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

AIM: 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. METHODS: 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. RESULTS: 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)]. CONCLUSIONS: 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.

First cases of SARS-CoV-2 BA.2.86 in Denmark, 2023.

We describe 10 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant BA.2.86 detected in Denmark, including molecular characteristics and results from wastewater surveillance that indicate that the variant is circulating in the country at a low level. This new variant with many spike gene mutations was classified as a variant under monitoring by the World Health Organization on 17 August 2023. Further global monitoring of COVID-19, BA.2.86 and other SARS-CoV-2 variants is highly warranted.

Estimation of SARS-CoV-2 Infection Fatality Rate by Age and Comorbidity Status Using Antibody Screening of Blood Donors During the COVID-19 Epidemic in Denmark.

BACKGROUND: Studies presenting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) for healthy individuals are warranted. We estimate IFR by age and comorbidity status using data from a large serosurvey among Danish blood donors and nationwide data on coronavirus disease 2019 (COVID-19) mortality. METHODS: Danish blood donors aged 17-69 years donating blood October 2020-February 2021 were tested with a commercial SARS-CoV-2 total antibody assay. IFR was estimated for weeks 11 to 42, 2020 and week 43, 2020 to week 6, 2021, representing the first 2 waves of COVID-19 epidemic in Denmark. RESULTS: In total, 84944 blood donors were tested for antibodies. The seroprevalence was 2% in October 2020 and 7% in February 2021. Among 3898039 Danish residents aged 17-69 years, 249 deaths were recorded. The IFR was low for people <51 years without comorbidity during the 2 waves (combined IFR=3.36 per 100000 infections). The IFR was below 3‰ for people aged 61-69 years without comorbidity. IFR increased with age and comorbidity but declined from the first to second wave. CONCLUSIONS: In this nationwide study, the IFR was very low among people <51 years without comorbidity.

Incubation Period, Spore Shedding Duration, and Symptoms of Enterocytozoon bieneusi Genotype C Infection in a Foodborne Outbreak in Denmark, 2020.

BACKGROUND: Microsporidia are rarely reported to cause outbreaks of diarrhea. We describe a foodborne outbreak of microsporidiosis from a workplace canteen in November 2020 in Denmark. METHODS: A probable case was defined as any person using the canteen between 4 November and 13 December 2020, reporting at least one gastrointestinal symptom, whereas a confirmed case also had an Enterocytozoon bieneusi positive stool sample. A web-based questionnaire was used to collect clinical, epidemiological, and food exposure data. We performed a retrospective cohort study and tested stool samples from affected individuals for bacterial, viral, and parasitic pathogens, including E. bieneusi. RESULTS: Altogether, 195 individuals completed the questionnaire. We identified 52 cases (65% male; median age 45 years [range 25-65]). Diarrhea (90%), fatigue (83%), and abdominal pain (79%) were the most commonly reported symptoms. Eight cases were laboratory-confirmed and had E. bieneusi genotype C. The incubation period was between 5 and 12 days, and polymerase chain reaction (PCR)-detectable spore shedding occurred up to 43 days after symptom onset. Disease was associated with consuming food from the workplace canteen on 4 November 2020 (relative risk [RR[, 2.8 [95% confidence interval [CI]: 1.4 - 5.4]) and lunchboxes containing open sandwiches (RR, 3.2 [95% CI: 1.4 - 7.2]) served that day. CONCLUSIONS: This is the second documented foodborne outbreak of E. bieneusi genotype C-associated diarrhea worldwide. Epidemiological findings advocated an open sandwiches lunchbox from 4 November 2020, as a likely source. E. bieneusi may be an under-reported cause of outbreaks of diarrhea, and testing for it might be useful in foodborne outbreak investigations.

COVID-19 preventive measures coincided with a marked decline in other infectious diseases in Denmark, spring 2020.

We aimed to descriptively analyse the possible impact of the national COVID-19 interventions on the incidence of common infectious diseases in Denmark during spring and summer 2020. This observational study focused on national register data on infections caused by 16 different bacterial and viral pathogens. We included new cases registered between 1 January 2016 and 31 July 2020. The weekly number of new cases were analysed with respect to the COVID-19-related interventions introduced during 2020. We found a marked decrease in infections associated with droplet transmission coinciding with the COVID-19 interventions in spring and summer 2020. These included decreases in both viral and bacterial airway infections and also decreases in invasive infections caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis. There was also a reduction in cases associated with foodborne transmission during the COVID-19 lockdown period. We found no effect of the lockdown on infections by invasive beta-haemolytic streptococci group B, C and G, Staphylococcus aureus bacteraemia, Neisseria gonorrhoeae or Clostridioides difficile. In conclusion, we found that the widespread interventions such as physical distancing, less travel, hygiene measures and lockdown of schools, restaurants and workplaces together coincided with a marked decline in respiratory infections and, to a smaller extent, some foodborne-transmitted infections.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection Fatality Rate Among Elderly Danes: A Cross-sectional Study on Retired Blood Donors.

BACKGROUND: Although the vast majority of individuals succumbing to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are elderly, infection fatality rate (IFR) estimates for the age group ≥70 years are still scarce. To this end, we assessed SARS-CoV-2 seroprevalence among retired blood donors and combined it with national coronavirus disease 2019 (COVID-19) survey data to provide reliable population-based IFR estimates for this age group. METHODS: We identified 60 926 retired blood donors aged ≥70 years in the rosters of 3 regionwide Danish blood banks and invited them to fill in a questionnaire on COVID-19-related symptoms and behaviors. Among 24 861 (40.8%) responders, we invited a random sample of 3200 individuals for blood testing. Overall, 1201 (37.5%) individuals were tested for SARS-CoV-2 antibodies (Wantai) and compared with 1110 active blood donors aged 17-69 years. Seroprevalence 95% confidence intervals (CIs) were adjusted for assay sensitivity and specificity. RESULTS: Among retired (aged ≥70 years) and active (aged 17-69 years) blood donors, adjusted seroprevalences were 1.4% (95% CI, .3-2.5%) and 2.5% (95% CI, 1.3-3.8%), respectively. Using available population data on COVID-19-related fatalities, IFRs for patients aged ≥70 years and for 17-69 years were estimated at 5.4% (95% CI, 2.7-6.4%) and .083% (95% CI, .054-.18%), respectively. Only 52.4% of SARS-CoV-2-seropositive retired blood donors reported having been sick since the start of the pandemic. CONCLUSIONS: COVID-19 IFR in the age group >69 years is estimated to be 65 times the IFR for people aged 18-69 years.

Malaria in Eritrean migrants newly arrived in seven European countries, 2011 to 2016.

Global migration has resulted in a large number of asylum applications in Europe. In 2014, clusters of Plasmodium vivax cases were reported among newly arrived Eritreans. This study aimed to assess malaria among Eritrean migrants in Europe from 2011 to 2016. We reviewed European migration numbers and malaria surveillance data for seven countries (Denmark, Germany, Netherlands, Norway, Sweden, Switzerland and the United Kingdom) which received 44,050 (94.3%) of 46,730 Eritreans seeking asylum in Europe in 2014. The overall number of malaria cases, predominantly P. vivax, increased significantly in 2014 compared to previous years, with the largest increases in Germany (44 P. vivax cases in 2013 vs 294 in 2014, p < 0.001) and Sweden (18 in 2013 vs 205 in 2014, p < 0.001). Overall, malaria incidence in Eritreans increased from 1-5 to 25 cases per 1,000, and was highest in male teenagers (50 cases/1,000). In conclusion, an exceptional increase of malaria cases occurred in Europe in 2014 and 2015, due to rising numbers of Eritreans with high incidence of P. vivax arriving in Europe. Our results demonstrate potential for rapid changes in imported malaria patterns, highlighting the need for improved awareness, surveillance efforts and timely healthcare in migrants.

Resurgence of Respiratory Syncytial Virus in the Summer of 2021 in Denmark-a Large out-of-season Epidemic Affecting Older Children.

Background: When coronavirus disease 2019 (COVID-19) restrictions were lifted in Denmark in the spring of 2021, a surge in respiratory syncytial virus (RSV) cases followed, causing a large out-of-season epidemic. This study aims to investigate the summer epidemic compared with 3 typical pre-COVID-19 RSV winter seasons using Danish registers to identify RSV cases, RSV-related admissions, and use of intensive care treatment. Methods: Incidence rates (IR) per 1000 person-years for RSV cases, RSV-related admissions, and intensive care treatment were calculated with 95% confidence interval (CI) for each season, stratified by age groups and incidence rate ratios (IRR) with 95% CI were calculated to compare the summer epidemic with the winter season for 2019-2020. Results: In the summer epidemic, the IR of RSV cases and admissions exceeded previous winter seasons for all age groups. The highest increases in IRs were seen among children aged 2 to 3 years and 4 to 5 years. The IRR of cases were 4.6 (95% CI, 4.1-5.2) and 3.3 (2.6-4.2) and the IRR of admissions were 3.3 (2.7-4.2) and 3.8 (2.3-6.5) in the 2 age groups, respectively, when compared with the winter season 2019-2020. Conclusions: Likely because of immunity debt following COVID-19 restrictions, the summer epidemic was significantly larger than previous winter seasons, most markedly among children aged 2 to 3 and 4 to 5 years but had a similar disease severity spectrum.

Relative vaccine protection, disease severity, and symptoms associated with the SARS-CoV-2 omicron subvariant BA.2.86 and descendant JN.1 in Denmark: a nationwide observational study.

BACKGROUND: During the 2023 Danish COVID-19 vaccination campaign, an updated monovalent mRNA vaccine targeting the SARS-CoV-2 omicron XBB.1.5 subvariant was administered. However, the rapid spread of a genetically divergent omicron BA.2.86 subvariant, JN.1, since September, 2023, poses potential challenges due to its rapid dominance and possible immune escape. Using national electronic health registry data from all regions of Denmark, we aimed to investigate whether the SARS-CoV-2 subvariant BA.2.86, and its descendant JN.1, differed from other circulating variants in terms of their ability to escape vaccine protection, the risk of infection leading to severe disease, and self-reported symptoms among infected people. METHODS: In this observational study, we included all residents of Denmark aged 65 years and older who tested positive for SARS-CoV-2 by PCR between Oct 1 and Dec 31, 2023, and for whom genomic data on the SARS-CoV-2 variant that had caused their infection were available. Data from clinical testing, sentinel, and self-sampling-based surveillance were linked with national electronic civil, vaccination, and hospitalisation registers. The relative protection of the XBB.1.5 updated COVID-19 vaccine against BA.2.86 infections versus infections with other variants was analysed in a case-only study, and the relative risk of hospitalisation in people infected with BA.2.86 versus other variants was analysed in a case-control study. Both analyses were adjusted for time, comorbidities, and previous vaccination history, among other potential confounders. Additionally, prevalence patterns in self-reported symptoms among people of all ages infected with SARS-CoV-2 were reported separately by subvariant. FINDINGS: Of the 7581 people in Denmark aged 65 years or older who tested positive for SARS-CoV-2 by PCR during the study period, 5882 (78%) samples were eligible for sequencing. 3862 (66%) of these passed quality control, were successfully sequenced, and the SARS-CoV-2 variant and subvariant identified, and these individuals were included in the study. Of these 3862 people, 2184 (57%) were infected with the BA.2.86 subvariant, including 1615 JN.1 infections. Participants infected with BA.2.86 had 1·52 (95% CI 1·25-1·86) times the odds, and those infected with JN.1 had 1·60 (1·27-2·02) times the odds, of having received the XBB.1.5 vaccine at least 7 days before their infection compared with participants infected with a non-BA.2.86 variant. The severity analysis showed no evidence of association between the infecting variant and the risk of COVID-19 hospitalisation (odds ratio 1·04 [95% CI 0·86-1·26] for BA.2.86 and 1·07 [0·85-1·34] for JN.1). Similarly, there was no evidence of differences in self-reported symptoms by variant strain. INTERPRETATION: Compared with other SARS-CoV-2 variants, BA.2.86 and the JN.1 sublineage were less sensitive to vaccine-induced immune protection from the XBB.1.5 updated COVID-19 vaccine; however, we found no evidence that infection with BA.2.86 or JN.1 resulted in increased disease severity or different symptom profiles. Although less effective against the new variants, XBB.1.5 vaccination remains protective and reduces the risk of infection and COVID-19 disease. FUNDING: The Danish Government and the EU's EU4Health programme.

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.

OBJECTIVES: To 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. METHODS: We 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. RESULTS: Among 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). DISCUSSION: In 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.

Estimated number of lives directly saved by COVID-19 vaccination programmes in the WHO European Region from December, 2020, to March, 2023: a retrospective surveillance study.

BACKGROUND: By March, 2023, 54 countries, areas, and territories (hereafter CAT) in the WHO European Region had reported more than 2·2 million COVID-19-related deaths to the WHO Regional Office for Europe. Here, we estimated how many lives were directly saved by vaccinating adults in the WHO European Region from December, 2020, to March, 2023. METHODS: In this retrospective surveillance study, we estimated the number of lives directly saved by age group, vaccine dose, and circulating variant-of-concern (VOC) period, regionally and nationally, using weekly data on COVID-19 mortality and infection, COVID-19 vaccination uptake, and SARS-CoV-2 virus characterisations by lineage downloaded from The European Surveillance System on June 11, 2023, as well as vaccine effectiveness data from the literature. We included data for six age groups (25-49 years, 50-59 years, ≥60 years, 60-69 years, 70-79 years, and ≥80 years). To be included in the analysis, CAT needed to have reported both COVID-19 vaccination and mortality data for at least one of the four older age groups. Only CAT that reported weekly data for both COVID-19 vaccination and mortality by age group for 90% of study weeks or more in the full study period were included. We calculated the percentage reduction in the number of expected and reported deaths. FINDINGS: Between December, 2020, and March, 2023, in 34 of 54 CAT included in the analysis, COVID-19 vaccines reduced deaths by 59% overall (CAT range 17-82%), representing approximately 1·6 million lives saved (range 1·5-1·7 million) in those aged 25 years or older: 96% of lives saved were aged 60 years or older and 52% were aged 80 years or older; first boosters saved 51% of lives, and 60% were saved during the Omicron period. INTERPRETATION: Over nearly 2·5 years, most lives saved by COVID-19 vaccination were in older adults by first booster dose and during the Omicron period, reinforcing the importance of up-to-date vaccination among the most at-risk individuals. Further modelling work should evaluate indirect effects of vaccination and public health and social measures. FUNDING: US Centers for Disease Control and Prevention.

Hospital admissions and need for mechanical ventilation in children with respiratory syncytial virus before and during the COVID-19 pandemic: a Danish nationwide cohort study.

BACKGROUND: The incidence of respiratory syncytial virus (RSV) increased in several countries after the relaxation of COVID-19 restrictions. We aimed to investigate the age-related risk of RSV-associated hospital admissions and need for mechanical ventilation during the RSV resurgence in summer and autumn 2021 compared with the four RSV seasons preceding the COVID-19 pandemic. We also aimed to describe the clinical complications necessitating mechanical ventilation. METHODS: This population-based cohort study included patients aged 0-17 years admitted to hospital with RSV in Denmark during the RSV resurgence in summer and autumn 2021, and the four pre-COVID-19 RSV seasons (2016-17, 2017-18, 2018-19, and 2019-20). We retrieved data on RSV-associated hospital admissions from the Danish National Patient Registry and demographic and clinical details of children who received mechanical ventilation through prospective real-time data collection in 2021-22 and retrospective data collection for the 2016-17 to 2019-20 RSV seasons from all eight paediatric and neonatal intensive care units in Denmark. Risk factors for severe RSV disease were as defined as age younger than 3 months or severe comorbidities. We calculated the risk of RSV-associated hospital admissions per 100 000 population in each RSV season from week 21 to week 20 of the following year. We also calculated the risk rate of receiving mechanical ventilation per 100 000 population and 1000 RSV-associated hospital admissions during each RSV season from week 21 to week 20 of the following year. We calculated risk ratios (RRs) for hospital admission and mechanical ventilation by dividing the risk rate of hospital admission and mechanical ventilation in 2021-22 by annual mean risk rates in the four pre-COVID-19 RSV epidemics (2016-17 to 2019-20). We compared RRs using Fisher's exact test. We compared complications leading to intubation between children with and without risk factors for severe RSV disease. The study is registered at ClinicalTrials.gov, NCT05186597. FINDINGS: Among 310 423 Danish children aged younger than 5 years, the mean number of RSV-associated hospital admissions increased from 1477 (SD 226) in the 2016-17 to 2019-20 RSV seasons to 3000 in the 2021-22 RSV season (RR 2·0 [95% CI 1·9-2·1]). 54 children with RSV received mechanical ventilation in 2021-22 compared with 15-28 annually in the 2016-17 to 2019-20 RSV seasons (2·3 [1·6-3·3]). The highest increase in hospital admissions and need for mechanical ventilation occurred among children aged 24-59 months (4·1 [3·6-4·7] for hospital admission; 4·6 [1·7-12·6] for mechanical ventilation). Among children admitted to hospital, the risk of mechanical ventilation was similar in 2021-22 and the four pre-COVID-19 seasons (risk rate 14·3 per 1000 RSV-associated hospital admissions [95% CI 10·4-19·3] vs 12·9 [10·1-16·1]; RR 1·1 [95% CI 0·8-1·6]). Across all RSV seasons studied, among children younger than 3 months or those with severe comorbidities, respiratory failure due to bronchiolitis led to mechanical ventilation in 69 (79%) of 87 children. Of 46 children with no risk factors for severe RSV, 40 (87%) received mechanical ventilation due to additional complications, including neurological (n=16; 35%), cardiac (n=1; 2%), and pulmonary complications (n=23; 50%; eg, wheeze responsive to bronchodilator therapy, severe bacterial co-infections, and pneumothorax). INTERPRETATION: In Denmark, RSV disease did not seem to be more severe for the individual child during the RSV resurgence in 2021 following relaxation of COVID-19 restrictions. However, hospital admissions were higher among older children, possibly due to a postponed first RSV infection or no recent reinfection. Older children without risk factors for severe RSV disease had atypical complications that led to intubation. If new RSV-preventive interventions for healthy infants delay first RSV infection, a higher number of older children might be admitted to hospital due to atypical clinical phenotypes, rather than classical bronchiolitis. FUNDING: National Ministry of Higher Education and Science and the Innovation Fund Denmark.

A Pragmatic Randomized Feasibility Trial of Influenza Vaccines.

BACKGROUND: The relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccines (QIV-HD) versus standard-dose quadrivalent influenza vaccines (QIV-SD) against hospitalizations and mortality in the general older population has not been evaluated in an individually randomized trial. Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements. METHODS: We conducted a pragmatic, open-label, active-controlled, randomized feasibility trial in Danish citizens aged 65 to 79 years during the 2021­2022 influenza season. Participants were randomly assigned 1:1 to receive QIV-HD or QIV-SD. Randomization was integrated into routine vaccination practice, and the trial relied solely on nationwide administrative health registries for data collection. Outcomes consisted of a feasibility assessment and descriptive rVE estimates. RESULTS: We invited 34,000 persons to participate. A total of 12,477 randomly assigned participants were included in the final analyses. Mean (±SD) age was 71.7±3.9 years, and 5877 (47.1%) were women. Registry-based data collection was feasible, with complete follow-up data for 99.9% of participants. Baseline characteristics were comparable to those of the overall Danish population aged 65 to 79 years. The incidence of hospitalization for influenza or pneumonia was 10 (0.2%) of 6245 in the QIV-HD group and 28 (0.4%) of 6232 in the QIV-SD group (rVE, 64.4%; 95% confidence interval, 24.4 to 84.6). All-cause death occurred in 21 (0.3%) and 41 (0.7%) participants in the QIV-HD and QIV-SD groups, respectively (rVE, 48.9%; 95% confidence interval, 11.5 to 71.3). CONCLUSIONS: Conducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. The findings of lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require replication in a future, fully powered trial. (Funded by Sanofi; ClinicalTrials.gov number, NCT05048589.)

Feasibility of randomizing Danish citizens aged 65-79 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.

BACKGROUND: High-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. METHODS: The 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. DISCUSSION: The 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 REGISTRATION: Clinicaltrials.gov : NCT05048589 , registered September 17, 2021.