Nocebo responses in randomized controlled trials of COVID-19 vaccines

Abstract

Objective: The aim of this study was to evaluate the frequency and magnitude of nocebo responses in COVID-19 vaccine trials. Materials and methods: We performed a meta-analysis of adverse effects (AEs), severe adverse effects (SAEs), withdrawal due to AEs, death, and immune-mediated SAEs observed in randomized controlled trials (RCTs) of COVID-19 vaccines. Results: Four RCTs with a total of 119,110 participants (65,254 from the vaccine group and 53,856 from the placebo group) were considered. The pooled estimate of AEs in the placebo and vaccine groups was 16.4% (95% confidence interval (CI), 9.1 - 27.7%) and 25.3% (95% CI, 22.7 - 28.1%), respectively. The pooled SAE rate in the placebo and vaccine groups was 0.7% (95% CI, 0.5 - 1.0%) and 0.6% (95% CI, 0.4 - 0.9%), respectively. The pooled estimate of participants who withdrew from treatment due to AEs in the placebo and vaccine groups was 0.3% (95% CI, 0.1 - 1.0%) and 0.2% (95% CI, 0.1 - 0.5%), respectively. The pooled death rate in the placebo and vaccine groups was 0.02% (95% CI, 0.01 - 0.04%) and 0.01% (95% CI, 0.01 - 0.03%), respectively. The pooled estimate of immune-mediated SAEs in the placebo and vaccine groups was 0.01% (95% CI, 0.01 - 0.04%) and 0.02% (95% CI, 0.01 - 0.05%), respectively. There were no differences observed in the pooled risk of AEs, SAEs, withdrawal due to AEs, death, and immune-mediated SAEs between placebo and vaccine groups. Conclusion: The frequency and magnitude of nocebo responses were 16.4% and 0.3%, respectively. Therefore, the incidence of nocebo responses was high, but their magnitude was low in COVID-19 vaccine trials.