Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: Prespecified Analysis of the NUDGE-FLU Trial.

BACKGROUND: Influenza vaccines have been demonstrated to effectively reduce the incidence of influenza infection and potentially associated risks of cardiovascular events in patients with cardiovascular disease (CVD). Despite strong guideline and public health endorsements, global influenza vaccination rates in patients with CVD are highly variable. This prespecified analysis of NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) examined the effect of digital behavioral nudges on influenza vaccine uptake based on the presence of CVD. METHODS: NUDGE-FLU was a randomized, pragmatic, nationwide, register-based trial that included Danish citizens 65 years of age or older during the 2022 to 2023 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 electronic letters with designs based on behavioral concepts. Danish nationwide registers were used to collect baseline and outcome data. The primary end point was receipt of an influenza vaccine on or before January 1, 2023. The effects of the intervention letters were examined according to the presence of CVD and across cardiovascular subgroups that included heart failure, ischemic heart disease, and atrial fibrillation. RESULTS: Of 964 870 NUDGE-FLU participants from 691 820 households, 264 392 (27.4%) had CVD. During follow-up, 83.1% of participants with CVD versus 79.2% of participants without CVD received an influenza vaccination (P<0.001). Compared with usual care, a letter emphasizing the potential cardiovascular benefits of influenza vaccination increased vaccination rates; this effect was consistent in participants with CVD (absolute difference, +0.60 percentage points [99.55% CI, -0.48 to 1.68]) and without CVD (+0.98 percentage points [99.55% CI, 0.27-1.70; P for interaction=0.41). A repeated letter strategy with a reminder follow-up letter 14 days later was also effective in increasing influenza vaccination, irrespective of CVD (CVD: absolute difference, +0.80 percentage points [99.55% CI, -0.27 to 1.86]; no CVD: +0.67 percentage points [99.55% CI, -0.06 to 1.40]; P for interaction=0.77). Effectiveness of both nudging strategies was consistent across all major CVD subgroups. None of the other 7 nudging strategies were effective, regardless of CVD status. CONCLUSIONS: Electronic letter interventions emphasizing the potential cardiovascular benefits of influenza vaccination and using a reminder letter strategy were similarly beneficial in increasing influenza vaccination rates among older adults with and without CVD and across cardiovascular subgroups. Electronic nudges may improve influenza vaccine uptake in individuals with CVD. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05542004.

Electronic nudges to increase influenza vaccination uptake in Denmark: a nationwide, pragmatic, registry-based, randomised implementation trial.

BACKGROUND: Influenza vaccination rates remain suboptimal despite effectiveness in preventing influenza infection and related complications. We investigated whether behavioural nudges, delivered via a governmental electronic letter system, would increase influenza vaccination uptake among older adults in Denmark. METHODS: We did a nationwide, pragmatic, registry-based, cluster-randomised implementation trial during the 2022-23 influenza season in Denmark. All Danish citizens aged 65 years or older or turning 65 years by Jan 15, 2023 were included. We excluded individuals living in nursing homes and individuals who had an exemption from the Danish mandatory governmental electronic letter system. Households were randomly assigned (9:1:1:1:1:1:1:1:1:1) to usual care or nine different electronic letters designed on the basis of different behavioural nudging concepts. Data were sourced from nationwide Danish administrative health registries. The primary endpoint was receipt of influenza vaccination on or before Jan 1, 2023. The primary analysis assessed an analytical set of one randomly selected individual per household, and a sensitivity analysis included all randomly assigned individuals and accounted for within-household correlation. The trial is registered with ClinicalTrials.gov, NCT05542004. FINDINGS: We identified 1 232 938 individuals aged 65 years or older in Denmark and excluded 56 436 (4·6%) individuals living in nursing homes and 211 632 (17·2%) with an exemption from the electronic letter system. We randomly assigned 964 870 (78·3%) participants across 691 820 households. Compared with usual care, influenza vaccination rates were higher in the group receiving an electronic letter highlighting potential cardiovascular benefits of vaccination (81·00% vs 80·12%; difference 0·89 percentage points [99·55% CI 0·29-1·48]; p<0·0001) and the group receiving repeated letters at randomisation and at day 14 (80·85% vs 80·12%; difference 0·73 percentage points [0·13-1·34]; p=0·0006). These strategies improved vaccination rates across major subgroups including those with and without established cardiovascular disease. The cardiovascular gain-framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season (pinteraction=0·0002). A sensitivity analysis of all randomly assigned individuals accounting for within-household clustering yielded similar findings. INTERPRETATION: Electronically delivered letters highlighting potential cardiovascular benefits of influenza vaccination or sent again as a reminder significantly increased vaccination uptake across Denmark. Although the magnitude of effectiveness was modest, the low-touch, inexpensive, and highly scalable nature of these electronic letters might be informative for future public health campaigns. FUNDING: Sanofi.

Epidemiology and burden of influenza in healthy children aged 6 to 35 months: analysis of data from the placebo arm of a phase III efficacy trial.

BACKGROUND: Despite World Health Organization recommendations, in many countries young children are not targeted for influenza vaccination. To help inform influenza vaccination policy, we examined the occurrence and burden of influenza in healthy children aged 6 to 35 months using data from a recent phase III placebo-controlled influenza vaccine trial conducted in countries in the Northern and Southern Hemispheres. METHODS: This was an analysis of data from participants included in the placebo arm of a phase III clinical trial in healthy children aged 6 to 35 months (EudraCT no. 2013-001231-51). Included children had never been vaccinated for influenza and were observed for one influenza season. Outcome measures included the occurrence of influenza-like illness (ILI), laboratory-confirmed influenza, virus types/subtypes, severe symptoms and complications of confirmed influenza, and healthcare use associated with confirmed influenza. RESULTS: Data from 2210 participants were analysed. ILI was reported for 811 participants (36.7%). Of these, 255 participants (31.4%) had 263 virologically confirmed episodes of influenza. The overall influenza attack rate was 11.5%. The most common influenza virus detected was A(H3N2) (40.7%), followed by B/Yamagata (23.6%), A(H1N1) (18.6%), and B/Victoria (8.0%). Grade 3 fever was reported in 24.3% of confirmed episodes, acute lower respiratory infection in 8.7%, acute otitis media in 6.1%, and pneumonia in 1.9%. In most influenza episodes (93.2%), antipyretics, analgesics, or non-steroidal anti-inflammatory drugs were taken. Antibiotics were prescribed for 41.4% of influenza episodes. More than half of the influenza episodes (57.0%) resulted in outpatient visits. Influenza resulted in overnight hospitalisation in 1.1% of episodes. CONCLUSIONS: Influenza is associated with a significant burden of disease in healthy children. This analysis also revealed that antibiotics continue to be frequently used for young children with influenza. TRIAL REGISTRATION: EudraCT no. 2013-001231-51 .

Annual public health and economic benefits of seasonal influenza vaccination: a European estimate.

BACKGROUND: Vaccination is currently the most effective means of preventing influenza infection. Yet evidence of vaccine performance, and the impact and value of seasonal influenza vaccination across risk groups and between seasons, continue to generate much discussion. Moreover, vaccination coverage is below recommended levels. METHODS: A model was generated to assess the annual public health benefits and economic importance of influenza vaccination in 5 WHO recommended vaccination target groups (children 6 - 23 months of age; persons with underlying chronic health conditions; pregnant women; health care workers; and, the elderly, 65 years of age) in 27 countries of the European Union. Model estimations were based on standard calculation methods, conservative assumptions, age-based and country-specific data. RESULTS: Out of approximately 180 million Europeans for whom influenza vaccination is recommended, only about 80 million persons are vaccinated. Seasonal influenza vaccination currently prevents an annual average of between 1.6 million and 2.1 million cases of influenza, 45,300 to 65,600 hospitalizations, and 25,200 to 37,200 deaths. To reach the 75% vaccination coverage target set by the EU Council Recommendation in 2009, an additional 57.4 million person would need to be vaccinated in the elderly and other risk groups. By achieving the 75% target rate set in EU-27 countries, average annual influenza- related events averted would increase from current levels to an additional +1.6 to +1.7 million cases, +23,800 to +31,400 hospitalization, +9,800 to +14,300 deaths, +678,500 to +767,800 physician visits, and +883,800 to +1,015,100 lost days of work yearly. Influenza-related costs averted because of vaccination would increase by an additional + €190 to + €226 million yearly, in vaccination target groups. CONCLUSIONS: Full implementation of current influenza vaccination recommendations of 75% vaccination coverage rate (VCR) in Europe by the 2014-2015 influenza season could immediately reduce an important public health and economic burden.

High-Dose Quadrivalent Influenza Vaccine for Prevention of Cardiovascular and Respiratory Hospitalizations in Older Adults.

BACKGROUND: We assessed the relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) in preventing respiratory or cardiovascular hospitalizations in older adults. METHODS: FinFluHD was a phase 3b/4 modified double-blind, randomized pragmatic trial. Enrolment of 121,000 adults ≥65 years was planned over three influenza seasons (October to December 2019-2021). Participants received a single injection of QIV-HD or QIV-SD. The primary endpoint was first occurrence of an unscheduled acute respiratory or cardiovascular hospitalization (ICD-10 primary discharge J/I codes), from ≥14 days post-vaccination until May 31. The study was terminated after one season due to COVID-19; follow-up data for 2019-2020 are presented. RESULTS: 33,093 participants were vaccinated (QIV-HD, n = 16,549; QIV-SD, n = 16,544); 529 respiratory or cardiovascular hospitalizations (QIV-HD, n = 257; QIV-SD, n = 272) were recorded. The rVE of QIV-HD versus QIV-SD to prevent respiratory/cardiovascular hospitalizations was 5.5% (95% CI, -12.4 to 20.7). When prevention of respiratory and cardiovascular hospitalizations were considered separately, rVE estimates of QIV-HD versus QIV-SD were 5.4% (95% CI, -28.0 to 30.1) and 7.1% (95% CI, -15.0 to 25.0), respectively. Serious adverse reactions were <0.01% in both groups. CONCLUSIONS: Despite insufficient statistical power due to the impact of COVID-19, rVE point estimates demonstrated a trend toward a benefit of QIV-HD over QIV-SD. QIV-HD was associated with lower respiratory or cardiovascular hospitalization rates than QIV-SD, with a comparable safety profile. Adequately powered studies conducted over multiple influenza seasons are needed to determine statistical significance of QIV-HD compared with QIV-SD against preventing respiratory and cardiovascular hospitalizations. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04137887.

High-dose influenza vaccine in older adults by age and seasonal characteristics: Systematic review and meta-analysis update.

This updated systematic review and meta-analysis of randomized and observational studies published up to April 2023 assessed the relative performance of high-dose inactivated influenza vaccine (HD-IIV) and standard-dose influenza vaccines (SD-IIV) against influenza-associated outcomes in older adults (≥65 years). The analysis included studies conducted over 12 influenza seasons (2009/2010 to 2019/2020, 2021/2022), including over 45 million individuals aged ≥ 65 years, and showed that HD-IIV provided significantly better protection than SD-IIV against influenza-like illness and influenza-related hospitalizations, as well as cardiovascular, cardiorespiratory, and all-cause hospitalizations. Subgroup analyses showed HD-IIV consistently provided better protection than SD-IIV against influenza outcomes across the age range (65+, 75+ 85+ years), and regardless of the predominantly circulating influenza strain and vaccine antigenic match/mismatch. Randomized studies continue to drive high-quality evidence on the effectiveness of high-dose inactivated influenza vaccine relative to SD-IIV against severe influenza outcomes in adults aged ≥ 65 years, supported by observational data.

Electronically Delivered Nudges to Increase Influenza Vaccination Uptake in Older Adults With Diabetes: A Secondary Analysis of the NUDGE-FLU Trial.

Importance: Influenza vaccination is associated with a reduced risk of mortality in patients with diabetes, but vaccination rates remain suboptimal. Objective: To assess the effect of electronic nudges on influenza vaccination uptake according to diabetes status. Design, Setting, and Participants: The NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) trial was a nationwide clinical trial of Danish citizens 65 years or older that randomized participants at the household level to usual care or 9 different electronic nudge letters during the 2022 to 2023 influenza season. End of follow-up was January 1, 2023. This secondary analysis of the NUDGE-FLU trial was performed from May to July 2023. Intervention: Nine different electronic nudge letters designed to boost influenza vaccination were sent in September to October 2022. Effect modification by diabetes status was assessed in a pooled analysis of all intervention arms vs usual care and for individual letters. Main Outcomes and Measures: The primary end point was receipt of a seasonal influenza vaccine. Results: The trial included 964 870 participants (51.5% female; mean [SD] age, 73.8 [6.3] years); 123 974 had diabetes. During follow-up, 83.5% with diabetes vs 80.2% without diabetes received a vaccine (P < .001). In the pooled analysis, nudges improved vaccination uptake in participants without diabetes (80.4% vs 80.0%; difference, 0.37 percentage points; 99.55% CI, 0.08 to 0.66), whereas there was no evidence of effect in those with diabetes (83.4% vs 83.6%; difference, -0.19 percentage points; 99.55% CI, -0.89 to 0.51) (P = .02 for interaction). In the main results of NUDGE-FLU, 2 of the 9 behaviorally designed letters (cardiovascular benefits letter and a repeated letter) significantly increased uptake of influenza vaccination vs usual care; these benefits similarly appeared attenuated in participants with diabetes (cardiovascular gain letter: 83.7% vs 83.6%; difference, 0.04 percentage points; 99.55% CI, -1.52 to 1.60; repeated letter: 83.5% vs 83.6%; difference, -0.15 percentage points; 99.55% CI, -1.71 to 1.41) vs those without diabetes (cardiovascular gain letter: 81.1% vs 80.0%; difference, 1.06 percentage points; 99.55% CI, 0.42 to 1.70; repeated letter: 80.9% vs 80.0%; difference, 0.87 percentage points; 99.55% CI, 0.22 to 1.52) (P = .07 for interaction). Conclusions and Relevance: In this exploratory subgroup analysis, electronic nudges improved influenza vaccination uptake in persons without diabetes, whereas there was no evidence of an effect in persons with diabetes. Trials are needed to investigate the effect of digital nudges specifically tailored to individuals with diabetes. Trial Registration: ClinicalTrials.gov Identifier: NCT05542004.

Reply to letter to editor by Hadigal et al. regarding the immunogenicity and safety trial of high-dose influenza vaccine in adults aged ≥60 years.

Hadigal et al. argued the recommendation of high-dose influenza vaccine over standard-dose formulation is not supported by comparisons of numbers-needed-to-vaccinate (NNV) nor aligned with the WHO mandate of improving vaccine coverage. However, the authors' NNV calculation was inaccurate. A preferential recommendation for vaccines preventing influenza/complications can increase coverage. Furthermore, the impact of vaccination is a function of efficacy/effectiveness and the vaccine-preventable fraction of disease burden; therefore Hadigal et al. should interpret the absolute risk reduction by vaccination within the context of overall disease burden. To address the threat of COVID-19 pandemic, authorities should implement concomitant influenza/COVID-19 vaccination to reduce the burden of cocirculation of influenza and SARS- CoV- 2 viruses and increase the coverage of proven influenza vaccines as per WHO mandate.

Immunological non-inferiority and safety of a quadrivalent inactivated influenza vaccine versus two trivalent inactivated influenza vaccines in China: Results from two studies.

WHO UNIVERSAL TRIAL NUMBERS (UTNS): U1111-1174-4615 and U1111-1174-4698. CLINICALTRIALS.GOV: NCT04210349 and NCT03430089.

Immunogenicity and safety of high-dose quadrivalent influenza vaccine in older adults in Taiwan: A phase III, randomized, multi-center study.

BACKGROUND: High-dose influenza vaccine offers better protection against influenza/associated complications compared with standard-dose formulation. We evaluated immunogenicity and safety of high-dose influenza vaccine (QIV-HD) and standard-dose (QIV-SD) in older adults (≥ 65 years) in Taiwan. METHODS: This was a phase III, randomized, modified double-blind, active-controlled, multi-center, descriptive study in older adults. Participants (N = 165) were randomized 1:1 to receive QIV-HD or QIV-SD vaccine (clinicaltrials.gov#NCT04537234). RESULTS: For all four influenza strains, geometric means titers (GMTs) of hemagglutination inhibition were higher for the QIV-HD than QIV-SD with adjusted GMT ratios (95 % CI) of 2.65 (1.87-3.75) for A/H1N1; 1.76 (1.31-2.38) for A/H3N2; 2.60 (1.90-3.56) for B/Victoria; and 2.01 (1.57-2.56) for B/Yamagata. The seroconversion was higher for QIV-HD than QIV-SD with similar safety profiles across both groups. CONCLUSION: QIV-HD was highly immunogenic for four influenza strains and have acceptable safety profile in older adults aged ≥ 65 years in Taiwan.

Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study.

BACKGROUND: Concomitant seasonal influenza vaccination with a COVID-19 vaccine booster could help to minimise potential disruption to the seasonal influenza vaccination campaign and maximise protection against both diseases among individuals at risk of severe disease and hospitalisation. This study aimed to assess the safety and immunogenicity of concomitant administration of high-dose quadrivalent influenza vaccine (QIV-HD) and a mRNA-1273 vaccine booster dose in older adults. METHODS: This study is an ongoing, phase 2, multicentre, open-label, descriptive trial at six clinical research sites in the USA. We describe the interim results up to 21 days after vaccination (July-August, 2021). Community-dwelling adults aged 65 years and older, who were previously vaccinated with a two-dose primary schedule of the mRNA-1273 SARS-CoV-2 vaccine, were eligible for inclusion. The second dose of the primary mRNA-1273 vaccination series was required to have been received at least 5 months before enrolment in the study. Participants were randomly assigned (1:1:1) using a permuted block method stratified by site and by age group (<75 years vs ≥75 years), to receive concomitant administration of QIV-HD and mRNA-1273 vaccine, QIV-HD alone, or mRNA-1273 vaccine alone. Randomisation lists, generated by Sanofi Pasteur biostatistics platform, were provided to study investigators for study group allocation. Unsolicited adverse events occurring immediately, solicited local and systemic reactions up to day 8, and unsolicited adverse events, serious adverse events, adverse events of special interest, and medically attended adverse events up to day 22 were reported. Haemagglutination inhibition antibody responses to influenza A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains and SARS CoV-2 binding antibody responses (SARS-CoV-2 pre-spike IgG ELISA) were assessed at day 1 and day 22. All analyses were descriptive. The study is registered with ClinicalTrials.gov, NCT04969276. FINDINGS: Between July 16 and Aug 31, 2021, 306 participants were enrolled and randomly assigned, of whom 296 received at least one vaccine dose (100 in the coadministration group, 92 in the QIV-HD, and 104 in the mRNA-1273 group). Reactogenicity profiles were similar between the coadministration and mRNA-1273 groups, with lower reactogenicity rates in the QIV-HD group (frequency of solicited injection site reactions 86·0% [95% CI 77·6-92·1], 91·3% [84·2-96·0], and 61·8% [50·9-71·9]; frequency of solicited systemic reactions 80·0%, [70·8-87·3], 83·7% [75·1-90·2], and 49·4% [38·7-60·2], respectively). Up to day 22, unsolicited adverse events were reported for 17·0% (95% CI 10·2-25·8) of participants in the coadministration group and 14·4% (8·3-22·7) of participants in the mRNA-1273 group, and tended to be reported at a slightly lower rate (10·9% [5·3-19·1]) in participants in the QIV-HD group. Seven participants each reported one medically attended adverse event (three in the coadministration group, one in the QIV-HD group, and three in the mRNA-1273 group). There were no serious adverse events, adverse events of special interest, or deaths. Haemagglutination inhibition antibody geometric mean titres increased from day 1 to day 22 to similar levels in the coadministration and QIV-HD groups, for each influenza strain (A/H1N1: 363 [95% CI 276-476] vs 366 [272-491]; A/H3N2: 286 [233-352] vs 315 [257-386]; B/Yamagata: 429 [350-525] vs 471 [378-588]; B/Victoria: 377 [325-438] vs 390 [327-465] for the coadministration and QIV-HD groups, respectively). SARS-CoV-2 binding antibody geometric mean concentrations also increased to similar levels in the coadministration and mRNA-1273 groups at day 22 (7634 [95% CI 6445-9042] and 7904 [6883-9077], respectively). INTERPRETATION: No safety concerns or immune interference were observed for concomitant administration of QIV-HD with mRNA-1273 booster in adults aged 65 years and older, supporting co-administration recommendations. FUNDING: Sanofi Pasteur.

Influenza vaccination in immunocompromised populations: Strategies to improve immunogenicity.

Immunocompromised individuals are at high risk of severe illness and complications from influenza infection. For this reason, immunization using inactivated influenza vaccines is recommended for transplant patients, individuals receiving immunosuppressant treatments, and other persons with immunodeficiency. However, these immunocompromised populations are more likely to have lower and non-protective responses to annual vaccination with a standard influenza vaccine. Here, we review strategies aimed to improve the immunogenicity of influenza vaccines in immunocompromised populations. The different strategies employed have included adjuvanted vaccines, high-dose vaccines, booster doses, intradermal vaccination, and temporary discontinuation of immunosuppressant treatment regimens. High-dose trivalent, inactivated, split-virus influenza vaccine (IIV3-HD) is so far one of the leading strategies for improving vaccine responses in HIV patients, transplant patients, and persons receiving immunosuppressant therapies for inflammatory diseases. Several studies in these populations have shown stronger humoral responses with IIV3-HD than existing standard-dose trivalent vaccine, and comparable safety. Accordingly, some scientific societies have stated that high-dose influenza vaccine could be a preferred option for immunocompromised patients. However, larger randomized controlled studies are needed to validate relative immunogenicity and safety of IIV3-HD and other enhanced vaccines and vaccination strategies in immunocompromised individuals.

Efficacy and effectiveness of high-dose influenza vaccine in older adults by circulating strain and antigenic match: An updated systematic review and meta-analysis.

BACKGROUND: Influenza vaccine efficacy/effectiveness can vary from season to season due in part to the dominant circulating strains and antigenic matching. This study reviews the relative vaccine efficacy/effectiveness (rVE) of high-dose inactivated trivalent influenza vaccine (HD-IIV3) compared to standard-dose influenza vaccines (SD-IIV) in adults aged ≥ 65 years against influenza-associated outcomes. Additional sub-analyses of HD-IIV3 rVE were performed by the predominantly circulating influenza strain and the antigenic match or mismatch of the vaccine against the predominant circulating strains. METHODS: An updated systematic review and meta-analysis was conducted for studies assessing the rVE of HD-IIV3 against probable/laboratory-confirmed influenza-like illness (ILI), hospital admissions, and death in adults aged ≥ 65 years. Results from individual seasons were extracted from the studies, and viral surveillance data were used to determine the dominant circulating strains and antigenic match for each season. Results were then stratified based on clinical outcomes and seasonal characteristics and meta-analyzed to estimate pooled rVEs of HD-IIV3. RESULTS: 15 publications were meta-analyzed after screening 1,293 studies, providing data on 10 consecutive influenza seasons and over 22 million individuals receiving HD-IIV3 in randomized and observational settings. Across all influenza seasons, HD-IIV3 demonstrated improved protection against ILI compared to SD-IIV (rVE = 15.9%, 95% CI: 4.1-26.3%). HD-IIV3 was also more effective at preventing hospital admissions from all-causes (rVE = 8.4%, 95% CI: 5.7-11.0%), as well as influenza (rVE = 11.7%, 95% CI: 7.0-16.1%), pneumonia (rVE = 27.3%, 95% CI: 15.3-37.6%), combined pneumonia/influenza (rVE = 13.4%, 95% CI: 7.3-19.2%) and cardiorespiratory events (rVE = 17.9%, 95% CI: 15.0-20.8%). Reductions in mortality due to pneumonia/influenza (rVE = 39.9%, 95% CI: 18.6-55.6%) and cardiorespiratory causes (rVE = 27.7%, 95% CI: 13.2-32.0%) were also observed. Similar pooled rVEs were observed in both matched and mismatched seasons and in seasons where A/H3N2 or A/H1N1 strains were predominantly circulating. CONCLUSIONS: Evidence over 10 consecutive influenza seasons and in more than 34 million individuals aged ≥ 65 years suggests that HD-IIV3 is consistently more effective than SD-IIV at reducing influenza cases as well as influenza-associated clinical complications irrespective of circulating strain and antigenic match. A video summary of the article can be accessed via the Supplementary data link at the end of this article.

Introductory paper: High-dose influenza vaccine.

Seasonal influenza has a significant impact on global public health each year, especially in older adults 65 years of age and above. This paper presents the evolution of high-dose influenza vaccine and the quantity as well as quality of evidence on this vaccine. Its introduces other peer-reviewed manuscripts included in this supplement covering the benefits high-dose influenza vaccine over ten consecutive influenza seasons. The development of the high-dose influenza vaccine represents an important step in the evolution of influenza vaccines, offering an advancement in prevention of influenza and a step in encouraging healthy aging in older adults. A video summary of the article can be accessed via the Supplementary data link at the end of this article.

Quantifying the Impact of Influenza Among Persons With Type 2 Diabetes Mellitus: A New Approach to Determine Medical and Physical Activity Impact.

BACKGROUND: We describe the impact of influenza on medical outcomes and daily activities among people with and without type 2 diabetes mellitus (T2DM). METHODS: Retrospective cohort analysis of a US health plan offering a digital wellness platform connecting wearable devices capable of tracking steps, sleep, and heart rate. For the 2016 to 2017 influenza season, we compared adults with T2DM to age and gender matched controls. Medical claims were used to define cohorts and identify influenza events and outcomes. Digital tracking data were aggregated at time slices of minute-, day-, week-, and year-level. A pre-post study design compared the peri-influenza period (two weeks before and four weeks after influenza diagnosis) to the six-week preceding period (baseline). RESULTS: A total of 54 656 T2DM and 113 016 non-DM controls were used for the study. People with T2DM had more influenza claims, vaccinations, and influenza antivirals per 100 people (1.96% vs 1.37%, 34.3% vs 24.3%, and 27.1 vs 22 respectively, P < .001). A total of 1086 persons with T2DM and 1567 controls had an influenza claim (47.4% male, median age 54, 6.4% vs 7.8% trackers, respectively). Glycemic events, pneumonia, and ischemic heart disease increased over baseline during the peri-influenza period for T2DM (1.74-, 7.4-, and 1.6-fold increase respectively, P < .01). In a device wearing subcohort, we observed 10 000 fewer steps surrounding the influenza event, with the lowest (5500 steps) two days postinfluenza. Average heart rate increased significantly (+5.5 beats per minute) one day prior to influenza. CONCLUSION: Influenza increases rates of pneumonia, heart disease, and abnormal glucose levels among people with T2DM, and negatively impacts daily activities compared to controls.

The disease burden of influenza beyond respiratory illness.

Although influenza is primarily considered a respiratory infection and causes significant respiratory mortality, evidence suggests that influenza has an additional burden due to broader consequences of the illness. Some of these broader consequences include cardiovascular events, exacerbations of chronic underlying conditions, increased susceptibility to secondary bacterial infections, functional decline, and poor pregnancy outcomes, all of which may lead to an increased risk for hospitalization and death. Although it is methodologically difficult to measure these impacts, epidemiological and interventional study designs have evolved over recent decades to better take them into account. Recognizing these broader consequences of influenza virus infection is essential to determine the full burden of influenza among different subpopulations and the value of preventive approaches. In this review, we outline the main influenza complications and societal impacts beyond the classical respiratory symptoms of the disease.

Comparing the impact of high-dose versus standard dose influenza vaccines on hospitalization cost for cardiovascular and respiratory diseases: Economic assessment in the US Veteran population during 5 respiratory seasons using an instrumental variable method.

OBJECTIVES: Cost savings associated with high-dose (HD) as compared to standard-dose (SD) influenza vaccination in the United States (US) Veteran's Health Administration (VHA) population have been attributed to better protection against hospitalization for cardiac and respiratory diseases. The relative contribution of each of these disease categories to the reported savings remains to be explored. METHODS: During a recently completed study of HD versus SD vaccine effectiveness (conducted in the VHA over five respiratory seasons from 2010/11 through 2014/15), we collected cost data for all healthcare services provided at both VHA and Medicare-funded facilities. In that analysis, we compared the costs of vaccination and hospital care for patients admitted with either cardiovascular or respiratory disease. Treatment selection bias and other confounding factors were adjusted using an instrumental variable (IV) method. In this brief report we use the same study cohort and methods to stratify the results by patients admitted for cardiovascular disease (CVD) and those admitted for respiratory disease. RESULTS: We analyzed 3.5 million SD and 0.16 million HD person-seasons. The IV-adjusted rVEs were 14% (7-20%) against hospitalizations for CVD and 15% (5-25%) against respiratory hospitalizations. Net cost savings per HD recipient were $138 ($66-$200) for CVD related hospitalizations and $62 ($10-$107) for respiratory disease related hospitalizations. CONCLUSIONS: In the US VHA population, the reduction in hospitalizations for CVD over five respiratory seasons contributed twice the cost savings (per HD recipient) of the reduction in hospitalizations for respiratory disease.

Impact of a quadrivalent inactivated influenza vaccine on influenza-associated complications and health care use in children aged 6 to 35 months: Analysis of data from a phase III trial in the Northern and Southern Hemispheres.

BACKGROUND: A multi-season phase III trial conducted in the Northern and Southern Hemispheres demonstrated the efficacy of a quadrivalent split-virion inactivated influenza vaccine (IIV4) in children 6-35 months of age. METHODS: Data collected during the phase III trial were analysed to examine the vaccine efficacy (VE) of IIV4 in preventing laboratory-confirmed influenza in age subgroups and to determine the relative risk for IIV4 vs. placebo for severe outcomes, healthcare use, and parental absenteeism from work associated with laboratory-confirmed influenza. RESULTS: VE (95% confidence interval [CI]) to prevent laboratory-confirmed influenza due to any A or B strain was 54.76% (40.24-66.03%) for participants aged 6-23 months and 46.91% (23.57-63.53%) for participants aged 24-35 months. VE (95% CI) to prevent laboratory-confirmed influenza due to vaccine-similar strains was 74.51% (53.55-86.91%) for participants aged 6-23 months and 59.78% (19.11-81.25%) for participants aged 24-35 months. Compared to placebo, IIV4 reduced the risk (95% CI) by 31.28% (8.96-89.34%) for acute otitis media, 21.76% (6.46-58.51%) for acute lower respiratory infection, 40.80% (29.62-55.59%) for healthcare medical visits, 29.71% (11.66-67.23%) for parent absenteeism from work, and 39.20% (26.89-56.24%) for antibiotic use. CONCLUSION: In children aged 6-35 months, vaccination with IIV4 reduces severe outcomes of influenza as well as the associated burden for their parents and the healthcare system. In addition, vaccination with IIV4 is effective at preventing against influenza in children aged 6-23 and 24-35 months. TRIAL REGISTRATION: EudraCT no. 2013-001231-51.

Immunogenicity of high-dose trivalent inactivated influenza vaccine: a systematic review and meta-analysis.

INTRODUCTION: High-dose trivalent, inactivated, split-virus influenza vaccine (IIV3-HD) has been available in the US since 2009 for adults aged ≥ 65 years. To better understand how IIV3-HD provides improved protection against influenza, we systematically reviewed clinical studies comparing immune responses to IIV3-HD and standard-dose trivalent vaccine (IIV3-SD). AREAS COVERED: The primary objective was to determine the relative hemagglutination inhibition (HAI) antibody response of IIV3-HD vs. IIV3-SD in adults aged ≥ 65 years. Based on seven randomized studies including more than 18,500 adults aged ≥ 65 years, combined HAI geometric mean titer (GMT) ratios (95% confidence interval) approximately 1 month post-vaccination were 1.74 (1.65-1.83) for influenza A/H1N1, 1.84 (1.73-1.95) for influenza A/H3N2, and 1.47 (1.36-1.58) for influenza B. HAI GMT ratios in these studies were similar irrespective of sex, older age (≥ 75 years), frailty, and underlying conditions. Trends were similar for A/H3N2 neutralization and anti-neuraminidase antibody titers. In immunocompromised individuals, HAI GMT ratios were mostly > 1. EXPERT OPINION: In agreement with its improved efficacy and effectiveness, IIV3-HD is consistently more immunogenic than IIV3-SD in adults aged ≥ 65 years. IIV3-HD also appears more immunogenic in immunocompromised individuals.