Approximately two-thirds of the negative side effects reported from COVID-19 vaccinations were also seen among people who got the placebo in clinical trials, suggesting they were caused by the expectation, rather than the vaccine itself — something researchers hope will encourage vaccinations in the future.
Researchers have taken another look at side effects reported in studies that led to the approval of COVID-19 vaccines last year. Reactions not severe enough to prevent approval, but still unpleasant, were two-thirds as common among people who received a placebo, they report in JAMA Network Open. This means the reactions deterring people from getting vaccinated are usually, although not always, caused by expectation, fear, or worry about vaccination, not the jab itself. We have little to fear from injections but fear itself.
We know the "placebo effect" — just thinking you've been given medication — can often improve people's health, although the reasons behind this are not understood, and the extent to which this occurs is still debated. Consequently, medical trials now almost always involve some participants getting a placebo as a control. In vaccine trials, this is usually a biologically inert saline solution. By subtracting any benefits this produces from what we see for those who received the actual vaccine, we can find out the real level of protection.
Placebos can also lead to negative effects, known as "nocebo", where people get sick because they expect to, including those not actually exposed. Scientists at Beth Israel Deaconess Medical Center decided to test the size of the nocebo effect for 12 COVID-19 vaccine trials and found more nocebo than vaccine effects.
Among more than 45,000 people enrolled in trials for seven vaccines, 28.5 percent of those who got the actual vaccine reported headaches and 26.3 reported fatigue following the first dose. Not only might these be regarded as small prices to pay for potentially life-saving protection, they're also conditions known to be particularly susceptible to the nocebo effect. The study reports 19.6 and 16.7 percent respectively of those who got the placebo reported the same effects.
On the other hand, chills and fever were largely restricted to those receiving the actual vaccine, but these were also considerably rarer.
Adverse events were more common for those getting the second round of the vaccine, reflecting the fact most participants were in mRNA trials, but fell 10 percent among the placebo group. Perhaps a recent mild experience provided protection, one might even say vaccination, against nocebo effects the second time round.
In all, the authors conclude nocebo effects accounted for 76 percent of the reported harmful effects from the first shot and 52 percent of those from the second. Severity was similar between placebo and vaccine for the first injection, but more likely to be severe for those vaccinated in the second round.
“Adverse events after placebo treatment are common in randomized controlled trials,” said lead author Dr Julia Haas in a statement. “Collecting systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide, especially because concern about side effects is reported to be a reason for vaccine hesitancy.” In January 2021, almost half a global survey's respondents were worried about COVID vaccine side effects, and similar concerns have been shown to impede take-up of the flu vaccine.
The good news is studies have shown informing people about nocebo effects reduces both their frequency and fears about getting vaccinated. "Medicine is based on trust," said senior author Professor Ted Kaptchuk. "Our findings lead us to suggest that informing the public about the potential for nocebo responses could help reduce worries about COVID-19 vaccination, which might decrease vaccination hesitancy."
Unfortunately, such campaigns don't have it all their own way. Inevitably, anti-vaxxers, when not inventing vaccine-induced deaths of people who never existed, have played up actually reported side effects. An interesting, but much more difficult to test, topic would be how much worse these stories are making the experience of getting a vaccine for people manipulated into expecting them.