Standard-dose Quadrivalent Influenza Vaccine Research Articles

Effect of high-dose vs. standard-dose quadrivalent influenza vaccine on death and hospitalizations in older adults with cardiovascular disease: a prespecified analysis of the DANFLU-1 study

Abstract Background The results of the DANFLU-1 trial indicated that high-dose quadrivalent influenza vaccines (HDQIV) as compared to standard-dose quadrivalent influenza vaccines (SDQIV) may reduce the incidence of death and hospitalization with pneumonia or influenza in older adults. Whether this effect differs by the presence of cardiovascular disease is unknown. Purpose To conduct a prespecified analysis aimed at assessing whether the presence of cardiovascular disease at baseline modified the effect of HDQIV vs SDQIV on clinical outcomes in the DANFLU-1 trial. Methods DANFLU-1 was a pragmatic, open-label trial randomizing 12,477 adults aged 65-79 years 1:1 to HDQIV vs SDQIV during the 2021/2022 influenza season. The trial used the Danish nationwide registers to collect both baseline and outcome data. Participants were included in October and November of 2021 and follow-up ended on May 31, 2022. In this prespecified analysis, we assessed the effectiveness of HDQIV vs SDQIV on clinical endpoints according to the presence of cardiovascular disease at baseline and across different cardiovascular subgroups including ischemic heart disease, heart failure and atrial fibrillation. Effectiveness was assessed with Cox proportional hazards regression. In addition, hospitalizations were also assessed with recurrent event analysis using negative binomial regression. Results The mean age of the 12,477 participants in the DANFLU-1 trial was 71.7 years (SD 3.9) and 6600 (53%) were male. During a median follow-up of 237 days (interquartile range 232-239 days), 62 participants died (0.5%), 38 (0.3%) were hospitalized with pneumonia or influenza, 220 (1.8%) were hospitalized with a cardiorespiratory diagnosis, and 192 (1.5%) were hospitalized with a cardiovascular diagnosis. HDQIV was associated with a lower incidence of death during follow-up as compared with SDQIV (HR 0.51 [95% CI 0.30-0.86], p=0.012), and this effect was consistent in participants with CVD and without CVD and across cardiovascular subgroups (Figure 1). HDQIV was also associated with a lower incidence of hospitalization with pneumonia or influenza (IRR 0.30 (95% CI 0.14-0.64, p=0.002), and this effect was consistent irrespective of CVD (subgroup estimates were inestimable due to low power) (Figure 2). There was no difference in the incidence of cardiorespiratory or cardiovascular hospitalization between the HDQIV and SDQIV group. No significant effect modification by the presence of CVD or cardiovascular subgroups was observed (Figure 1 and 2). Conclusions In this prespecified analysis of the DANFLU-1 randomized trial, high-dose influenza vaccine was associated with a reduced rate of death and hospitalization with influenza or pneumonia and this effect was consistent in participants with CVD and across cardiovascular subgroups.Figure 1:Time to event analysisFigure 2:Recurrent event analysis

Relative effectiveness of high-dose vs. standard-dose quadrivalent influenza vaccine according to time of day of vaccination: a post-hoc analysis of the DANFLU-1 randomised clinical trial

Abstract Background Circadian variations have been shown to affect antibody response following vaccination. We sought to evaluate whether time of day of vaccination (ToV) modified the relative effectiveness of high-dose (QIV-HD) vs. standard-dose (QIV-SD) quadrivalent influenza vaccination, and further whether ToV was independently associated with hospitalisations and mortality. Methods This is a post-hoc analysis of the DANFLU-1 trial which was a randomized trial of QIV-HD vs. QIV-SD in adults aged 65-79 years conducted during the 2021-2022 influenza season. Vaccination took place between 7:05 AM and 8:08 PM. For this study, we stratified participants into early and late vaccination groups according to ToV before or after 11 AM, respectively. Prespecified outcomes included hospitalisations for pneumonia or influenza, respiratory disease, cardiovascular disease, and cardio-respiratory disease as well as all-cause hospitalisations and mortality. Hospitalisations were analysed as recurrent events using negative binomial regression, while mortality was analysed using Cox proportional hazard models, both of which were also used to test for interaction. For multivariable analysis, models were adjusted for baseline risk factors including sex, age, and multiple lung diseases. ToV was furthermore assessed as a continuous variable with 2-hour increments. Results In the final study population, the early group consisted of 5,371 (43%) participants (mean age 71.6±3.9 years, male sex 53.6%, QIV-SD 50.1%), while the late group consisted of 7,106 (57%) (mean age 71.8±4.0 years, male sex 52.4%, QIV-HD 49.9%). During follow-up, we observed 43 hospitalisations for pneumonia or influenza, 76 respiratory hospitalisations, and 62 mortalities. In recurrent event analysis, QIV-HD was associated with lower incidence of hospitalisation for pneumonia or influenza compared with QIV-SD irrespective of whether administered early (IRR 0.17 (95% CI 0.03-0.86), p=0.032) or late (IRR 0.37 (95% CI 0.16-0.88), p=0.024) (p-value for interaction = 0.69) (Figure 1). Effect estimates were consistent for all outcomes excluding cardiovascular hospitalisations regardless of early or late vaccination, and no effect modification was found (Figure 1). Interestingly, late vaccination was associated with higher incidence rate of respiratory hospitalisation (IRR 3.00 (95% CI 1.13-7.98), p=0.024, Figure 2), irrespective of vaccine type. The same association was found for ToV as a continuous variable (IRR 1.28 per 2-hour increment (95% CI 1.02-1.60), p=0.035). All above associations remained significant in multivariable analysis. Conclusion QIV-HD was associated with lower incidence of hospitalisation for pneumonia or influenza regardless of time of day for vaccination. In addition, later vaccination was associated with higher incidence of respiratory hospitalisation independent of vaccine type and known risk factors. Due to low power, however, this finding should be regarded as exploratory.Figure 1:Forest plotFigure 2:Incidence rates

Relative effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against hospitalizations and mortality according to frailty score: a post-hoc analysis of the DANFLU-1 trial

Abstract Background Frailty is a major risk factor for adverse cardiovascular events. Influenza vaccination has been shown to protect against cardiovascular fatal and nonfatal events. However, limited data exist on the added benefit of high-dose versus standard-dose influenza vaccination according to frailty status. Purpose We sought to assess the relative effectiveness of high-dose (QIV-HD) versus standard-dose (QIV-SD) quadrivalent influenza vaccination according to frailty status in elderly individuals. Methods This is a post-hoc analysis of the randomized controlled feasibility trial of QIV-HD versus QIV-SD conducted during the 2021–2022 influenza season in adults aged 65–79 years. We assessed the following prespecified outcomes: hospitalizations for pneumonia or influenza, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations and all-cause mortality. Level of frailty was defined according to the Hospital Frailty Risk Score based on ICD-10 codes for relevant comorbidities any time prior to vaccination. We divided the participants into two categories according to Frailty Score (FS): low frailty (0-4 points) and intermediate or high frailty (≥5 points). We analyzed outcomes as time to first event using Cox proportional hazards regression. Results Among 12,473 randomly assigned participants to QIV-HD versus QIV-SD (mean age 71.7 years, 47.1% female), 10,711 (85.9%) were categorized as having low frailty and 1,762 (14.1%) had intermediate or high frailty. In total, 38 individuals were hospitalized for pneumonia or influenza during follow-up, 219 were hospitalized for cardiorespiratory illness, 1055 were hospitalized due to any cause and 62 died during follow-up. FS significantly modified the effect of QIV-HD versus QIV-SD for all-cause mortality (P for interaction 0.02). In participants with low frailty, QIV-HD was associated with a lower risk of all-cause mortality (Figure 1: HR 0.26, 95% CI 0.13 to 0.55), whereas there was no evidence of effect among those with intermediate or high frailty (HR 1.68, 95% CI 0.66 to 4.26). QIV-HD versus QIV-SD was associated with a lower incidence of hospitalizations for pneumonia and influenza, this effect was consistent regardless of frailty status (P for interaction 0.88). QIV-HD was not associated with a significantly lower incidence of hospitalizations due to cardiovascular, cardiorespiratory or respiratory disease or any cause regardless of frailty status. Conclusions In this post-hoc analysis of a large-scale pragmatic trial, QIV-HD was similarly associated with a lower incidence of hospitalizations for pneumonia and influenza among older adults irrespective of frailty status. The potential benefit of QIV-HD versus QIV-SD may therefore be applicable regardless of frailty status. However, our results suggest that QIV-HD is associated with a lower risk of all-cause mortality among adults with low frailty only.Figure 1.

Immunogenicity and Reactogenicity of High-dose or Standard-dose Influenza Vaccine in a Second Consecutive Influenza Season.

Pediatric hematopoietic cell transplant (HCT) recipients are at high-risk for morbidity from influenza virus infection. We demonstrated in a primary phase II randomized controlled trial that two post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart were more immunogenic than two doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen. A subcohort of study participants re-enrolled and had hemagglutinin inhibition (HAI) titers measured at baseline and four weeks after each vaccine dose in year two. We estimated geometric mean fold rise (GMFR) in HAI titer from baseline for each group and used linear mixed effects models to estimate adjusted geometric mean ratios (aGMR, comparing HD-TIV to SD-QIV) for each antigen at each time point. We described systemic and injection-site reactions. A total of 65 subcohort patients participated (33 SD-QIV, 32 HD-TIV). Post-vaccine GMFR and aGMR estimates were higher for both groups following a single influenza vaccine dose in year two compared to two doses of the same formulation in year one. Both groups had similar frequencies of injection-site and systemic reactions. A single dose of HD-TIV or SD-QIV was more immunogenic in year two than two doses of the same formulation in year one. Reactogenicity was comparable between groups. One dose of influenza vaccine may be sufficient after a two-dose schedule in the prior year post-HCT.

Time of day for vaccination, outcomes, and relative effectiveness of high-dose vs. standard-dose quadrivalent influenza vaccine: A post hoc analysis of the DANFLU-1 randomized clinical trial

Morning influenza vaccination enhances antibody response. In this post hoc analysis of the DANFLU-1 trial, we sought to evaluate the association between time of day for vaccination (ToV) and outcomesand whether ToV modified the relative effectiveness of high-dose (QIV-HD) vs. standard-dose (QIV-SD) quadrivalent influenza vaccine. DANFLU-1 was a pragmatic feasibility trial of QIV-HD vs. QIV-SD. Outcomes included hospitalizations and mortality. For subgroup analysis, the population was dichotomized at median ToV into two groups (early and late). The study population included 12,477 participants. Mean age was 71.7±3.9 years with 5877 (47.1%) female participants. Median ToV was 11.29AM. Earlier ToV was associated with fewer respiratory hospitalizations independent of vaccine type, which persisted in adjusted analysis (IRR 0.88 per 1-hour decrement (95% CI 0.78- 0.98, p=0.025). No effect modification by continuous or dichotomous ToV was found. In subgroup analysis, effects consistently favored QIV-HD against hospitalizations for pneumonia or influenza (early: IRR 0.30; late: 0.29), all-cause hospitalizations (early: IRR 0.87; late: 0.86), and mortality (early: HR 0.53; late: 0.50). In this exploratory post hoc analysis, earlier ToV was associated with fewer respiratory hospitalizations. The relative effectiveness of QIV-HD vs. QIV-SD was not modified by ToV. Further research is needed to confirm findings. Clinicaltrials.gov: NCT05048589.

Relative Effectiveness of High-Dose vs. Standard-Dose Quadrivalent Influenza Vaccine in Older Adults with Cardiovascular Disease: A Prespecified Analysis of the DANFLU-1 Randomized Clinical Trial.

Background: Influenza vaccination reduces the risk of adverse outcomes in patients with cardiovascular disease (CVD). We sought to evaluate whether the presence of CVD modified the relative effectiveness of high-dose (QIV-HD) vs. standard-dose (QIV-SD) quadrivalent influenza vaccine in this prespecified analysis of the DANFLU-1 trial. Methods: DANFLU-1 was a pragmatic, open-label, randomized feasibility trial of QIV-HD vs. QIV-SD in adults aged 65-79 years during the 2021/2022 influenza season in Denmark. Vaccines were allocated in a 1:1 ratio. Baseline and follow-up data regarding diagnoses and mortality were obtained from Danish national registers. The trial is registered at Clinicaltrials.gov: NCT05048589. The CVDs assessed included heart failure (HF), ischemic heart disease (IHD), atrial fibrillation, and a combined group denoted "chronic CVD" consisting of the aforementioned diseases, among others. Prespecified outcomes included hospitalizations for pneumonia or influenza, respiratory disease, CVD, cardiorespiratory disease, all-cause hospitalizations, and mortality. Effect modification was tested using interaction terms. Results: The final study population included 12,477 participants (mean age 71.7±3.9 years, 5,877 (47.1%) female), of whom 2,540 (20.4%) had chronic CVD. QIV-HD vs. QIV-SD was associated with a lower incidence of hospitalizations for pneumonia or influenza (IRR 0.30 (95%-CI 0.14-0.64)) and all-cause mortality (IRR 0.51 (0.30-0.86)) regardless of chronic CVD (p for interaction=0.57 and 0.49, respectively). The relative effectiveness of QIV-HD vs. QIV-SD against all-cause hospitalizations was modified in participants with chronic CVD (Overall: IRR 0.87 (0.76-0.99); no chronic CVD: 0.79 (0.67-0.92); chronic CVD: 1.11 (0.88-1.39); p for interaction=0.026). No other effect modification was observed by the presence of chronic CVD, HF, IHD, or atrial fibrillation. Conclusions: The relative effectiveness of QIV-HD vs. QIV-SD was consistent against hospitalizations for pneumonia or influenza and all-cause mortality regardless of chronic CVD. However, the relative effectiveness against all-cause hospitalizations was modified by the presence of chronic CVD. These results should be considered hypothesis-generating.

The relative effectiveness of a high-dose quadrivalent influenza vaccine versus standard-dose quadrivalent influenza vaccines in older adults in France: a retrospective cohort study during the 2021–2022 influenza season

ObjectivesHigh-dose quadrivalent influenza vaccine (HD-QIV) was introduced during the 2021/2022 influenza season in France for adults aged ≥65 years as an alternative to standard-dose quadrivalent influenza vaccine (SD-QIV). The aim of this study is to estimate the relative vaccine effectiveness of HD-QIV vs. SD-QIV against influenza-related hospitalizations in France. MethodsCommunity-dwelling individuals aged ≥65 years with reimbursed influenza vaccine claims during the 2021/2022 influenza season were included in the French national health insurance database. Individuals were followed up from vaccination day to 30 June 2022, nursing home admission or death date. Baseline socio-demographic and health characteristics were identified from medical records over the five previous years. Hospitalizations for influenza and other causes were recorded from 14 days after vaccination until the end of follow-up. HD-QIV and SD-QIV vaccinees were matched using 1:4 propensity score matching with an exact constraint on age group, sex, week of vaccination, and region. Incidence rate ratios were estimated using zero-inflated Poisson or zero-inflated negative binomial regression models. ResultsWe matched 405 385 HD-QIV to 1 621 540 SD-QIV vaccinees. HD-QIV was associated with a 23.3% (95% CI, 8.4–35.8) lower rate of influenza hospitalizations compared with SD-QIV (69.5/100 000 person years vs. 90.5/100 000 person years). Post-matching, we observed higher rates in the HD-QIV group for hospitalizations non-specific to influenza and negative control outcomes, suggesting residual confounding by indication. DiscussionHD-QIV was associated with lower influenza-related hospitalization rates vs. SD-QIV, consistent with existing evidence, in the context of high SARS-CoV-2 circulation in France and likely prioritization of HD-QIV for older/more comorbid individuals.

Cost-effectiveness of recombinant influenza vaccine compared with standard dose influenza vaccine in adults 18–64 years of age

BackgroundThe Advisory Committee on Immunization Practices (ACIP) uses the Evidence to Recommendations Framework that includes cost-effectiveness analyses (CEA) for determining vaccine recommendations. ACIP’s preference for protecting adults ≥ 65 years is enhanced vaccines, including recombinant influenza vaccine (RIV4), adjuvanted or high dose influenza vaccine. Less is known about the CEA of enhanced vaccines for younger adults. MethodsWe used decision analysis modeling from a societal perspective to determine the cost-effectiveness, measured in quality adjusted life years (QALYs), of RIV4 compared with standard dose quadrivalent influenza vaccine (SD-IIV4) in adults 18–64 years old. Model inputs included 2018–2020 vaccine effectiveness (VE) estimates based on medical record data from a large local health system, 2019–2020 national vaccination and influenza epidemic parameters, with costs and population distributions fitted to the season. ResultsAmong adults ages 18–64 years, RIV4 cost $94,186/QALY gained, compared to SD-IIV4. Among those 50–64 years old, RIV4 was relatively more cost-effective ($61,329/QALY gained). Cost-effectiveness estimates for 18–64-year-olds were sensitive to the absolute difference in VE between SD-IIV4 and RIV4, among other parameters. Use of RIV4 in 18–64-year-olds would result in fewer cases (669,984), outpatient visits (261,293), hospitalizations (20,046) and deaths (1,018) annually. The majority (59 %; 597 of 1018) of the decreases in deaths occurred in the 50–64-year-olds. ConclusionsWhile RIV4 was effective and cost-effective relative to SD-IIV4 for both 50–64-year-old and 18–64-year-old adults, cost-effectiveness was sensitive to small changes in parameters among 18–64-year-olds. Because substantial public health benefits occur with enhanced vaccines, health systems and policy makers may opt for preferential product use in select age/risk groups (e.g., 50–64 year olds) to maximize their cost-benefit ratios.

Public health and economic benefits of seasonal influenza vaccination in risk groups in France, Italy, Spain and the UK: state of play and perspectives

BackgroundSeasonal influenza epidemics have a substantial public health and economic burden, which can be alleviated through vaccination. The World Health Organization (WHO) recommends a 75% vaccination coverage rate (VCR) in: older adults (aged ≥ 65 years), individuals with chronic conditions, pregnant women, children aged 6–24 months and healthcare workers. However, no European country achieves this target in all risk groups. In this study, potential public health and economic benefits achieved by reaching 75% influenza VCR was estimated in risk groups across four European countries: France, Italy, Spain, and the UK.MethodsA static epidemiological model was used to estimate the averted public health and economic burden of increasing the 2021/2022 season VCR to 75%, using the efficacy data of standard-dose quadrivalent influenza vaccine. For each country and risk group, the most recent data on population size, VCR, pre-pandemic influenza epidemiology, direct medical costs and absenteeism were identified through a systematic literature review, supplemented by manual searching. Outcomes were: averted influenza cases, general practitioner (GP) visits, hospitalisations, case fatalities, number of days of work lost, direct medical costs and absenteeism-related costs.ResultsAs of the 2021/2022 season, the UK achieved the highest weighted VCR across risk groups (65%), followed by Spain (47%), France (44%) and Italy (44%). Based on modelling, the 2021/2022 VCR prevented an estimated 1.9 million influenza cases, avoiding 375,200 GP visits, 73,200 hospitalisations and 38,400 deaths. To achieve the WHO 75% VCR target, an additional 24 million at-risk individuals would need to be vaccinated, most of which being older adults and patients with chronic conditions. It was estimated that this could avoid a further 918,200 influenza cases, 332,000 GP visits, 16,300 hospitalisations and 6,300 deaths across the four countries, with older adults accounting for 52% of hospitalisations and 80% of deaths. An additional €84 million in direct medical costs and €79 million in absenteeism costs would be saved in total, with most economic benefits delivered in France.ConclusionsOlder adults represent most vaccine-preventable influenza cases and deaths, followed by individuals with chronic conditions. Health authorities should prioritise vaccinating these populations for maximum public health and economic benefits.

Effects of high-dose versus standard-dose quadrivalent influenza vaccine among patients with diabetes: A post-hoc analysis of the DANFLU-1 trial.

High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza. DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c. Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), pinteraction = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]. In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status.

Feasibility and Findings of Including Self-Identified Adult Congenital Heart Disease Patients in the INVESTED Trial

BackgroundAdult congenital heart disease (ACHD) patients have significant morbidity and rise in cardiac admissions. Their outcome with high-dose influenza vaccination is unknown in comparison to those without ACHD. ObjectivesThe purpose of this study was to compare all-cause mortality or cardiopulmonary hospitalizations in self-identified ACHD versus non-ACHD patients receiving high- or low-dose influenza vaccination within the INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure trial. MethodsWe prospectively included ACHD patients in the INVESTED (INfluenza Vaccine to Effectively Stop cardioThoracic Events and Decompensated heart failure) trial. The primary endpoint was all-cause death or hospitalization for cardiovascular or pulmonary causes. ResultsOf the 272 ACHD patients, 132 were randomly assigned to receive high-dose trivalent and 140 to standard-dose quadrivalent influenza vaccine. Compared to the non-ACHD cohort (n = 4,988), ACHD patients were more likely to be younger, women, smokers, have atrial fibrillation, and have a qualifying event of heart failure. The primary outcome was 49.8 events versus 42.8 events per 100 person-years (adjusted HR: 1.17; 95% CI: 0.95-1.45; P = 0.144) in the ACHD group and non-ACHD group, respectively. The interaction between ACHD status and randomized treatment effect was not significant for the primary outcome (P = 0.858). Vaccine-related adverse events were similar in both groups. ConclusionsPatients who self-identify as being ACHD had similar primary outcome of all-cause death or hospitalization for cardiovascular or pulmonary causes compared to non-ACHD cohort. High-dose influenza vaccination was similar to standard-dose influenza vaccination on the primary outcome in patients who self-identify as ACHD.

Effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against recurrent hospitalizations and mortality in relation to influenza circulation: A post-hoc analysis of the DANFLU-1 randomized clinical trial

ObjectivesTo evaluate the relative effectiveness of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) against recurrent hospitalizations and its potential variation in relation to influenza circulation. MethodsWe did a post-hoc analysis of a pragmatic, open-label, randomized trial of QIV-HD versus QIV-SD performed during the 2021–2022 influenza season among adults aged 65–79 years. Participants were enrolled in October 2021–November, 2021 and followed for outcomes from 14 days postvaccination until 31 May, 2022. We investigated the following outcomes: Hospitalizations for pneumonia or influenza, respiratory hospitalizations, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations, and all-cause death. Outcomes were analysed as recurrent events. Cumulative numbers of events were assessed weekly. Cumulative relative effectiveness estimates were calculated and descriptively compared with influenza circulation. The trial is registered at Clinicaltrials.gov: NCT05048589. ResultsAmong 12,477 randomly assigned participants, receiving QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza (10 vs. 33 events, incidence rate ratio [IRR] 0.30 [95% CI, 0.14–0.64]; p 0.002) and all-cause hospitalizations (647 vs. 742 events, IRR 0.87 [95% CI, 0.76–0.99]; p 0.032) compared with QIV-SD. Trends favouring QIV-HD were consistently observed over time including in the period before active influenza transmission; i.e. while the first week with a ≥10% influenza test positivity rate was calendar week 10, 2022, the first statistically significant reduction in hospitalizations for pneumonia or influenza was already observed by calendar week 3, 2022 (5 vs. 15 events, IRR 0.33 [95% CI, 0.11–0.94]; p 0.037). DiscussionIn a post-hoc analysis, QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza and all-cause hospitalizations compared with QIV-SD, with trends evident independent of influenza circulation levels. Our exploratory results correspond to a number needed to treat of 65 (95% CI 35–840) persons vaccinated with QIV-HD compared with QIV-SD to prevent one additional all-cause hospitalization per season. Further research is needed to confirm these hypothesis-generating findings.

1168. Cost-effectiveness of high-dose quadrivalent influenza vaccine versus standard-dose quadrivalent influenza vaccine for older people in a country with high influenza vaccination rate

Abstract Background The high-dose quadrivalent formulation (QIV-HD) has shown improved protection against influenza and its complications in older adults. We aimed to evaluate the cost-effectiveness of QIV-HD compared with QIV-SD among Korean adults aged ≥ 65 years in reducing influenza-related disease burden. Methods We evaluated the 2016/2017 and 2017/2018 seasons and their average values using a static decision tree model. For the main analysis, hospitalization was defined as cardiorespiratory disease-related. The difference in efficacy between standard-dose (SD) and high-dose (HD) was calculated based on the results of a clinical trial comparing Fluzone® High-Dose Vaccine and Fluzone® Vaccine in older adults. Incremental cost-effectiveness ratios (ICERs) were assessed from the healthcare system perspective. A discount rate of 4.5% was applied to life-year-gained (LYG) values and utilities. We performed deterministic and probabilistic sensitivity analyses to account for both epidemiological and economic sources of uncertainty. Results In the analysis of the 2017/2018 season, the QIV-HD strategy generated an excess of 0.003953 quality-adjusted life-years (QALYs) compared with QIV-SD. The ICER was 6,467.56 USD/QALY. For the 2016/2017 season, QIV-HD caused an excess of 0.003272 QALYs and ICER was 7,902.46 USD /QALY. From the average data of the two seasons, an excess of 0.003561 QALYs were generated and the ICER was 7,190.44 USD/QALY. In the one-way sensitivity analysis, the parameters with the greatest impact on the results were the relative VE of QIV-HD vs. QIV-SD against influenza-associated hospitalization. PSAs were conducted for the 2016/2017 and 2017/2018 seasons, with the cost of the QIV-HD vaccine fixed at 50,000 KRW (40.48 USD) or 65,000 KRW (52.62 USD). The results showed that for a WTP threshold of 24,692.36 USD/QALY, the probability that QIV-HD is a cost-effective option for the Korean health system is 100% in all seasons and QIV-HD vaccine costs considered. Conclusion From the healthcare system perspective, QIV-HD was a more cost-effective vaccination option in reducing influenza-related disease burden and healthcare costs in Koreans aged ≥ 65 years compared with QIV-SD. Disclosures Hee Jin Cheong, M.D., Ph.D., Sequiris: Advisor/Consultant Jung-Min Lee, n/a, Sanofi Korea: Stocks/Bonds

Immunogenicity and Safety of Alternative Influenza Vaccination Strategies in Repeated Seasons in Pediatric Hematopoietic-Cell Transplant Recipients

Abstract Background Pediatric hematopoietic cell transplant (HCT) recipients are at increased risk for morbidity and mortality from influenza infection. Annual influenza vaccination is recommended; however, HCT recipients have diminished immune responses to vaccination. Our recent trial demonstrated that two doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart post-HCT were more immunogenic than two doses of standard dose quadrivalent influenza vaccine (SD-QIV). We assessed the impact of this strategy in a consecutive season post-HCT. Methods The initial trial was a multi-center double-blinded phase II randomized controlled trial comparing two doses of HD-TIV to two doses of SD-QIV in children 3-17 years old given 3-35 months post-allogeneic HCT. Participants completing the initial trial could re-enroll the subsequent influenza season to receive the same two-dose vaccine formulation. Hemagglutinin inhibition (HAI) titers were measured at baseline and 28-42 days following each dose. Injection-site and systemic adverse events were assessed. The immunogenicity endpoints were the post-dose 1 and post-dose 2 geometric mean HAI titers (GMTs) in the second year of participation. Results A total of 170 participants were enrolled in the initial trial, with 65 re-enrolling for a second year (n=33 SD-QIV and n=32 HD-TIV). Post-dose 1 and 2 GMTs were higher for both the SD-QIV and HD-TIV groups in the second year compared the first year (Table 1). In year two, the adjusted geometric mean ratio (aGMR) comparing HD-TIV to SD-QIV was higher post-dose 1 for A/H1N1 (aGMR=1.99, 95% CI:[1.07, 3.68]). The HD-TIV group demonstrated a higher frequency of four-fold titer rise after a single dose compared to two doses of SD-QIV for A/H3N2 (61% vs. 48%) and B/Victoria (77% vs. 65%). Frequency of injection site and systemic reactions were similar between the HD-TIV and SD-QIV groups in year two. Conclusions The post-dose 1 and 2 GMTs were consistently higher for HD-TIV compared to SD-QIV in year two, and aGMR reached statistical significance after a single dose of HD-TIV for A/H1N1. Year two reactogenicity was comparable for both vaccination strategies. Further studies with larger numbers of participants are needed to demonstrate if one or two doses of HD-TIV are needed in subsequent influenza seasons post-HCT when a two-dose vaccination series is given in the first post-HCT season. Table 1. Point estimates and 95% CIs for geometric mean HAI titer, titer ≥1:40, and proportion with ≥4-fold rise from baseline for each vaccine regimen, stratified for each antigen. Also included is the ratio of the observed values (n) to the number of evaluable subjects (N) at each visit. Baseline titers are measured prior to first vaccine dose, post-dose 1 titers are measured 28-42 days following first dose (prior to the second dose), post-dose 2 titers are measured 28-42 days following second dose. Table 1 Note: If 100% achieved seroprotection or seroconversion, “n/a” was entered as a two-sided 95% CI could not be calculated.

Cost-effectiveness of high-dose quadrivalent influenza vaccine versus standard-dose quadrivalent influenza vaccine for older people in a country with high influenza vaccination rate

ABSTRACT The highdose quadrivalent influenza vaccine (QIVHD) has shown improved protection against influenza and its complications in older adults. We aimed to evaluate the costeffectiveness of QIVHD compared with QIVSD among Korean adults aged ≥ 65 years in reducing influenzarelated disease burden. We evaluated the 2016/2017 and 2017/2018 seasons and their average values using a static decision tree model. The difference in efficacy between standard-dose (SD) and high-dose (HD) was calculated based on the results of a clinical trial comparing Fluzone® High-Dose Vaccine and Fluzone® Vaccine in older adults. Incremental cost-effectiveness ratios (ICERs) were assessed from the healthcare system perspective. A discount rate of 4.5% was applied to life-year-gained (LYG) values and utilities. We performed deterministic and probabilistic sensitivity analyses to account for both epidemiological and economic sources of uncertainty. In the analysis of the 2017/2018 season, the QIV-HD strategy generated an excess of 0.00182 life-years (Lys)/person and 0.003953 quality-adjusted life-years (QALYs)/person compared with QIV-SD. The ICER was 6,467.56 United States Dollars (USD)/QALY. In the analysis from the 2016/2017 season, QIV-HD caused a surplus of 0.00117 Lys/person and 0.003272 QALYs/person compared with QIV-SD. ICER was 7,902.46 USD /QALY. From the average data of the 2016/2017 and 2017/2018 seasons, an excess of 0.00147 Lys/person and 0.003561 QALYs/person were generated using QIV-HD compared with QIV-SD, while the ICER was 7,190.44 USD /QALY. From the healthcare system perspective, QIV-HD was a more cost-effective vaccination option in reducing influenza-related disease burden and healthcare costs in Koreans aged ≥ 65 years compared with QIV-SD.

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease

Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial. To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity. This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US. Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons. The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state. Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity. In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events. ClinicalTrials.gov Identifier: NCT02787044.

DANFLU-1: Feasibility of a Pragmatic Randomised Trial to Assess the Relative Effectiveness of High-dose (QIV-HD) vs Standard-dose Quadrivalent Influenza Vaccine (QIV-SD) on Severe Cardio-respiratory Outcomes in Elderly Adults

DANFLU-1: Feasibility of a Pragmatic Randomised Trial to Assess the Relative Effectiveness of High-dose (QIV-HD) vs Standard-dose Quadrivalent Influenza Vaccine (QIV-SD) on Severe Cardio-respiratory Outcomes in Elderly Adults

A Comparative Analysis of Influenza-Associated Disease Burden with Different Influenza Vaccination Strategies for the Elderly Population in South Korea.

Influenza affects all age groups, but the risk of hospitalization and death due to influenza is strongly age-related and is at its highest among the elderly aged 65 years and older. The objective of this study is to compare the differences in influenza-associated disease burden under three different influenza vaccination strategies—the standard-dose quadrivalent influenza vaccine (QIV), high-dose QIV (HD-QIV), and MF59®-adjuvanted QIV (aQIV)—for the elderly population aged 65 years and older in South Korea. A one-year decision-tree model was developed to compare influenza disease burdens. The input data for the model were obtained from published literature reviews and surveillance data from the Korea Disease Control and Prevention Agency (KDCA). The analysis indicated that aQIV is more effective than QIV, preventing 35,390 influenza cases, 1602 influenza-associated complications, 709 influenza-associated hospitalizations, and 145 influenza-associated deaths annually. Additionally, aQIV, when compared to HD-QIV, also reduced the influenza-associated burden of disease, preventing 7247 influenza cases, 328 influenza-associated complications, 145 influenza-associated hospitalizations, and 30 influenza-associated deaths annually. Switching the vaccination strategy from QIV to aQIV is predicted to reduce the influenza-associated disease burden for the elderly in South Korea. The public health gains from aQIV and HD-QIV are expected to be comparable. Future studies comparing the effectiveness of the vaccines will further inform future vaccination strategies for the elderly in South Korea.

An Economic Evaluation of the Adjuvanted Quadrivalent Influenza Vaccine Compared with Standard-Dose Quadrivalent Influenza Vaccine in the Spanish Older Adult Population.

Standard-dose quadrivalent influenza vaccines (QIV) are designed to provide protection against all four influenza strains. Adjuvanted QIV (aQIV), indicated for individuals aged 65+ years, combines MF59® adjuvant (an oil-in-water emulsion of squalene oil) with a standard dose of antigen, and is designed to produce stronger and longer immune response, especially in the elderly where immunosenescence reduces vaccine effectiveness. This study evaluated the cost-effectiveness of aQIV vs. egg-based standard-dose QIV (QIVe) in the elderly population, from the payer and societal perspective in Spain. A dynamic transmission model, which accounts for herd protection, was used to predict the number of medically attended infections in Spain. A decision tree structure was used to forecast influenza-related costs and benefits. Influenza-related probabilities of outpatient visit, hospitalization, work absenteeism, mortality, and associated utilities and costs were extracted from Spanish and European published literature. Relative vaccine effectiveness (rVE) was sourced from two different meta-analyses: the first meta-analysis was informed by laboratory-confirmed influenza studies only, resulting in a rVE = 34.6% (CI95% 2–66%) in favor of aQIV; the second meta-analysis included real world evidence influenza-related medical encounters outcomes, resulting in a rVE = 13.9% (CI95% 4.2–23.5%) in benefit of aQIV. All costs were expressed in 2021 euros. Results indicate that replacing QIVe with aQIV in the Spanish elderly population would prevent on average 43,664 influenza complicated cases, 1111 hospitalizations, and 569 deaths (with a rVE = 34.6%) or 19,104 influenza complicated cases, 486 hospitalizations, and 252 deaths (with a rVE = 13.9%). When the rVE of aQIV vs. QIVe is 34.6%, the incremental cost per quality adjusted life years (QALY) gained was €2240 from the payer; from the societal perspective, aQIV was cost saving compared with QIVe. If the rVE was 13.9%, the incremental cost per QALY was €6694 and €3936 from the payer and societal perspective, respectively. Sensitivity analyses validated the robustness of these findings. Results indicate that replacing QIVe with aQIV in the Spanish elderly population is a cost-effective strategy for the Spanish healthcare system.

Feasibility of randomizing Danish citizens aged 65\u201379 years to high-dose quadrivalent influenza vaccine vs. standard-dose quadrivalent influenza vaccine in a pragmatic registry-based setting: rationale and design of the DANFLU-1 Trial

BackgroundHigh-dose influenza vaccines provide better protection against influenza infection than standard-dose in persons aged 65 years and above; however, in most countries, high-dose vaccines are not widely implemented. Assessing the relative effectiveness of high-dose compared to standard-dose vaccines on hospitalizations and mortality would enable more robust public health and cost-effectiveness estimates. This study aims to investigate the feasibility of conducting a pragmatic randomized clinical trial in Denmark comparing high-dose to standard-dose vaccines utilizing existing vaccination infrastructure and the Danish nationwide health registries for data collection.MethodsThe DANFLU-1 trial (NCT05048589) is a pragmatic, open-label, active-controlled randomized trial randomizing Danish citizens aged 65–79 years to either high-dose quadrivalent influenza vaccine or standard-dose quadrivalent influenza vaccine. The study utilizes the infrastructure of a private vaccination provider (Danske Lægers Vaccinations Service) for recruitment, inclusion, randomization, and vaccination. All collection of baseline and follow-up data including safety monitoring is performed centrally by the Department of Cardiology at Herlev and Gentofte Hospital, Copenhagen, Denmark using the Danish nationwide health registries. The study aims to include 40,000 participants during the 2021/2022 influenza season. The primary endpoints address feasibility and include the number of participants enrolled, randomization balance, and representativeness compared to the Danish general population. Relative vaccine effectiveness will also be assessed, however, this feasibility study is not powered for clinical outcomes and may be affected by the COVID-19 pandemic.DiscussionThe DANFLU-1 study is investigating the feasibility of conducting a large-scale pragmatic clinical trial in Denmark utilizing existing infrastructure and the Danish nationwide registries. This will provide valuable insight, especially for potential future fully powered vaccine trials, but also for trials wishing to investigate other interventions.Trial registrationClinicaltrials.gov: NCT05048589, registered September 17, 2021.