Rate of adverse events in placebo arms of COVID-19 vaccine trials

1. This meta-analysis suggested that the nocebo response, an adverse event (AE) in response to a placebo, accounted for 76.0% of systemic AEs against the first COVID-19 vaccine dose and 51.8% of systemic AEs to the second dose.

2. Severe systemic AEs occurred at a similar rate in the vaccine group compared to the placebo group after the first dose but were more frequent after the second dose in the vaccine group.

Evidence Rating Level: 1 (Excellent)

Study Rundown: An estimated 20% of the global population plans to refuse vaccination with any one of the many COVID vaccinations. A major reason for vaccine hesitancy may be vaccine adverse events (AEs). AEs can occur to patients in the placebo group, called a nocebo response, because of expectations manifesting symptoms or misattributing background symptoms. This meta-analysis attempts to quantify the nocebo effect in COVID-19 vaccination trials. Randomized clinical trials (RCTs) featuring a two-dose COVID-19 vaccine arm and a true placebo arm that were published before July 14, 2021 were screened for inclusion in this meta-analysis by two independent reviewers. 45,380 participants (n = 22,578 placebo recipients; n = 22,802 vaccine recipients) from 12 studies were included from high quality trials. 35.2% of participants that received a single dose of placebo reported having a systemic AE. Participants experienced statistically significantly fewer AEs with their second dose of placebo compared to their first. The most common nocebo effects were headache and fatigue. The vaccine group experienced more AEs after 1 dose and superiorly more AEs after 2 doses than the placebo group. AEs in response to placebo made up 76.0% of systemic and 24.3% of local AEs after the first dose and 51.8% of systemic and 16.2% of local AEs after the second COVID-19 vaccine dose. From the 2 trials that reported the severity of AEs, severe systemic AEs occurred at a similar rate after the first dose but were more frequent after the second dose of the vaccine compared to the placebo. One limitation of this study is the few trials included what were highly heterogeneous, thereby preventing meta-regression. However, this is a strength as the varied included trial phases and vaccines used in practices reflect healthcare suggesting that this data on nocebo rates is generalizable. Another limitation of this study is its ability to draw conclusions about the severity of AEs, as only 2 studies reported data on this. However, this meta-analysis was rigorous in classifying AEs as local or systemic and reporting the most common AE symptoms.

Click to read the study in JAMA Network Open

Relevant Reading: Experiencing COVID-19 symptoms without the disease: The role of nocebo in reporting of symptoms

In-Depth [systematic review and meta-analysis]: The Medline and Cochrane Central Register of Controlled Trials Studies were searched for studies published on AE in COVID vaccine trials. This meta-analysis included RCTs reporting the AEs in the 7 days after each dose of a two-dose COVID vaccine or placebo given to persons ≥16 years old. Two independent reviewers screened all eligible studies and selected the articles fit for inclusion. This meta-analysis included 22,578 placebo recipients and 22,802 vaccine recipients from 12 studies. Per a risk-of-bias assessment, the publications were generally of high quality, with only 1 study being flagged for a high dropout rate of 16% in only the placebo group and 4 studies being flagged for having sentinel participants. The most common AEs in the placebo group were headache (1^st dose: 19.3%, 95% CI = 13.6%-25.1%; 2^nd dose: 16.2%, 95% CI = 12.5%-19.8%) and fatigue (1^st dose: 16.7%, 95% CI = 9.8%-23.6%; 2^nd dose: 14.9%, 95% CI = 9.8%-20.1%). 35.2% of the placebo recipients reported at least 1 systemic AE (95% CI = 26.7%-43.7%) and 16.2% reported a local AE (95% CI = 11.3%-21.1%) after 1 dose. Compared to the placebo group, there were significantly more AEs after 1 dose of vaccine, with 46.3% of vaccine group participants having systemic AEs (95% CI = 38.2%-54.3%; pooled log OR = -0.47, 95% CI = -0.54 to -9.40, P < 0.001) and 66.7% having local AEs (95% CI = 53.2%-80.3%; pooled log OR = -2.44, 95% CI = -3.21 to -1.66). After 2 doses of placebo, compared to 1, there were significantly fewer systemic AEs (31.8% vs 35.2%, 95% CI = 28.7%-35.0%; log OR = 0.33, 95% CI = 0.18-0.47, P < 0.001) and fewer local AEs (11.8% vs 16.2%, 95% CI = 6.6%-17.1%; log OR = 0.22, 95% CI = 0.08-0.36, P = 0.002). After the second dose, the effect size difference between the AE reported in the vaccinated compared to the placebo group was superior to that after the first dose (OR = -1.36, 95% CI = -1.86 to -0.86; P < 0.001). Nocebo systemic AE responses were 76.0% of responses after 1 dose of COVID-19 vaccine dose and 51.8% of responses after 2 doses. There was high heterogeneity between the studies for reported systemic, local, and any-type AEs (I² ≥ 50%). 2 trials reported the severity of AEs. The subset of participants with severe systemic AEs was similar between the placebo and vaccinated group after the first dose. After the second dose, however, a larger proportion of vaccinated participants reported a severe systemic AE than placebo participants.

Image: PD

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