The feasibility of pragmatic influenza vaccine randomized controlled real-world trials in Denmark and England

Abstract

We estimated the frequency of non-specific influenza-associated clinical endpoints to inform the feasibility of pragmatic randomized controlled trials (RCT) assessing relative vaccine effectiveness (rVE). Hospitalization rates of respiratory, cardiovascular and diabetic events were estimated from Denmark and England’s electronic databases and stratified by age, comorbidity and influenza vaccination status. We included a seasonal average of 4.5 million Danish and 7.2 million English individuals, 17 and 32% with comorbidities. Annually, approximately 1% of Danish and 0.5% of English individuals were hospitalized for selected events, ~50% of them respiratory. Hospitalization rates were 40–50-fold and 2–10-fold higher in those >50 years and with comorbidities, respectively. Our findings suggest that a pragmatic RCT using non-specific endpoints is feasible. However, for outcomes with rates <2.5%, it would require randomization of ~100,000 participants to have the power to detect a rVE difference of ~13%. Targeting selected groups (older adults, those with comorbidities) where frequency of events is high would improve trial efficiency.

Comparative effectiveness of adjuvanted versus high-dose seasonal influenza vaccines for older adults: a systematic review and meta-analysis

“…However, it is well-known that the available correlates of SIV-induced protection derived from immunogenicity data are imperfect (Domnich et al, 2020) and should be reviewed. In this regard, efficacy against LCI is historically seen as "gold standard" for assessing the SIV-induced protection, and RCT are considered the most valid study designs to demonstrate a causal relationship (Nealon et al, 2022;WHO, 2017). The lack of head-to-head RCTs and inconclusive observational data on the comparative effectiveness of aTIV vs hdTIV call for future preferably publicly funded RCTs on the relative efficacy of aTIV vs hdTIV.…”

“…No study among those included in this SRMA used LCI as influenza-related outcome, which is considered the "gold standard" clinical endpoint (Nealon et al, 2022;WHO, 2017). The endpoints considered in the included studies mostly comprised medical encounters for influenza or expected influenza-attributable complications and can be considered proxy measures.…”

“…The use of non-specific register-derived influenza-related outcomes has been demonstrated to be a feasible alternative in estimating rVE in pragmatic RCTs, provided that the sample size is sufficiently large (Nealon et al, 2022). On the other hand, within the included studies, there was a vast diversity of non-specific endpoints ranging from all-cause hospitalizations to medically attended ILI.…”

The impact of clinical risk conditions on influenza and pneumonia diagnoses in England: a nationally representative retrospective cohort study, 2010–2019

“…Any such comparison would be liable to strong confounding by indication and ‘healthy vaccinee’ biases by which the baseline health characteristics of vaccine recipients – rather than their vaccination status – predict their health outcomes [22]. Indeed, we previously observed up to fourfold elevated rates of cardiovascular and up to ninefold higher rates of respiratory disease in younger adult influenza vaccine recipients than non-recipients, presumably due to English recommendations for influenza vaccine only in adults with existing chronic health conditions who are relatively likely to suffer hospitalisations [23]. In contrast, randomized experiments, free of these biases, measuring the efficacy of influenza vaccination on preventing cardiovascular events have found strong protective effects deserving of future research [24, 25].…”

The World of Vaccines: Phases of Clinical Trials and Current Status of COVID-19 Vaccines

“…101 Since the primary purpose of this study is to assess long-term safety and protection, parallel designs with a full dosing regimen of an existing vaccine or a historical control are employed to compare the safety and effectiveness of the new vaccine for the same infectious disease. [100][101][102] Moreover, the safety and efficacy of newer vaccines may also be studied in special populations who were excluded in the previous phases of vaccine clinical trials. 100,103 In accelerated and priority trials, a Phase 4 study is planned with a cross-over design to evaluate the efficacy of a homologous or heterologous booster dose of vaccine in comparison to previous exposure to the same vaccine and participants are followed up for at least 2 years with an intermittent assessment of the risk of infection and protection from disease after the full (prime-booster) vaccine regimen.…”