Opinion – Bruno Gualano: Anxiety and bad expectations are behind the most common adverse events in vaccines

In the 16th century, the Austrian physician Franz Mesmer preached that all living and inanimate beings would be endowed with an invisible natural force with healing properties, evoked through the “mesmerization” of objects. Fed up with the litany, French monarch Luis 16 appointed Benjamin Franklin and Antoine Lavoiser to investigate the practice.

The famous scientists then decided to compare the responses of patients exposed to “mesmerized” or merely ordinary objects, without declaring them as such. As the reactions did not differ between conditions, Franklin and Lavoiser concluded that the effects of mesmerism were the product of “imagination”, and that its creator was nothing more than a charlatan.

This is touted as the first placebo-controlled experiment in history. Who tells it is Ted Kaptchuck —one of the greatest authorities on the subject— in an article published in the Bulletin of the History of Medicine (Intentional ignorance: a history of blind assessment and placebo controls in medicine), which narrates the advances of science on the intriguing placebo effect.

The placebo effect can be defined as a positive organic response produced by an inert intervention. For example, people treated with homeopathy, especially when they believe in its effectiveness, may have some favorable clinical results, but which are equivalent to those produced by non-active substances – called controls or placebos, in the context of a clinical trial. Can we say that homeopathy “works”? Yes, thanks to (or at the expense of) the placebo effect.

The true opposite of the placebo effect is nocebo—a negative organic response induced by an inert intervention. Just as good expectations are capable of leading to positive outcomes, hopelessness does the opposite.

Kaptchuck and team conducted a recent study that illustrates the ubiquity of the nocebo effect in our lives. The researchers reviewed 12 studies that reported the frequency of non-serious adverse events in people vaccinated against Covid-19 and in those who received the injection with the inactive substance.

Compared to the falsely immunized, the vaccinated had a higher frequency of systemic (fatigue, headache, malaise, joint pain) and localized (pain, redness and swelling associated with the injection) adverse events. However, the number of adverse events among those who received the placebo was substantial: 35% and 32% after the first and second doses, respectively.

By calculating the ratio of occurrences between vaccinated and unvaccinated, the researchers were able to estimate that 76% of systemic adverse events after the first dose are not associated with the immunizer itself, but with the nocebo effect.

The findings are relevant to public health. Specialists, regulatory agencies and the media themselves usually attribute symptoms such as fatigue and headache directly to the action of vaccines, although these also often occur in the absence of any active treatment, as seen in the study. This kind of halved information can produce anxiety and bad expectations, increasing the number of adverse events associated with the nocebo effect.

Obviously, clarification about potential adverse events inherent to any type of medication is an ethically necessary measure. However, recent data suggest that people who are also informed about the existence of the nocebo effect are less likely to experience side effects.

The main cause of reluctance or refusal to vaccinate is fear of adverse events. As Kaptchuck advises, educational campaigns should clarify that up to 3 in 4 occurrences associated with immunizations are actually due to the nocebo effect. Such a measure could reduce vaccine reluctance — a phenomenon listed by the WHO among the ten global health threats.

I conclude by recommending our dear reader to renew optimism about vaccines. Not “just” because they save lives — as has been abundantly documented — but also because pessimists tend to suffer more from the nocebo effect.