vaccine hesitancy.”
Co-authors included Sarah Ballou, PhD, and John Kelly, PhD of BIDMC; Friederike L. Bender, MS, Marcel Wilhelm, PhD, and Winfried Rief, PhD from Philipps University Marburg; and Franklin G. Miller PhD, of Weill Cornell Medical College.
This work was supported in part by a postdoctoral fellowship from the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD) to Haas.
The authors declare not to have any interest conflicts.
