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

Abstract

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.

Figure 1.. PRISMA Flow Diagram

Figure 2.. Forest Plots of Any Systemic Adverse Events After the First and Second Doses of the COVID-19 Vaccine or Placebo

Random-effects pooled proportions are shown. Boxes represent the effect size of each study and whiskers, 95% CIs. Box size indicates the study’s weight in the analysis. Diamonds indicate pooled estimates, with whiskers indicating 95% CIs. Studies that did not provide data for the “any systemic adverse event” category were not included in these analyses but only in analyses on other adverse event categories. All placebos used were inert saline solutions. ^amRNA-1273 (Moderna, mRNA vaccine, phase 3 trial). Probability of being randomized to placebo group, 50%. ^bmRNA-1273 (Moderna, mRNA vaccine, phase 2 trial). Vaccine group was selected for comparison in trials that investigated multiple dosing schemes (100 μg [high dose]). Probability of being randomized to placebo group, 33%. ^cNVX-CoV2373 (Novavax, protein-based vaccine, phase 3 trial). Vaccine contained adjuvants. Probability of being randomized to placebo group, 50%. ^dNVX-CoV2373 (Novavax, protein-based vaccine, phase 1-2 trial). Vaccine contained adjuvants. Vaccine group was selected for comparison in trials that investigated multiple dosing schemes (5 μg [low dose] + adjuvant). Probability of being randomized to placebo group, 20%. ^eBNT162b2 (BioNTech/Pfizer, mRNA vaccine, phase 2-3 trial). Probability of being randomized to placebo group, 50%. ^fSCB-2019 (Clover, protein-based vaccine, phase 1 trial). Vaccine contained adjuvants. Vaccine group was selected for comparison in trials that investigated multiple dosing schemes (30 μg [high dose] + adjuvant). Probability of being randomized to placebo group, 20%. ^gNVX-CoV2373 (Novavax, protein-based vaccine, phase 2a-b trial); vaccine contained adjuvants. Probability of being randomized to placebo group, 50%.