Vaccine adverse effects may be in our heads — a systematic review and meta-analysis

Vaccine adverse effects are a point of contention with anti-vaccine activists. They always seem to overstate their frequency and claim that it’s much more frequent than reported. On the other hand, many of us on the science side agree that the number of adverse events is vastly overstated, especially in the Vaccine Adverse Events Reporting System (VAERS), which is not a very good system for tracking these things.

Well, a new systematic review and meta-analysis, published in a respected journal, indicates that many reports of adverse effects in the COVID-19 vaccine clinical trials can be attributed to the placebo effect. As I like doing, let’s review this new paper.

vaccine adverse events
Photo by OSPAN ALI on Unsplash

Vaccine adverse effects — the systematic review

The paper, by Julia Haas, Ph.D., of Beth Israel Deaconess Medical Center in Boston, and colleagues, was published in the peer-reviewed journal, JAMA Network Open on 18 January 2022. The systematic review and meta-analysis, which are considered the pinnacle of the hierarchy of biomedical and vaccine research, examined 12 published articles that included adverse event reports for 45,380 COVID-19 vaccine trial participants, divided into 22,578 placebo recipients and 22,802 vaccine recipients. The systematic review included vaccines from Moderna, Pfizer, Novavax, Sanofi Pasteur, AstraZeneca, Clover, and Johnson & Johnson. The studies were performed in the USA, Australia, South Africa, and other countries.

The researchers found that:

  • About one third of placebo recipients in COVID-19 reported at least one systematic adverse event following both doses of vaccines.
  • So-called “nocebo responses,” the ratio of adverse events between the placebo and vaccine arms of the studies, accounted for 76% of the reported vaccine systematic adverse events after the first dose, and 52% of them after the second vaccine dose.
  • After the first dose, 35.2% of placebo recipients experienced systematic adverse events with headache (19.3%) and fatigues (16.7%) being the most common.
  • After the second dose, 31.8% of the placebo group experienced systematic adverse events.
  • After the first dose, 46.3% of the vaccine group experienced systematic adverse events.
  • After the second dose, 66.7% of the vaccine group experience them.
  • As expected, significantly more individuals in the vaccine group reported adverse events, but the difference between the vaccine and placebo groups increased after the second dose. The odds ratio between groups was -0.47 after the first dose and -1.36 after the second dose.

Based on this data, Haas’ team hypothesized that the second dose of vaccine:

…produced both a more robust immune response and a correspondingly more robust set of AEs and that […] participants in the vaccine arms, after experiencing more AEs after the first dose than did participants in the control groups, had higher expectations for AEs after the second dose compared with participants in the placebo arms.

The authors described some limitations to the data including the small number of trials, as well as high heterogeneity from a lack of standardized data — different methods of assessing AEs to different vaccines tested to different probabilities of receiving a vaccine or placebo.

Haas’ group suggested that both vaccine manufacturers and the media should educate the public about nocebo responses. They proposed:

…participants in the placebo arm of the randomized clinical trials testing this intervention reported similar AEs, probably because of worry and anxiety.

Photo by Dex Ezekiel on Unsplash


I had noticed a large number of adverse events in these COVID-19 vaccine clinical trials, especially in the placebo group. Unfortunately, I wasn’t aware of a statistical model that would show the true adverse event rate by comparing it to the placebo group. Now I know about the nocebo effect.

I’m not a big fan of the placebo effect, because it really only has an effect on subjective indicators like pain and headache (which were the majority of systemic adverse events in these trials). But with the amount of attention and focus that was put on these clinical trials in 2020, it makes sense that the placebo (or nocebo) effect would be a large part of the adverse events in both the vaccine and placebo groups.

But I think this initial analysis, based on powerful systematic reviews and meta-analyses, does indicate that a large proportion of systematic adverse events were “in their head.” I hope that someone with the statistical skills to perform these kinds of analyses would look at other vaccine clinical trials to determine if there are also nocebo effects there.

Although this is not a thorough statistical analysis and is just my anecdote, I had zero adverse effects after each of my three Moderna vaccinations (including the booster). I’m like the anti-nocebo effect, since I am so vehemently skeptical of the placebo effect, I’m convinced it’ll never happen to me.

Remember, this study only accounted for a portion of the COVID-19 vaccine adverse events with the nocebo effect. Clearly, there were people in the vaccine arm of the trials who did experience real adverse events, and they have been tracked accordingly. What this study says is that we greatly overestimated the rate of adverse events in the vaccine group, which is something that we should be aware of in the future.

This is just more information that those who are opposed to vaccinations, especially for COVID-19, are misusing data. They need to compare the risk of adverse events in the vaccine group to the same risk in the placebo group, giving us the actual risk for each adverse event.


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