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One-Third of COVID-19 Vaccine Clinical Trial Participants Reported Adverse Events, Despite Receiving a Placebo

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A new study from researchers at Beth Israel Deaconess Medical Center (BIDMC) suggests that some of the adverse events reported in the COVID-19 vaccine trials are attributable to the placebo effect.

The placebo effect

The coronavirus pandemic has encouraged a wider understanding of how a novel therapeutic or preventative is developed and ultimately authorized for human use. Clinical trials are a major component of this pipeline, providing the opportunity to demonstrate a candidate’s safety and efficacy in human populations.

Randomized, placebo-controlled studies are considered to be the “gold standard” experimental method for testing an intervention, for example, a drug or a vaccine.

What is a randomized placebo-controlled study?

In this approach, study participants are assigned – at random – to receive either an intervention (known as the intervention group), a placebo or standard of care (known as the control group). A placebo resembles the intervention that is being tested, but it is not an active substance – for example, a syringe of saline may be provided as a placebo for a vaccine clinical trial. Differences in measured outcomes, e.g., an improvement in health, between the intervention and the control group are attributed to the effect of the intervention. If there are no differences in measured outcomes between the placebo group and the intervention group, traditionally this has been interpreted as meaning the intervention has “failed”. However, this outlook is changing.

The “placebo effect” occurs when an individual’s physical or mental health shows an improvement after receiving a placebo. The exact molecular mechanisms underpinning the placebo effect are unclear, but there are a number of different theories relating to conditioning, genetics and expectations.

The nocebo effect

While the placebo effect is generally a well-known phenomenon, you may be less familiar with the “nocebo” effect. This is defined as “the induction of a symptom perceived as negative by sham treatment and/or by the suggestion of negative expectations”. It occurs in the absence of treatment and can be induced by either the patient’s negative expectations, or by suggestions from clinical staff.  

Ted Kaptchuk is a professor of medicine at Harvard Medical School, and director of the Program in Placebo Studies and the Therapeutic Encounter (PiPS) at BIDMC in Boston. He is a leading figure in placebo research and understanding the potential impact of placebos in various illnesses. “Our laboratory investigates placebo and nocebo effects. We are interested in developing ways to lower nocebo effects in clinical trials and clinical practice,” Kaptchuk said in an interview with Technology Networks.

During the global pandemic, Kaptchuk and colleagues’ research focus turned to the nocebo effect of placebo injections in COVID-19 vaccine clinical trials. The Centers for Disease Control and Prevention list pain, fatigue, headache and other minor symptoms as common side effects of receiving a COVID-19 vaccine. Data on the potential occurrence of such side effects was initially gathered in the early Phase clinical trials. However, as Dr. Julia Haas, an investigator in the Program in Placebo Studies at BIDMC emphasized in a press release, adverse events can also commonly occur in placebo groups of clinical trials – an example of the nocebo effect.

As potential adverse side effects of COVID-19 vaccines are considered to be one of the largest contributing factors to vaccine hesitancy, Haas said it is important to collect systematic evidence regarding nocebo responses in vaccine trials.

Consequently, Kaptchuk and team conducted a meta-analysis of randomized and placebo-controlled COVID-19 vaccine trials to get a baseline understanding of nocebo frequency and severity. Their study findings are published in JAMA Network Open.

Placebo effect accounts for over two-thirds of COVID-19 vaccine adverse events

The meta-analysis included 12 articles reporting on randomized, double-blind clinical trials of COVID-19 vaccines, published before July 14 2021. The total number of participants across the trials analyzed was 45,380 – all participants were aged 16 years and over. Studies were required to assess solicited adverse events within seven days of injection for both the placebo and intervention arms for inclusion.

Event reporting terminology – vaccines
Systemic adverse event
Events that occur in tissues distant from the site of contact between the body and the vaccine.
Local adverse event
Events that occur at the site of contact between the body and the vaccine.
Solicited adverse events
Adverse events that participants are asked to record as part of the uniform collection of information. Unsolicited adverse events are volunteered by the participant and are not required as part of the uniform collection of information. 

The researchers found that systemic adverse events were reported by 35% of participants after receiving their first dose of a placebo, with headache (19.6%) and fatigue (16.7%) being most commonly reported. Local events – such as pain or swelling at the injection site – were reported in 16.7% of placebo participants. In contrast, 46% of participants receiving a vaccine experienced one systemic adverse event.

The researchers therefore suggest that, while this cohort received a pharmacologically active treatment, some of the reported adverse events are attributable to nocebo effect. Kaptchuk explained this calculation, “After the first injection, for every 100 adverse effects in the vaccine arm of Covid trials there were 76 adverse effects in the placebo injection arm. From this we infer that about 76% of the adverse events in the vaccine arm are due to nocebo. This is a standard way of analyzing adverse effects in clinical trials,” he said.

Following the second dose of a placebo, 32% of trial participants reported a systemic event and 12% reported a local effect. 61% of individuals receiving a COVID-19 vaccine, in comparison, reported a systemic event after the second dose, and 73% reported a local event. Subsequently, the research team calculate that nocebo accounted for ~52% of side effects reported after dose two.

“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 Kaptchuk. “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.”

Strategies to reduce nocebo effects

Concluding their publication, the authors encourage that “public vaccination programs should consider these high nocebo responses”. What exactly might that entail?

Kaptchuk outlined that “open label placebo” approaches to clinical trials and clinical practise could be an effective strategy. “Open-label placebo is a treatment that honestly informs patients that the treatment is a placebo. For many of the subjective systems chronic conditions that are defined by self-report (e.g., pain, fatigue and malaise) preliminary evidence suggests that open-label placebo turns down the volume of the symptoms.” He added that, “When patients are informed that the treatment is really a placebo, they do not get side effects.”

Kaptchuk noted that, in his opinion, the most important weakness of the team’s research is that, as of yet, they do not have a definitive strategy to lower nocebo effects. A simple and honest message to patients could be a starting point, he said, “The message would something like: ‘when the medication I’m prescribing today was tested against a placebo control in a randomized trial, the placebo treatment caused similar effects to the real medication. We think this is about anxiety and worry’.” He concluded that larger, and more definitive studies on this approach and other potential methods will be required to lower nocebo effects.

Professor Ted Kaptchuk was speaking to Molly Campbell, Senior Science Writer and Editor for Technology Networks.

Reference: Haas JW, Bender FL, Ballou S, et al. Frequency of adverse events in the placebo arms of COVID-19 vaccine trials: A systematic review and meta-analysis. JAMA Network Open. 2022;5(1):e2143955-e2143955. doi: 10.1001/jamanetworkopen.2021.43955