ABSTRACT
Background
Respiratory syncytial virus (RSV) can cause serious illness in older adults and those with chronic conditions. While the bivalent RSVpreF vaccine has been shown to protect against RSV-related respiratory tract disease, its impact on severe RSV-related and broader cardiorespiratory hospitalizations remains untested in a fully powered randomized trial. This pragmatic, individually randomized, open-label, parallel-group trial aims to evaluate RSVpreF vaccine effectiveness (VE) in reducing the risk of RSV-related and all-cause cardiorespiratory hospitalizations in adults aged 60 and older.
Methods
DAN-RSV is randomizing Danish adults 1:1 to receive either RSVpreF or no RSV vaccine. The trial uses nationwide registries for recruitment, where eligible citizens are identified and invited via the national electronic messaging system and can provide electronic informed consent remotely. Baseline, safety, and outcome data are collected through the national health registries using the civil registration number provided at consent. Up to 130,000 participants will be enrolled during the 2024/2025 winter season. The primary objective is to assess vaccine effectiveness (VE) against RSV-related respiratory tract disease hospitalization. Secondary endpoints include RSV-related and all-cause lower respiratory tract disease hospitalizations, RSV-related and all-cause cardiorespiratory hospitalizations, and all-cause death.
Conclusion
DAN-RSV is an innovative trial combining the gold standard of individual randomization with pragmatic data collection via centralized health records and national health registries. This design offers a feasible approach to assess the impact of RSVpreF on clinically meaningful cardio-respiratory outcomes in adults ≥60 years in a real-world setting– while minimizing bias through use of randomization. The results will support cost-effectiveness analyses and inform future vaccination policies.
Trial registration
NCT06684743, registered November 9, 2024 ( https://clinicaltrials.gov/study/NCT06684743 )
Background
Respiratory syncytial virus (RSV) is a major respiratory pathogen prevalent during the winter season in temperate climates and during the rainy seasons in tropical climates. Infection with RSV can cause severe respiratory illness in older adults and those with concomitant medical conditions. ,,,,, This can lead to worsening of existing conditions, hospitalization, functional decline, and even death. ,,, In industrialized countries, RSV infection has been reported to be a major cause of respiratory illness among older adults with an estimated annual burden of 5.2 million cases, 470,000 hospitalizations, and 33,000 deaths These estimates underrecognize the true burden of RSV by 2-fold given variability in diagnostic sensitivity, testing rates, and case definitions for RSV among older adults. The most recognized complications to RSV infection are pulmonary, but a relationship between RSV-infection and cardiovascular morbidity and mortality has been suggested as studies have shown that RSV-infection is associated with cardiovascular complications in up to 22% of adult RSV patients, including acute heart failure, acute coronary syndrome, and arrhythmias, and thus a major contributor to the development of cardiovascular disease. ,,,,,,, RSV infection is also associated with a significantly higher risk of hospitalization in people with existing cardiovascular disease. Therefore, averting cardiac disease may be another benefit of RSV vaccination, and patients with cardiovascular disease may be an important target population for RSV vaccines.
A recent phase 3 trial of the bivalent RSV prefusion F protein-based vaccine (RSVpreF), an RSV vaccine for adults, documented its efficacy in reducing infection with RSV. At the end of the first season, vaccine efficacy of RSVpreF against RSV-associated lower respiratory tract illness was 88.9% (95%CI: 53.6-98.7) compared with placebo. At the end of the second season, vaccine efficacy was 77.8% (95%CI: 51.4-91.1). To date, the real-world vaccine effectiveness (VE) of RSVpreF vaccine against RSV-related hospitalization has not been assessed in a randomized setting. Observational data from real-world VE studies in the United States have indicated RSVpreF VE against RSV-related hospitalizations to be in the range of 73% to 91% ,,, in studies employing a number of observational designs, including test-negative design case-control studies, retrospective cohorts, and target-trial emulations.
All of the available real-world VE estimates of the RSVpreF vaccine are based on observational data which is limited by potential confounding due to issues such as information bias related to sources of exposure ascertainment, testing rates, and assay sensitivity for outcome assessment. There would therefore be significant public health interest in quantifying the benefit of the RSVpreF vaccine against clinically important and impactful outcomes such as RSV-related hospitalizations among adults aged ≥60 years in a real-world setting using randomization. These data would be important in performing public health impact and cost-effectiveness analyses to guide future vaccination policies. In the European Union, the RSVpreF vaccine is currently approved for active immunization for the prevention of lower respiratory tract disease caused by RSV in adults aged ≥18 years.
While explanatory randomized controlled trials (RCTs) serve as the gold standard for decision-making and are required for the regulatory approval of any new vaccine, their results can have limited generalizability due to restrictive eligibility criteria and highly controlled designs. Building on traditional RCTs, pragmatic trial design combines individual randomization with real-world patient populations and efficient data collection via electronic health records and national registries—offering unbiased, causal evidence grounded in routine clinical practice. With this approach, rigorous randomization of treatment allocation is integrated with existing data-collection platforms and routine healthcare data registries which may be used to collect baseline and follow-up information, greatly reducing trial complexity and costs. The Danish healthcare system is tax-funded and provides universal healthcare services free-of-charge. In Denmark, many individuals presenting with influenza-like symptoms undergoes simultaneous testing for influenza A and B, RSV, and SARS-CoV-2 at emergency departments prior to hospital admission to guide isolation decisions. All healthcare activities in the Danish healthcare system including microbiologic test results, vaccinations, causes of death, duration of hospital contacts, diagnosis codes, medical procedures, and biochemical results are recorded in nationwide administrative registries which enable effective collection of such information for all citizens. , The nationwide health registries allow for identification of all potentially eligible participants in Denmark and for remote collection of baseline, outcome, and safety data. This infrastructure makes it possible to conduct large-scale randomized trials in a real-world setting powered for clinically important endpoints with relatively low attack rates such as pathogen-specific hospitalization.
The feasibility of conducting such large-scale vaccine trials with individual randomization in the Danish healthcare system was demonstrated in the pilot study DANFLU-1 (NCT05048589) where participants were randomized 1:1 to a high-dose or standard-dose influenza vaccine during the 2021/22 influenza season. , The DAN-RSV (A Pragmatic Randomized Trial to Evaluate Bivalent RSV Prefusion F Protein–based VE for Preventing RSV Hospitalizations in Adults Aged 60 Years or Above) study was designed as an individually randomized open-label trial powered for severe clinical endpoints. The real-world setting of this trial will help determine the public health impact of the RSVpreF vaccine and provide high-quality data for vaccine recommendations and health economic analyses.
Purpose
The purpose of the DAN-RSV trial is to evaluate RSVpreF VE against RSV-related and all-cause respiratory and cardiovascular outcomes, as well as mortality, in Danish adults aged ≥60 years.
Methods
Study design and organization
DAN-RSV is a pragmatic, open-label, individually randomized trial conducted in Denmark during the 2024/2025 winter season using the nationwide registries for collection of baseline, safety, and outcome data. Participants will be randomly allocated to receive the RSVpreF vaccine or no RSV vaccine in a 1:1 ratio.
In this collaboration between the Center for Translational Cardiology and Pragmatic Randomized Trials (CTCPR) at the Department of Cardiology, Copenhagen University Hospital– Herlev and Gentofte, University of Copenhagen, Denmark, and the private vaccination provider Danske Lægers Vaccinations Service/European LifeCare Group (ELCG), CTCPR acts as trial sponsor and the central trial coordination site and is responsible for the overall study design, conduct, registry-based recruitment and data collection, and safety monitoring. DAN-RSV is funded by Pfizer Inc. who participated in the study design and protocol and statistical analysis plan development, but have no responsibilities in trial conduct, data collection, or data analysis. For this trial, ELCG is responsible for organizing vaccination sessions, obtaining informed consent, randomization, and administering the study vaccine (RSVpreF). During the 2024/2025 RSV season, ELCG organized vaccination sessions at >40 unique locations across Denmark.
In November 2024, 1,399,220 eligible Danish citizens were invited to participate in the trial through invitation letters sent through the governmental electronic letter system. To minimize participation burden, trial participation required only 1 study visit and an innovative informed consent system was used which allowed participants to provide electronic informed consent online and undergo randomization immediately thereafter, prior to their vaccination visit ( Figure 1 ). This simplifies the procedure at the vaccination clinic and ensures that only participants randomized to receive the RSVpreF vaccine need to attend a physical visit. However, participants will still have the option to provide informed consent in person at the vaccination clinic, and these will undergo randomization during the study visit.
SPIRIT schedule of enrolment, interventions, and assessments. *In cases where informed consent was provided online prior to study visit, the participant was immediately randomized online, and allocation would then occur prior to the study visit. The date of randomization marks Day 0. ⁎⁎ In cases where informed consent was provided in person at the vaccination clinic, allocation and vaccine administration would occur on the same day (day 0). ⁎⁎⁎ ITT population will include endpoint events from 14 days after booked clinic visit; as-treated population will include endpoint events from 14 days after the actual vaccination date for those in the RSVpreF-group, and will include a balanced follow-up time for controls to account for gain or loss of follow up time in the vaccinated cohort due to any rescheduled vaccination dates. RSVpreF = bivalent RSV prefusion F protein–based vaccine.
Trial population and recruitment
To ensure a representative sample of adults aged ≥60 years from the general population, the trial had no formal exclusion criteria but required that the study vaccine was administered according to routine clinical practice guidelines including evaluating contraindications to the RSVpreF vaccine (known allergy/hypersensitivity to the vaccine or its recipients, fever/illness on the vaccination day [these were offered a vaccination at a later date], or prior receipt of an RSV vaccine). The trial enrolled adults aged ≥60 years regardless of comorbidity status.
Participants were primarily recruited via electronic invitation letters distributed through the Danish governmental digital mail system, Digital Post. This platform is predominantly used for high-priority communications from public authorities, the public healthcare system, and financial institutions; however, it is also accessible for research purposes to support participant recruitment and correspondence. From age 15, all Danish citizens are automatically enrolled to receive official communications via this system, although individuals may apply for exemption to receive physical mail instead. Upon delivery of a message through Digital Post, users are notified via email and text message and may access the correspondence through various web portals or smartphone applications.
In Denmark, all permanent residents are assigned a unique personal identifier (CPR number) at birth or upon immigration. This identifier enables precise cross-linkage of administrative and health registries and also serves as the “delivery address” within the governmental digital mail infrastructure.
Through application to the Danish Health Data Authority, researchers affiliated with authorized Danish institutions may obtain contact information for potential study participants, identified through data available in the Danish administrative registries. In November 2024, CTCPR received data extracts containing contact information on all trial-eligible Danish citizens with access to the Digital Post system which allowed for delivery of 1,399,220 invitation letters (86.0% of the Danish population aged ≥60 years). Each invitation letter included a link to the trial website where further information could be read. The website also contained a video of the principal investigator explaining the trial to the possible participants. After reviewing the material, potential participants could book a visit for participation. After having booked a study visit, participants had the option to provide informed consent online. The trial was approved to use nonsynchronous informed consent—an experimental program run by the Danish Medical Research Ethics Committee where participants in low-intervention clinical trials can provide online nonsynchronous informed consent after having reviewed the study information material without real-time contact with any trial staff. Participants were provided with contact information for study staff in case of any questions. Participants also had the option to provide informed consent in person at the study visit instead if this was preferred. If informed consent was provided online prior to the study visit, participants were immediately randomized and informed about their study allocation. Only participants randomized to receive the RSVpreF vaccine were required to attend their study visit, participants randomized to no RSV vaccine were notified that they had been allocated to the control group and that they did not have to attend their study visit thereby greatly reducing participation burden for controls.
Potential participants were also recruited through ELCG’s prior vaccinees database, ELCG’s website, and patient organizations.
Trial enrolment was completed in December 2024 where the targeted number of participants had been recruited. A total of 131,379 participants were randomized during the 2024/2025 RSV season ( Figure 2 ). Of these, 65,688 were allocated to the RSVpreF vaccine group and 65,691 were allocated to the control group (no RSV vaccine). Randomization took place from November 2024 to December 2024 and vaccination took place from November 2024 to February 2025. Of all randomized participants, 128,839 (98.1%) provided informed consent online prior to the study visit.
Enrolment and randomization. Participants were randomly assigned RSVpreF vaccine or no RSV vaccine in a 1:1 ratio during the 2024/2025 season. RSVpreF, bivalent RSV prefusion F protein–based vaccine.
Randomization and blinding
Participants were individually randomized 1:1 to the RSVpreF vaccine or no RSV vaccine. If participants had provided informed consent online prior to the study visit, randomization occurred immediately after consent using a link to a centralized randomization algorithm. If participants provided informed consent in person at the study visit, randomization was performed using tablet computers linked to the centralized randomization. The randomization list was generated with permuted blocks of varying block size (block sizes: 6, 8, and 10) using R software (R Foundation for Statistical Computing, Vienna, Austria).
The trial employed an open-label design; both participants and investigators were aware of treatment allocation, which was disclosed immediately following randomization. Nevertheless, outcome assessment is deemed effectively blinded since data on clinical endpoints- such as hospitalizations and mortality- are passively collected through national health registries by healthcare professionals unaffiliated with the research team, as part of routine clinical practice. The trial did not use endpoint adjudication.
Intervention and comparator
Participants allocated to the RSVpreF vaccine group received a single intramuscular injection of the Abrysvo vaccine (bivalent RSV prefusion F subunit vaccine, manufactured by Pfizer) which contains 2 recombinant stabilized RSV prefusion F antigens representing subgroups RSV-A and RSV-B. One dose contains: RSV subgroup A stabilized prefusion F antigen (60 micrograms), RSV subgroup B stabilized prefusion F antigen (60 micrograms). Prefusion F is the primary target of neutralizing antibodies that block RSV infection.
Participants allocated to the control group did not receive any vaccine as part of the trial.
Co-administration with other seasonal vaccines including influenza and COVID-19 vaccines/boosters was allowed in the trial.
Data collection and data sources
The trial was designed to minimize active data collection beyond standard vaccination procedures conducted by personnel at the vaccination sites. Additional trial data collection at the site was limited to confirmation of trial participation and documentation of vaccine administration. For participants who had not completed informed consent online in advance, both consent and randomization were conducted on-site using a tablet computer. Data entered via tablet devices were transferred daily to the central trial database.
All other data for the trial (including baseline characteristics, safety, and follow-up data) were collected through the Danish administrative health registries. Each Danish citizen’s unique CPR number allows for unambiguous and data-linkage between all administrative registries including health registries. Through application to the Danish Health Data Authority, the CPR numbers for the trial participants were uploaded to a secure remote-access server environment (“Forskermaskinen”) hosted by the government. Upon upload, the encrypted CPR numbers can be used for data-linkage between health registries and other administrative registries.
We used data from several administrative registries for the present trial. The Danish National Patient Registry provides comprehensive data on all inpatient and outpatient contacts within the Danish public healthcare system. The Danish Civil Registration System includes key demographic information such as date of birth, death, immigration, and emigration. Specific causes of death can be obtained from the Danish Registry of Causes of Death. Records of all vaccinations, including RSV vaccinations administered outside the trial, are available through the Danish Vaccination Registry. The Danish Microbiology Database contains results from all routinely conducted microbiological tests, including tests for RSV. In addition, several national registries contain detailed socioeconomic information, including data on personal income, pensions, unemployment, and sickness benefits, thereby facilitating precise characterization of participants’ sociodemographic profiles. Educational attainment is available through the Population Education Registry. Baseline data will be extracted from these registries for the period spanning the date of randomization and up to ten years prior, consistent with approaches used in previous Danish registry-based studies. ,, Safety monitoring is supplemented by additional data obtained through manual review of electronic health records.
To minimize bias, all registry-based data collection in this trial uses prespecified definitions. Definitions of baseline characteristics and vaccinations are listed in Supplementary Tables I and II.
Endpoints
All data used to assess endpoints during the study will be collected from Danish nationwide registries. Endpoints will be counted through May 31, 2025 for this first season analysis. The intention-to-treat (ITT) analysis will count endpoints from 14 days after the initially booked vaccination date, even if a vaccination appointment is rescheduled resulting in an actual earlier or later vaccine administration date, while the as-treated analysis will count endpoints from 14 days after the actual vaccination date for those in the RSVpreF-group, and will include a balanced follow-up time for controls to account for gain or loss of follow up time in the vaccinated cohort due to any rescheduled vaccination dates.
The primary endpoint of the trial is hospitalization for RSV-related respiratory tract disease. Three key secondary endpoints are also defined; the 1st key secondary endpoint considers the primary endpoint analyzed using the as-treated study population with balanced follow-up time between allocation groups; the second evaluates VE against RSV-related lower respiratory tract disease (LRTD) hospitalization; the third considers VE against all-cause respiratory tract disease hospitalization. A full list of all prespecified study endpoints is included in Table 1 , and the prespecified registry-based definitions of each endpoint is listed in Supplementary Table III. Additional endpoints include healthcare resource utilization endpoints such as hospital and intensive care unit stays, number of primary care visits, and nursing home admissions.
Table 1
List of study endpoints.
Primary endpoint
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Secondary endpoints
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Exploratory endpoints
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Healthcare resource consumption endpoints
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