Really just a little prick? A meta-analysis on adverse events in placebo control groups of seasonal influenza vaccination RCTs

Bender, Friederike L.; Rief, Winfried; Wilhelm, Marcel

doi:10.1016/j.vaccine.2022.11.033

Cited by 10 publications

(9 citation statements)

References 65 publications

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“…However, a recent meta-analysis suggested that a significant proportion of placebo recipients in influenza vaccine trials experienced systemic AEs, such as headache or fatigue, owing to nocebo responses. 29 Researchers of nocebo response have called attention to ubiquitous nocebo responses in COVID-19 vaccination, 30,31 but systematic quantification is needed. The current systematic review and meta-analysis aimed to assess the frequencies of AEs reported in the placebo groups of COVID-19 vaccine trials and compare them with the frequencies of AEs reported in the vaccine groups.…”

Section: Introductionmentioning

confidence: 99%

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials

et al. 2022

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IMPORTANCEAdverse 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 MEASURESThe 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. RESULTSTwelve 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

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Section: Introductionmentioning

confidence: 99%

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials

et al. 2022

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“…Consider the contrast E(Y a=1;m= 1 jB a=1;m= 1 = b) v:s: E(Y a=0;m= 1 jB a=0;m= 1 = b): (8) This contrast is not a causal effect, in the sense that this contrast is not a comparison of counterfactual outcomes in the same subset of individuals. However, when Assumption 6 holds, we can rewrite (8) as (9) which is a causal effect of treatment a = 1 v.s. a = 0 among those with a particular belief b when m = −1.…”

Section: Conditional Causal Effectsmentioning

confidence: 99%

“…[4][5][6][7] Conventional vaccine trials are designed to identify the immunologic effects of vaccines. 8 These trials often have blinded treatment and control groups 9,10 and the rationale for (patient) blinding is precisely to eliminate the nonimmunologic effects of vaccination. Indeed, an ideal placebo control satisfies two criteria: it does not have any cross-reactivity with the pathogen in question and it is perceived to be indistinguishable from the vaccine, for example, by inducing common vaccine side effects such as fever or soreness in the place of injection.…”

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confidence: 99%

Distinguishing Immunologic and Behavioral Effects of Vaccination

Stensrud,

Nevo,

Obolski

2024

Epidemiology

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The interpretation of vaccine efficacy estimands is subtle, even in randomized trials designed to quantify the immunologic effects of vaccination. In this article, we introduce terminology to distinguish between different vaccine efficacy estimands and clarify their interpretations. This allows us to explicitly consider the immunologic and behavioral effects of vaccination, and establish that policy-relevant estimands can differ substantially from those commonly reported in vaccine trials. We further show that a conventional vaccine trial allows the identification and estimation of different vaccine estimands under plausible conditions if one additional post-treatment variable is measured. Specifically, we utilize a “belief variable” that indicates the treatment an individual believed they had received. The belief variable is similar to “blinding assessment” variables that are occasionally collected in placebo-controlled trials in other fields. We illustrate the relations between the different estimands, and their practical relevance, in numerical examples based on an influenza vaccine trial.

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“…Influenza vaccination causes a short-term inflammatory response which may result in adverse effects such as headache, malaise and hyperhidrosis in the week following vaccination. Serious adverse effects of influenza vaccination are rare [3]. Whilst influenza vaccination is associated with a reduced risk of stroke in the 6 months after vaccination (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.76-0.79) [4], the short-term inflammatory response could paradoxically be associated with a slight increase in stroke risk.…”

Section: Introductionmentioning

confidence: 99%

Risk of stroke within 3, 7, 14, 21 and 30 days after influenza vaccination in Alberta, Canada: A population‐based study

Tanaka,

Demchuk,

Malo

et al. 2023

Euro J of Neurology

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Background and purposeInfluenza vaccination is associated with a longer‐term protective effect against stroke; however, it has a short‐term inflammatory response which may increase short‐term risk of stroke. The aim was to investigate the association between influenza vaccination and short‐term risk of stroke in adults.MethodsAdministrative data were obtained from the Alberta Health Care Insurance Plan for all adults in Alberta, Canada, from September 2009 to December 2018. The hazard of any stroke (acute ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage and transient ischaemic attack) within 3, 7, 14, 21 and 30 days of influenza vaccination compared to unexposed time was analysed using Andersen−Gill Cox models, with adjustment for age, sex, anticoagulant use, atrial fibrillation, chronic obstructive pulmonary disease, diabetes, hypertension, income quintile, and rural or urban home location.ResultsIn the entire cohort consisting of 4,141,209 adults (29,687,899 person‐years), 1,769,565 (42.7%) individuals received at least one vaccination. In total 38,126 stroke events were recorded with 1309 occurring within 30 days of a vaccination event. Influenza vaccination was associated with a significantly reduced hazard of stroke within 3 days (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.73–0.93), 7 days (HR 0.87, 95% CI 0.80–0.95), 14 days (HR 0.87, 95% CI 0.81–0.93), 21 days (HR 0.85, 95% CI 0.80–0.91) and 30 days (HR 0.66, 95% CI 0.65–0.68).ConclusionsAn increased early risk associated with vaccination was not observed. The risk of stroke was reduced at all time points within 30 days after influenza vaccination.

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Really just a little prick? A meta-analysis on adverse events in placebo control groups of seasonal influenza vaccination RCTs

Cited by 10 publications

References 65 publications

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials

Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials

Distinguishing Immunologic and Behavioral Effects of Vaccination

Risk of stroke within 3, 7, 14, 21 and 30 days after influenza vaccination in Alberta, Canada: A population‐based study

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