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Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine TrialsA Systematic Review and Meta-analysis

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Question  What was the frequency of adverse events (AEs) in the placebo groups of COVID-19 vaccine trials?

Findings  In this systematic review and meta-analysis of 12 articles including AE reports for 45 380 trial participants, systemic AEs were experienced by 35% of placebo recipients after the first dose and 32% after the second. Significantly more AEs were reported in the vaccine groups, but AEs in placebo arms (“nocebo responses”) accounted for 76% of systemic AEs after the first COVID-19 vaccine dose and 52% after the second dose.

Meaning  This study found that the rate of nocebo responses in placebo arms of COVID-19 vaccine trials was substantial; this finding should be considered in public vaccination programs.


Importance  Adverse events (AEs) after placebo treatment are common in randomized clinical drug trials. Systematic evidence regarding these nocebo responses in vaccine trials is important for COVID-19 vaccination worldwide especially because concern about AEs is reported to be a reason for vaccination hesitancy.

Objective  To compare the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials with those reported in the vaccine groups.

Data Sources  For this systematic review and meta-analysis, the Medline (PubMed) and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched systematically using medical subheading terms and free-text keywords for trials of COVID-19 vaccines published up to July 14, 2021.

Study Selection  Randomized clinical trials of COVID-19 vaccines that investigated adults aged 16 years or older were selected if they assessed solicited AEs within 7 days of injection, included an inert placebo arm, and provided AE reports for both the vaccine and placebo groups separately. Full texts were reviewed for eligibility by 2 independent reviewers.

Data Extraction and Synthesis  Data extraction and quality assessment were performed independently by 2 reviewers, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline and using the Cochrane risk-of-bias tool. Meta-analyses were based on random-effects models.

Main Outcomes and Measures  The primary outcomes were the proportions of placebo recipients reporting overall, systemic, and local (injection-site) AEs as well as logarithmic odds ratios (ORs) to evaluate group differences. Outcomes were tested for significance using z tests with 95% CIs.

Results  Twelve articles with AE reports for 45 380 participants (22 578 placebo recipients and 22 802 vaccine recipients) were analyzed. After the first dose, 35.2% (95% CI, 26.7%-43.7%) of placebo recipients experienced systemic AEs, with headache (19.3%; 95% CI, 13.6%-25.1%) and fatigue (16.7%; 95% CI, 9.8%-23.6%) being most common. After the second dose, 31.8% (95% CI, 28.7%-35.0%) of placebo recipients reported systemic AEs. The ratio between placebo and vaccine arms showed that nocebo responses accounted for 76.0% of systemic AEs after the first COVID-19 vaccine dose and for 51.8% after the second dose. Significantly more vaccine recipients reported AEs, but the group difference for systemic AEs was small after the first dose (OR, −0.47; 95% CI, −0.54 to −0.40; P < .001; standardized mean difference, −0.26; 95% CI, −0.30 to −0.22) and large after the second dose (OR, −1.36; 95% CI, −1.86 to −0.86; P < .001; standardized mean difference, −0.75; 95% CI, −1.03 to −0.47).

Conclusions and Relevance  In this systematic review and meta-analysis, significantly more AEs were reported in vaccine groups compared with placebo groups, but the rates of reported AEs in the placebo arms were still substantial. Public vaccination programs should consider these high rates of AEs in placebo arms.

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Article Information

Accepted for Publication: November 22, 2021.

Published: January 18, 2022. doi:10.1001/jamanetworkopen.2021.43955

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Haas JW et al. JAMA Network Open.

Correction: This article was corrected on February 11, 2022, to fix an error in Figure 1.

Corresponding Author: Julia W. Haas, PhD, Program in Placebo Studies, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Ste 1309, Boston, MA 02215 (

Author Contributions: Dr Haas and Ms Bender contributed equally to this study. Dr Rief and Prof Kaptchuk contributed equally to this study. Dr Haas and Ms Bender had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Haas, Bender, Ballou, Wilhelm, Miller, Kaptchuk.

Acquisition, analysis, or interpretation of data: Haas, Bender, Kelley, Rief, Kaptchuk.

Drafting of the manuscript: Haas, Bender, Kaptchuk.

Critical revision of the manuscript for important intellectual content: Bender, Ballou, Kelley, Wilhelm, Miller, Rief, Kaptchuk.

Statistical analysis: Haas, Bender, Kelley, Wilhelm.

Obtained funding: Haas.

Administrative, technical, or material support: Rief.

Supervision: Ballou, Kelley, Wilhelm, Rief, Kaptchuk.

Conflict of Interest Disclosures: Dr Haas reported receiving a postdoctoral scholarship from the German Academic Exchange Service (Deutscher Akademischer Austauschdienst) during the conduct of the study. No other disclosures were reported.

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