https://orcid.org/0000-0002-9023-581X
ABSTRACT
Nirsevimab has been recently licensed for universal RSV prophylaxis in infants. NIRSE-GAL is a three-year population-based study initiated in Galicia in September 2023. It aims to evaluate nirsevimab effectiveness against RSV-related hospitalizations lower respiratory tract infections (LRTI), severe RSV, all-cause LRTI, and all-cause hospitalization. NIRSE-GAL also aims to estimate nirsevimab impact on primary healthcare use in the short and mid-term, children’s wheezing and asthma, and medical prescriptions for RSV. The immunization campaigns will be scheduled based on the expected start week for the RSV season and will last the whole season. Immunization will be offered to: i) infants born during the campaign (seasonal), ii) infants < 6 months at the start of the campaign (catch-up), and iii) infants with high-risk factors, aged 6–24 months at the start of the campaign (high-risk). The follow-up period will start: i) the immunization date for all immunized infants, ii) the start of the campaign, for the non-immunized catch-up or high-risk groups, or iii) the birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of study. Nirsevimab effectiveness will be estimated using Poisson and Cox regression models. Sensitivity and stratified analyses will be undertaken. The number of averted cases and the number needed to immunize will be estimated. Immunization failure and nirsevimab safety will be monitored. NIRSE-GAL was approved by the ethics committee of Galicia (CEIC 2023–377) and registered in ClinicalTrials.gov (ID: NCT06180993). Findings will be mainly shared via peer-reviewed publications and scientific conferences.
Introduction
Respiratory Syncytial Virus (RSV) infections contribute considerably to infant morbidity and mortality, especially in children younger than five.Citation1 A meta-analysis of data from 481 studies, estimated that globally, in 2019, there were 33 million episodes of acute lower respiratory tract infection (LRTI) associated with RSV, 3.6 million hospital admissions 26,300 hospital deaths, and 101,400 total deaths attributable to RSV in children aged 0 to 60 months.Citation1 While affecting infants in all regions, the RSV-associated acute LRTI incidence rate peaked in those younger than 3 months in low-income and lower-middle-income countries, and in infants aged between 3 and 6 months in upper-middle-income and high-income countries.Citation1 In regions with a temperate climate, RSV infections occur in annual outbreaks that begin in late autumn and last until spring,Citation2,Citation3 hence, infants born from October to December are at a higher risk of hospitalization for RSV infection in the first year of life as compared to those born in a different period of the year.Citation4 All infants born before and during the RSV season are susceptible to RSV hospitalization, and around half of RSV hospitalizations occur in infants born before the season, while the other half take place in infants born during the season. ,Citation5–7 The Burden of Acute Respiratory Infections (BARI) study of 51,292 Spanish children under five recruited between 2017 and 2018, found that the rate of medically attended acute LRTI and RSV-specific cases was the highest in the first year of life (134.4 per 1000 children), followed by 119.4 per 1000 children in the second year, and 35.3 per 1000 children between 2 and 5 years.Citation8
In Spain, the present study country, several studies pointed out the heavy social, economic and public health burden of RSV infections.Citation4,Citation8-Citation10 Data collected between 1997 and 2011 showed that nearly €50 million are spent on RSV-related hospitalizations.Citation9 Such medical cost is expected to be significantly higher when considering primary healthcare and emergency services derived expenses. Recent data from the BARI study concluded that although hospitalization is the main driver of direct healthcare cost per medically attended RSV-related case, relying on hospitalization data alone will underestimate the RSV infections requiring medical care. Likewise, using RSV-specific codes exclusively to identify RSV-related cases highlighted the magnitude of potentially underestimated RSV cases, calling for improvement in RSV testing and codification.Citation8 Comorbid infants are at higher risk of hospitalization for RSV and admission to a pediatric intensive care unit than non-comorbid infants.Citation4,Citation9 The mean annual rate of hospitalization for RSV-positive pneumonia in Spain linearly increased nearly 15% per year between 2012 and 2018, reaching 12.17 hospitalizations per 100,000 population, with no change in trend.Citation10
To help combat the public health impact of RSV infections, especially in young infants, two immunization products were licensed in 2023: nirsevimab (Beyfortus, AstraZeneca/Sanofi Pasteur), an extended half-life monoclonal antibody against RSV, and the inactivated pre-F RSVA/RSVB maternal vaccine (Abrysvo, Pfizer).Citation11 Nirsevimab was approved for medical use in the European Union on October 31st, 2022, and in the United Kingdom on November 09th, 2022.Citation12 It was subsequently approved in Canada (April 2023),Citation13 and the United States (July 2023).Citation14
In March 2023, Galicia, an autonomous community in Northwest Spain, pioneered in implementing nirsevimab as a universal prophylactic measure against RSV.Citation15,Citation16 The first nirsevimab immunization campaign was scheduled from September 25th, 2023, to March 31st, 2024. The campaign start date was set to target the infants as early as possible at the beginning of the 2023–2024 RSV season, while its closure date was decided based on data from previous RSV seasons, excluding the COVID-19 pandemic period.
To evaluate nirsevimab effectiveness against RSV and its severe forms and to assess the impact of nirsevimab implementation, the NIRSE-GAL study (www.nirsegal.es),Citation17 was established in collaboration with the Galician Directorate of Public Health of the Xunta de Galicia. NIRSE-GAL is a population-based three-year follow-up study that uses data from registries of the Galician Directorate of Public Health. In addition to nirsevimab effectiveness against RSV-related hospitalization, the NIRSE-GAL study aims to determine nirsevimab effectiveness against severe forms of RSV, all-cause hospitalization, and all-cause-LRTI hospitalization. NIRSE-GAL also proposes to evaluate the short and mid-term impact of nirsevimab on primary healthcare utilization, children wheezing and asthma, and medical prescriptions for RSV.
Methods
Study settings
NIRSE-GAL is a population-based prospective longitudinal study in Galicia, Northwest Spain, that was established under a framework collaboration with the Galician General Directorate of Public Health. NIRSE-GAL study period is from September 2023 to September 2026, representing three years follow-up period.
Galicia is a place for nearly 2.7 million inhabitants who benefit from universal access to the public health system (SERGAS).Citation18 98% of the Galician population benefits from the public health system.Citation19 Migration is uncommon in the Galician population, decreasing the rate of eventual loss to follow-up of the study participants.
In 2022, 14495 births took place in Galicia,Citation18 and the pediatric vaccination coverage rate was as high as 90%.Citation20 Data from previous RSV seasons spanning the period 2016–2019 and 2022 show that the number of the annual RSV-related hospitalizations in Galicia ranged from 370 to 711 for infants younger than 6 months and from 40 to 91 for infants aged from 6 months to 1 year. In the same period, the rate of RSV-related hospitalization ranged between 3,351 and 5,035 hospitalizations per 100,000 in infants younger than 1 year, between 5,110 and 6,953 per 100,000 in infants less than 6 months.Citation21 Supplementary material Appendix I details RSV hospitalizations by year and age group.
SERGAS provides healthcare through 14 public hospital complexes containing 9,818 hospital beds distributed in seven sanitary areas (data for 2022).Citation22,Citation23 SERGAS applies a fully digital and centralized system where primary care, hospitalizations, medical prescriptions and dispensations, and vaccination, among others, are automatically registered, allowing for data extraction in real time. Each individual in Galicia is attributed a unique identification number at birth which is then used in all SERGAS registries.
RSV case monitoring
Active monitoring of RSV cases in Galicia will commence at the earliest timepoint, considering the expected start of the next RSV season. For the 2023–2024 season, RSV cases were programmed to be actively monitored from September 25th, 2023, until March 31st, 2024. The campaign closure date was decided based on the expected RSV season end according to data from the previous 12 seasons, excluding those taking place during the COVID-19 pandemic (2020/2021 and 2021/2022). Data on RSV seasons occurring during the COVID-19 pandemic were not considered to account for changes in RSV epidemiology during that period.Citation24 For future RSV seasons, the campaign start and close dates will be adjusted, if required, as we will be able to actively trace any RSV case through the RSV surveillance program described below.
RSV testing in Galicia is routinely performed in the hospital and emergency department settings. Nevertheless, a primary healthcare surveillance program including RSV was developed for the purpose of the NIRSE-GAL study. This surveillance program retrieves data on all NIRSE-GAL eligible participants from the following seven SERGAS information system registries: (i) Healthy Child regional program in Galicia, which encompasses two pre-scheduled visits in the first 15 days of life as part of the regular pediatric control, (ii) Galician registry healthcare card, (iii) hospital admissions, (iv) microbiology laboratories test results, (v) Minimum Basic Data Set (MBDS) hospital registry, (vi) newborn metabolic disorders screening test registry, and (vii) vaccine registry. A specialized clinical team retrieves data according to pre-established definitions (detailed in the Endpoints section). The clinical team reviews any missing information and requests it if needed. Subsequently, the pseudonymization team extracts and completes the data from clinical records.
All electronic records needed for the NIRSE-GAL will be updated weekly through the Galician Regional Surveillance Information System.
RSV case ascertainment
Cases will be identified from the registries “hospital admissions” and “microbiology laboratories test results.” Public health specialists with a clinical background in RSV surveillance will review the cases. For case ascertainment and classification, these steps will be followed: i) admission with LRTI (yes/no); ii) RSV-related LRTI (yes/no); iii) RSV-related LRTI with ICU admission (yes/no); iv) RSV-related LRTI with noninvasive mechanical ventilation (yes/no); and v) RSV-related LRTI with invasive mechanical ventilation (yes/no). In the case of any uncertainty regarding the case evaluation, a second assessment of the doubtful case will be carried out by an expert advisory committee (EAC). Disagreements will be resolved by discussion between the reviewers and the EAC. If a consensus is not achieved, the EAC evaluation will prevail.
Breakthrough case assessment
To inspect any potential immunization failure in any RSV-related hospitalization LRTI in infant who had received nirsevimab, the reviewers will apply the following criteria for the classification as breakthrough case: i) the patient received nirsevimab at least seven days before hospital admission for RSV-related LRTI, ii) the patient did not present compatible clinical symptoms and/or RSV positive result in the seven days after nirsevimab administration, and iii) the patient did not show RSV positive test result in the 15 days prior to immunization and 30 days before admission. The EAC will resolve any doubtful breakthrough case.
Study population
The number of eligible children is expected to be approximately 14,000 per each RSV season. The NIRSE-GAL study participants are stratified into three categories according to their birth date and risk conditions: i) seasonal group: infants who were born during the RSV season, i.e., from September 25th, 2023 to March 31st, 2024 for the 2023–2024 RSV season, ii) catch-up group: infants who were younger than six months at the beginning of the RSV season, i.e., born between April 1st, and September 24th, 2023 for the 2023–2024 RSV season and iii) high-risk group: children aged between 6 and 24 months at the start of the RSV season, i.e., born between September 25th,2021, and March 31st, 2023, for the 2023–2024 RSV season, and who have any of the high-risk conditions: congenital heart diseases with considerable hemodynamic impact, whether cyanotic or acyanotic, bronchopulmonary dysplasia, severe immunosuppression: oncohaematological diseases, continuous treatment with immunosuppressants or primary immuno-deficiencies (with special attention to severe combined immunodeficiency and congenital agammaglobulinaemia), congenital metabolic disorders, neuromuscular diseases, severe pulmonary diseases, genetic syndromes causing considerable respiratory problems, trisomy 21, cystic fibrosis, patients in palliative care. The same stratification of the study participants will be applied in the 2024–2025 and 2025–2026 RSV seasons, however, if the immunization recommendation changes in those seasons, the stratification strategy will follow the updated recommendation.
Nirsevimab administration
As nirsevimab was implemented in the Galician immunization program, it is administered through the SERGAS network of public hospitals and primary healthcare centers, according to the Galician official recommendation for scheduling appointments for immunization practice. Nirsevimab-administered doses are registered as per routine immunization protocols.
The 2023–2024 nirsevimab campaign was preceded by educational, and training activities for the involved healthcare professionals.Citation15 Informative materials were also disseminated to the general population.Citation15
Participants in the seasonal group will receive nirsevimab in the hospital during the first day of life, unless there is a medical contraindication. The treating gynecologist, pediatric nurse, pediatrician and/or neonatologist will inform the parent about the study and their right to accept or decline nirsevimab administration to their infant. Catch-up and high-risk groups will be offered immunization by sending an electronic appointment to their parents. The message includes a QR code and weblink to the NIRSE-GAL study to help the parents learn more about the study. Appointments will be flexible and placed over a 3-week period before the start of the RSV season. Eligible participants who miss the original appointment will be recaptured through SERGAS public primary healthcare centers. Based on previous experiences in immunization in Galicia, nirsevimab coverage in the target population is expected to exceed 80%.
Eligible infants will receive an intramuscular dose of nirsevimab of 50 or 100 mg in the thigh or the deltoid muscle, depending on the infant’s weight. Seasonal and catch-up groups will receive a single dose of nirsevimab. Preterm infants will receive a single dose of nirsevimab before 12 months of age, while children belonging to other high-risk conditions will receive nirsevimab before the start of each RSV until completing two years of age. The same protocol will be followed in the 2023–2024, Citation2024–2025 and 2025–2026 RSV seasons.
Follow-up period
The follow-up start date is defined as: i) the date of immunization for all immunized infants, ii) the campaign start date for the non-immunized catch-up or high-risk group (for the 2023–2024 RSV season, it will be September 25th, 2023), or iii) birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of the observation period, whichever occurred first.
NIRSE-GAL study objectives and endpoints
A timetable of each of the NIRSE-GAL study primary and secondary objectives over the three-year study period (October 2023 - October 2026) and their corresponding endpoints is presented in .
Table 1. Timeline of NIRSE-GAL study objectives and endpoint assessment over the three-year study period (2023–2026). The primary endpoint will be assessed for the 5 months of the RSV season. The secondary and exploratory endpoints will be evaluated, when possible, at 3, 5, 12, 15, 17, 24, 27, 29 and 36 months after nirsevimab administration.
Primary objective
To evaluate the effectiveness of nirsevimab on hospitalization for RSV-related LRTI during the 2023–2024, Citation2024–2025, 2025–2026 RSV seasons in seasonal, catch-up, and high-risk groups. The 2023–2024 RSV season is defined from October 1st to March 1st.
Secondary objectives
All secondary endpoints will be evaluated during the 2023–2024, Citation2024–2025, and 2025–2026 RSV seasons in seasonal, catch-up, and high-risk groups.
To estimate the nirsevimab effectiveness against 4 key secondary endpoints: i) very severe RSV-related LRTI defined by requiring neonatal and/or pediatric ICU admission; ii) very severe RSV-related LRTI defined by label of severity (this label is established according to the presence of additional diagnosis and/or procedures and/or co-morbidities); iii) all-cause LRTI hospitalization; iv) all-cause hospitalization.
To evaluate the impact of nirsevimab on i) primary care attendance for any reason; ii) primary care attendance due to respiratory diseases; iii) acute otitis media diagnosis; iv) pneumonia diagnosis; v) acute respiratory diagnosis; and vi) antibiotic use in children. These endpoints are ascertained in nirsevimab-eligible infants using the International Classification of Primary Care (CIAP-2) codes which are available in the supplementary material file, Appendix II.
To evaluate the impact of nirsevimab on: i) RSV-related visits in emergency departments; and ii) all-cause visits in emergency departments.
Longitudinal assessment of the impact of nirsevimab on (recurrent) wheezing and asthma based on: i) Bronchodilator and corticosteroids prescription; ii) Incidence of related ICD-10/CIAP-2 codes in primary care and hospitalization.
To evaluate the safety of nirsevimab based on adverse events spontaneously reported to the pharmacovigilance system.
To evaluate nirsevimab uptake.
Composite endpoints
The following endpoints will be analyzed as composite endpoints and the CIAP-2 codes to ascertain each of them are described in Supplementary material file, Appendix II. The composite endpoints are: i) all respiratory cause attendance; ii) Otitis media; iii) Pneumonia; iv) all acute respiratory infection; iv) all upper respiratory infections; v) all lower respiratory infections; vi) all otitis; vii) wheezing/asthma; viii) all subacute/chronic respiratory cause. Composite endpoint analyses will be undertaken in the 2023–2024, Citation2024–2025, and 2025–2026 RSV seasons in seasonal, catch-up, and high-risk groups.
Exploratory objectives
To evaluate RSV-related LRTI hospitalization rate in infants during the RSV epidemic season and at 3, 5, 12, 15, 17, 24, 27, 29 and 36 months after nirsevimab administration.
To explore the impact of age group, sex, nirsevimab receival and comorbidities on the above-listed primary and secondary endpoints.
To evaluate the impact of nirsevimab on bacterial respiratory infections based on: i) hospitalization rates due to bacterial pneumonia and related diagnostic codes; ii) hospitalization rates due to all-bacterial infection; iii) medical attention in primary care due to bacterial respiratory infection related codes; and iv) medical attention in primary care due to all-bacterial infection. Further details are available in supplementary material file, Appendix II.
To study the rate of reinfection/re-admission and related healthcare utilization for RSV infections during the three-year observation period.
To explore the trend in the duration of hospital admissions for RSV during the three-year observation period.
All secondary, composite, and exploratory endpoints will be measured, when possible, at 3, 5, 12, 15, 17, 24, 27, 29 and 36 months after nirsevimab administration.
Safety monitoring
Nirsevimab has received marketing approval for administration in neonates and infants during their first RSV season and has showed a favorable safety profile,Citation25–29 that is similar to that of placebo or palivizumab. The most common side effects reported for nirsevimab are rash, pyrexia (fever), and injection site reactions (such as redness, swelling, and pain where the injection is given).
The NIRSE-GAL study is an observational non-interventional study for assessing the effectiveness of routine nirsevimab administration. The involved clinicians follow local requirements regarding the submission of cases of suspected adverse reactions to the competent authority where the reaction occurred. To report any adverse event related to nirsevimab administration, the yellow card (Tarjeta amarilla – the official system of Galicia for vaccine pharmacovigilance) will be used.Citation30 Additionally, all-cause hospitalizations within 15 days after immunization will be compared with previous years’ hospitalizations in infants during the same time frame (median days of immunization to 15 days after birth). This comparison will allow exploring any potential increase in all-cause hospitalization rate that could be eventually associated with the occurrence of unforeseen severe adverse events related to the immunization campaign.
Statistical considerations
The statistical analysis for the primary and the 4 key secondary endpoints, mentioned earlier, will be performed using data collected from nirsevimab-eligible participants, comparing nirsevimab recipients to non-recipients. Adjusted Poisson regression models will be the first choice to estimate nirsevimab effectiveness. If the nirsevimab coverage for the 2023–2024 RSV season exceeded 90%, most likely the number of observations in the nirsevimab non-recipients group will be insufficient to achieve an 80% statistical power to detect a 65% effectiveness in reducing the incidence of RSV-LRTI hospitalization, assuming a hospitalization rate of 6.138 per 100 children younger than six months.Citation31 In that case, a modeling analysis will be performed where data collected after nirsevimab introduction will be compared to historical data collected in the years of 2016–2023, excluding the COVID-19 pandemic period, where there was low or no RSV circulation.
The pre-established 90% cutoff coverage for the statistical analysis may change as the total number of RSV-LRTI hospitalizations in the nirsevimab non-recipients also depends on the incidence of RSV infections. Illustrations of different scenarios of treatment effectiveness (50%, 77%, and 89%), nirsevimab coverage (0%, 60%, 70%, 80%, 90%, and 100%) and incidence of LRTI-related-RSV hospitalization are provided as supplementary material attached to this article (Appendix III).
Nirsevimab coverage will be continuously monitored using data retrieved weekly. A descriptive summary of primary and key secondary endpoints will be updated weekly. Full mid-season (October-December), end-season (October-February), and before the start of the next RSV season (March-September) analysis will be performed in the cumulative nirsevimab-eligible children during the three-year study period.
Statistical analysis
Continuous and categorical baseline characteristics data of nirsevimab-eligible children will be summarized as mean (standard deviation) or median (range) and total (percentages), respectively. Stratified summaries by nirsevimab recipients and non-recipients will be provided. Secondary objectives will follow the same final analyses as that of the primary objective.
Scenario with nirsevimab coverage < 90%
For the main analysis (nirsevimab coverage < 90%) each individual will contribute to the study by person-time data. Individuals will be followed up until the occurrence of the outcome, loss to follow up, death, or end of study, whatever occurred first. A Poisson regression model with robust variance will be used for estimating the effectiveness of nirsevimab in preventing LRTI-related-RSV hospitalization, very severe RSV LRTI, all-cause LRTI hospitalization and all-cause hospitalization in nirsevimab recipients comparing to the non-recipients. Adjusted incidence rate ratios (IRR) and their 95% confidence intervals (CI) will be estimated from the Poisson model. The models will be directly adjusted for enrollment group (catch-up, seasonal, or high-risk) as a proxy of the age at the time of hospitalization and sex for their biological plausibility. The potential confounding effect of prematurity and Healthy Child program visits will be tested in a univariate analysis against the outcome. They will be selected for the multiple regression analysis if p-value is less than 0.02, and retained in the final model if the originally estimated IRR is changed by at least 10%. The effectiveness of nirsevimab will be defined as: (1 - IRR)*100. Similarly, Cox proportional hazard models will be applied to estimate hazard ratios (HR) of RSV hospitalization and their 95% CI. Nirsevimab effectiveness will be then calculated as (1 - HR)*100. The number needed to immunize will be then estimated based on the absolute risk reduction, incidence rate, or the estimated averted cases, whatever is more appropriate depending on the number of events.Citation32
Scenario with nirsevimab coverage > 90%
In the case of nirsevimab coverage > 90% in the 2023–2024 RSV season, a comparison with the historical data will be undertaken to ensure enough observations in the comparison group. The evolution of the incidence of 2023–2024 RSV-related hospitalization in infants younger than one will be compared weekly with data from previous seasons (2016–2017, 2017–2018, 2018–2019, 2021–2022, and 2022–2023) that correspond to the same epidemic week using Poisson regression model adjusted for the year-to-year RSV circulation variation based on the RSV hospitalization rate in the same week for children in their 2nd RSV season. Denominators for the incidence rate calculation will be obtained from monthly births reported by the Galician Institute of Statistics.Citation33
The analysis will be undertaken in two groups of children. The first group consists of infants in their 1st RSV season. These infants are born between April 1st and March 31st and will be eligible for nirsevimab. The second group includes toddlers in their 2nd RSV season who are ineligible for nirsevimab. As an example, for the 2023–24 season, infants born between April 1st, 2023, and March 31st, 2024, will be in their first RSV season and will be eligible for nirsevimab administration; while those born between April 1st, 2022, and March 31st, 2023, will be passing their second RSV season, hence, they will be ineligible to receive nirsevimab. The same criteria will be applied to cohorts from previous RSV seasons, even though they did not receive nirsevimab.
Sensitivity analysis
A sensitivity analysis on outcome ascertainment will be undertaken. In the main analysis, RSV-related hospitalizations were classified as per the revision undertaken by the public health specialist. Hospitalizations taking place after immunization will be considered a breakthrough case. For the sensitivity analysis, the case ascertainment will rely on the final agreement between reviewers and EAC on RSV-related hospitalization and breakthrough cases.
Averted case estimation
To estimate the number of averted cases in the mid-season of 2023–2024, cumulative weekly incidence rates of RSV-related hospitalization LRTI will be calculated in children in their 1st and 2nd RSV seasons, along with the ratio between them, for each of the five historical RSV seasons (2016–2017, 2017–2018, 2018–2019, 2021–2022, and 2022–2023). For instance, we will first estimate the number of expected cases in each historical RSV season using that season´s ratio of the hospitalization rate in children in their 1st RSV season to the hospitalization rate in children in their second RSV season, and the incidence rate observed for children in their 2nd RSV season in 2023–2024 (“nirsevimab” season). Then the median of the estimated cases based on five historical RSV seasons is considered as the expected cases in the 2023–2024 season that would have been observed without nirsevimab implementation. The number of averted cases will be then estimated using the 2023–2024 hospitalization and expected cases. In the case of having a sufficient number of hospitalizations in both the nirsevimab and the non-nirsevimab group (n > 30), the number of averted cases will be estimated using data from the current 2023–2024 RSV season comparing nirsevimab recipients to non-recipients.
In both scenarios of nirsevimab coverage, subgroup analyses by age, sex, prematurity, and comorbidities will be conducted. In the case of insufficient observations for a specific outcome, descriptive statistics will be presented.
Ethics
The NIRSE-GAL study protocol was approved by the regional independent reference ethics committee of Galicia (CEIC 2023–377). The study was developed in compliance with the International Council for Harmonization Guidelines for Good Clinical Practice and with the principles of the Declaration of Helsinki. Data will be obtained through the electronic registries of the Galician surveillance system for RSV by personnel independent of data analysis. Data will be anonymized before analysis.
Dissemination
Findings of the NIRSE-GAL will be submitted for peer-reviewed publication. They will be also disseminated in local, national and international scientific conferences and meetings, and shared with the general public through media networks. The findings will be also made available on the NIRSE-GAL website (www.nirsegal.es/en). NIRSE-GAL was designed to inform public health authorities on nirsevimab effectiveness and hence will be useful to make decisions on nirsevimab implementation, public health impact and cost-effectiveness.
Discussion
Given the novelty of nirsevimab’s availability, findings from real-world studies on its immunization effectiveness and impact will be crucial for decision-makers considering the implementation of RSV prophylaxis measures. The NIRSE-GAL study, in addition to the results it may yield, also proposes a detailed strategy that could be beneficial to other academic groups and public health institutions for planning data collection and analysis.
Beyond the acute endpoints paralleled in clinical development studies, NIRSE-GAL suggests assessing additional endpoints of utmost importance for analyzing the actual public health impact of RSV prophylaxis. Including broader endpoints like all-cause LRTI hospitalization and all-cause hospitalization may be particularly interesting for gauging the impact of prophylaxis, especially in settings where RSV-specific detection may be lacking or only recently performed. Furthermore, these broader endpoints may capture the impact of RSV as a co-infecting agent, its potential interactions with other pathogens like pneumococci, or the incremental effects of RSV infection on patients with preexisting conditions.
The protocol also aims to determine the short and mid-term impact of nirsevimab on primary care utilization, morbidity (wheezing and asthma), and healthcare consumption for RSV. Due to the lack of routine RSV testing in primary care, we propose using primary care codification and composite scores assessed longitudinally to capture any differences compared to rates observed in previous years as well as between those receiving nirsevimab and those who did not. The potential impact of the nirsevimab campaign on the economic and health impact of RSV, extending beyond the acute episode, could alter the cost-effectiveness balance. It is well established that children with a history of RSV infections have a significantly higher risk of developing recurrent wheezing episodes and chronic obstructive airway disease, as well as receiving more antibiotics and using primary and emergency healthcare services more frequently, compared to children with no history of RSV infection.Citation34,Citation35 However, it is unknown if nirsevimab, which prevents disease but not infection, may impact this course, and NIRSE-GAL could be crucial to confirm these findings and assess the mid-term impact of nirsevimab against respiratory morbidity in real-world conditions.
The NIRSE-GAL study will collect data using a centralized digital healthcare information system, including different registries with a common personal identification number assigned at birth, to ensure longitudinal follow-up for at least 3 years, according to the protocol. This surveillance system, developed, implemented, and tested before the start of the immunization campaign with nirsevimab, feeds from seven SERGAS information systems: (i) Galician healthcare card registry, (ii) vaccine registry, (iii) hospital admissions, (iv) microbiology laboratory test results, (v) newborn metabolic disorders screening test registry, (vi) Healthy Child regional program in Galicia, which includes two pre-scheduled visits in the first 15 days of life as part of the regular pediatric control, and (vii) Minimum Basic Data Set (MBDS) hospital registry. The Spanish MBDS includes data on hospitalization episodes, diagnoses, and procedures performed during that hospitalization, all coded using international classification codes.Citation36 Also, using historical data from the past five RSV seasons, excluding the COVID-19 pandemic period, and not relying solely on direct comparison with data from the 2022–23 RSV season, will allow us to account for changes in RSV circulation in the season after the pandemic.
In our protocol, we agreed on an arbitrary definition of a breakthrough case, which may assist other institutions. We will exclude as immunization failures those cases where infants had received nirsevimab within 7 days before admission for RSV-related LRTI. The rationale for this definition is that maximum blood levels of nirsevimab are reached from the 7th day (according to nirsevimab package insert data). Moreover, given that the incubation time for RSV can vary between 2–7 days at a minimum,Citation37 it is unlikely that there is pulmonary involvement before 7 days from the infection. Although debatable, it is improbable that an LRTI-RSV admission occurring within 7 days following the administration of nirsevimab can be explained as an immunization failure.
The NIRSE-GAL results will be significant for conducting appropriate cost-effectiveness studies. Given the novelty of nirsevimab and the limited availability of such studies at the time the decision was made, Galician authorities adopted a pragmatic approach – a public health decision addressing immediate healthcare needs. This decision was based on an analysis of the disease burden and the anticipated cost savings from discontinuing the use of palivizumab. However, this decision will be revisited based on the findings from the NIRSE-GAL study.
As crucial as the rapid implementation of new available preventive tools like nirsevimab is the precise evaluation of its real-world deployment, as it may better delineate the protective capability of this long-acting monoclonal antibody. It could also be valuable for countries currently considering universal RSV prophylaxis in infants, providing policymakers and health authorities with population-based evidence to formulate effective and efficient RSV immunization prevention strategies.
Conclusions
To the best of our knowledge, Galicia pioneered the implementation of nirsevimab in its 2023–2024 immunization calendar, and the NIRSE-GAL is the first real-world prospective population-based study on comprehensive assessment of nirsevimab effectiveness and impact. Findings from NIRSE-GAL study will be crucial to draw conclusions on nirsevimab effectiveness and impact in real-world settings. The study protocol will help design further studies in other settings.
Authors contribution statement
Narmeen Mallah: literature search, investigation, methodology, writing – original draft, and writing – review & editing. Sonia Ares-Gomez: investigation, methodology, administration: and writing – review & editing. Jacobo Pardo-Seco, Alberto Malvar-Pintos, and Maria-Isolina Santiago-Perez: methodology. Olaia Pérez-Martinez, María-Teresa Otero-Barros, Nuria Suarez-Gaiche, Rosa-María Alvarez-Gil, Olga-María Ces-Ozores, Victoria Nartallo-Penas, Susana Mirás-Carballal, Marta Piñeiro-Sotelo, Juan-Manuel González-Pérez, Carmen Rodriguez-Tenreiro-Sánchez, Irene Rivero-Calle, and Antonio Salas: resources and project administration. Rolf Kramer, Jing Jin, Leticia Platero-Alonso: methodology. Carmen Duran-Parrondo: supervision, resources, project administration. Federico Martinón-Torres: conceptualization, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, visualization. All authors: writing – review & editing. Narmeen Mallah, Sonia Ares-Gomez and Federico Martinón-Torres: equal contribution.
Supplementary Material File.docx
Download MS Word (48 KB)Acknowledgments
The NIRSE-GAL study (CEIC 2023–377, ClinicalTrials.gov number NCT06180993) is funded by Sanofi/AstraZeneca through a research grant to the Healthcare Research Institute of Santiago de Compostela. This work was also supported by a Framework Partnership Agreement between the Consellería de Sanidad de la Xunta de Galicia and GENVIP-IDIS-2021–2024 (SERGAS-IDIS March 2021; Spain). In addition, it received support from i) ISCIII: TRINEO: PI22/00162; DIAVIR: DTS19/00049; Resvi-Omics: PI19/01039 (to A.S.), ReSVinext: PI16/01569, Enterogen: PI19/01090, OMI-COVI-VAC: PI22/00406 (to F.M.-T.), cofinanced FEDER, ii) GAIN: IN607B 2020/08 and IN607A 2023/02 (to A.S.), GEN-COVID (IN845D 2020/23 (to F.M.-T.), IIN607A2021/05 (to F.M.-T.); iii) ACIS: BI-BACVIR (PRIS-3, to A.S.), CovidPhy (SA 304 C, to A.S.); and iv) Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CB21/06/00103; to A.S. and F.M.-T.). This study is also supported by grants from the Galician Supercomputing Center (CESGA), the Spanish Ministry of Science and Innovation, the Galician Government, and the European Regional Development Fund (ERDF), the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS project (Grant Agreement number 279185).
Supplementary material
Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2348135.
Disclosure statement
Federico Martinón-Torres has acted as principal investigator in randomized controlled trials of Ablynx, Abbot, Seqirus, Sanofi Pasteur MSD, Sanofi Pasteur, Cubist, Wyeth, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis and GSK, with honoraria paid to his institution. Federico Martinon-Torres reports a relationship with GSK Vaccines SRL that includes: consulting or advisory. Federico Martinon-Torres reports a relationship with Pfizer Inc that includes: consulting or advisory. Federico Martinon-Torres reports a relationship with Sanofi Pasteur Inc that includes: consulting or advisory. Federico Martinon-Torres reports a relationship with Janssen Pharmaceuticals Inc that includes: consulting or advisory. Federico Martinon-Torres reports a relationship with MSD that includes: consulting or advisory. Federico Martinon-Torres reports a relationship with Seqirus Pty Ltd that includes: consulting or advisory. IRC has received speaking fees from MSD, GSK, Sanofi, Moderna and Pfizer. IRC has participated in advisory boards organized by MSD, GSK, Sanofi and Pfizer. IRC has been involved in clinical trials funded by Ablynx, Abbot, Seqirus, Sanofi Pasteur MSD, Sanofi Pasteur, Cubist, Wyeth, Merck, Pfizer, Roche, Regeneron, Jansen, Medimmune, Novavax, Novartis and GSK, although the funds were paid to her institution. Rolf Kramer, Jing Jin and Leticia Platero-Alonso are Sanofi employees and may hold shares and/or stock options in the company. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Additional information
Funding
References
- Li Y, Wang X, Blau DM, Caballero MT, Feikin DR, Gill CJ, Madhi SA, Omer SB, Simões EAF, Campbell H. et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis. Lancet. 2022;399(10340):2047–10. doi:10.1016/S0140-6736(22)00478-0.
- Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen JL, Bont L. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013;368(19):1791–9. doi:10.1056/NEJMoa1211917.
- Welliver RC. Respiratory syncytial virus and other respiratory viruses. Pediatr Infect Dis J. 2003;22(2 Suppl):S6–10. discussion S-2. doi:10.1097/01.inf.0000053880.92496.db.
- Viguria N, Martinez-Baz I, Moreno-Galarraga L, Sierrasesumaga L, Salcedo B, Castilla J, Morrow BM. Respiratory syncytial virus hospitalization in children in northern Spain. PLoS One. 2018;13(11):e0206474. doi:10.1371/journal.pone.0206474.
- Demont C, Petrica N, Bardoulat I, Duret S, Watier L, Chosidow A, Lorrot M, Kieffer A, Lemaitre M. Economic and disease burden of RSV-associated hospitalizations in young children in France, from 2010 through 2018. BMC Infect Dis. 2021;21(1):730. doi:10.1186/s12879-021-06399-8.
- Reeves RM, Hardelid P, Panagiotopoulos N, Minaji M, Warburton F, Pebody R. Burden of hospital admissions caused by Respiratory Syncytial Virus (RSV) in infants in England: a data linkage modelling study. J Infect. 2019;78(6):468–75. doi:10.1016/j.jinf.2019.02.012.
- Mira-Iglesias A, Demont C, Lopez-Labrador FX, Mengual-Chulia B, Garcia-Rubio J, Carballido-Fernandez M, Tortajada‐Girbés M, Mollar‐Maseres J, Schwarz‐Chavarri G, Puig‐Barberà J. et al. Role of age and birth month in infants hospitalized with RSV-confirmed disease in the Valencia Region, Spain. Influenza Other Respir Viruses. 2022;16(2):328–39. doi:10.1111/irv.12937.
- Martinon-Torres F, Carmo M, Platero L, Drago G, Lopez-Belmonte JL, Bangert M, Díez-Domingo J, Garcés-Sánchez M. Clinical and economic burden of respiratory syncytial virus in Spanish children: the BARI study. BMC Infect Dis. 2022;22(1):759. doi:10.1186/s12879-022-07745-0.
- Gil-Prieto R, Gonzalez-Escalada A, Marin-Garcia P, Gallardo-Pino C, Gil-de-Miguel A. Respiratory syncytial virus bronchiolitis in children up to 5 years of age in Spain: epidemiology and comorbidities: an observational study. Medicine (Baltimore). 2015;94(21):e831. doi:10.1097/MD.0000000000000831.
- Heppe-Montero M, Walter S, Hernandez-Barrera V, Gil-Prieto R, Gil-de-Miguel A. Burden of respiratory syncytial virus-associated lower respiratory infections in children in Spain from 2012 to 2018. BMC Infect Dis. 2022;22(1):315. doi:10.1186/s12879-022-07261-1.
- Langedijk AC, Bont LJ. Respiratory syncytial virus infection and novel interventions. Nat Rev Microbiol. 2023;21(11):734–49. doi:10.1038/s41579-023-00919-w.
- European Medicines Agency. Beyfortus nirsevimab. 2023 Jan 30. https://www.ema.europa.eu/en/medicines/human/EPAR/beyfortus#ema-inpage-item-authorisation-details.
- Government of Canada. Drug product database. 2024 Mar 14. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=102594.
- Food and Drug Administration (FDA). FDA approves new drug to prevent RSV in babies and toddlers. 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-prevent-rsv-babies-and-toddlers.
- Martinon-Torres F, Miras-Carballal S, Duran-Parrondo C. Early lessons from the implementation of universal respiratory syncytial virus prophylaxis in infants with long-acting monoclonal antibodies, Galicia, Spain, September and October 2023. Euro Surveill. 2023;28(49). doi:10.2807/1560-7917.ES.2023.28.49.2300606.
- Martinon-Torres F, Navarro-Alonso JA, Garces-Sanchez M, Soriano-Arandes A. The path towards effective respiratory syncytial virus immunization policies: recommended actions. Arch Bronconeumol. 2023;59(9):581–8. doi:10.1016/j.arbres.2023.06.006.
- NIRSE-GAL. Evaluación de la efectividad e impacto de Nirsevimab en Galicia 2023. 2024. https://www.nirsegal.es/.
- Galician Statistical Institute [Instituto Galego de Estadística]. 2024 Mar 24. https://www.ige.gal/.
- Galician Health Service (SERGAS). Activities report SERGAS 2018. [Memoria actividades SERGAS 2018] 2018 [accessed 2024 Feb 20]. https://www.sergas.es/A-nosa-organizacion/Documents/832/MemoriaActividade2018.pdf.
- Government of Spain-Ministry of Health [Ministerio de Sanidad]. Vaccination information system [Sistema de Información de Vacunaciones (SIVAMIN)]. 2022. https://pestadistico.inteligenciadegestion.sanidad.gob.es/publicoSNS/I/sivamin/informe-de-evolucion-de-coberturas-de-vacunacion-por-vacuna.
- Galician Health Service (SERGAS). Respiratoty syncital virus [virus sincitial respiratorio]. 2024 Mar 24. https://www.sergas.es/Saude-publica/Virus-Sincitial-Respiratorio?idioma=es.
- Estatistica IGd. Hospitais [hospitals] 2022. https://www.ige.gal/web/mostrar_actividade_estatistica.jsp?idioma=gl&codigo=0202001.
- Galician Health Service (SERGAS). Hospitals. 2024. https://www.sergas.es/bucen/busca-hospitais.
- Olsen SJ, Winn AK, Budd AP, Prill MM, Steel J, Midgley CM, Kniss K, Burns E, Rowe T, Foust A. et al. Changes in influenza and other respiratory virus activity during the COVID-19 pandemic — United States, 2020–2021. MMWR Morb Mortal Wkly Rep. 2021;70(29):1013–19. doi:10.15585/mmwr.mm7029a1.
- Simoes EAF, Madhi SA, Muller WJ, Atanasova V, Bosheva M, Cabanas F, Baca Cots M, Domachowske JB, Garcia-Garcia ML, Grantina I. et al. Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials. Lancet Child Adolesc Health. 2023;7(3):180–9. doi:10.1016/S2352-4642(22)00321-2.
- Muller WJ, Madhi SA, Seoane Nunez B, Baca Cots M, Bosheva M, Dagan R, Hammitt LL, Llapur CJ, Novoa JM, Saez Llorens X. et al. Nirsevimab for prevention of RSV in term and late-preterm infants. N Engl J Med. 2023;388(16):1533–4. doi:10.1056/NEJMc2214773.
- Hammitt LL, Dagan R, Yuan Y, Baca Cots M, Bosheva M, Madhi SA, Muller WJ, Zar HJ, Brooks D, Grenham A. et al. Nirsevimab for prevention of RSV in healthy late-preterm and term infants. N Engl J Med. 2022;386(9):837–46. doi:10.1056/NEJMoa2110275.
- Griffin MP, Yuan Y, Takas T, Domachowske JB, Madhi SA, Manzoni P, Simões EAF, Esser MT, Khan AA, Dubovsky F. et al. Single-dose nirsevimab for prevention of RSV in preterm infants. N Engl J Med. 2020;383(5):415–25. doi:10.1056/NEJMoa1913556.
- Domachowske J, Madhi SA, Simoes EAF, Atanasova V, Cabanas F, Furuno K, Garcia-Garcia ML, Grantina I, Nguyen KA, Brooks D. et al. Safety of nirsevimab for RSV in infants with heart or lung disease or prematurity. N Engl J Med. 2022;386(9):892–4. doi:10.1056/NEJMc2112186.
- Galician Health Service (SERGAS). Pharmacovigilance security [Seguridad Pharmacovigilancia]. https://www.sergas.gal/Saude-publica/Seguridade-e-farmacovixilancia?idioma=es.
- Galician Health Service (SERGAS). Circulation of the respiratory syncytial virus in Galicia: validity of the wave threshold. Revision 2023 [Circulación do virus respiratorio sincitial en Galicia: validez do limiar de onda. Revisión 2023]. Boletín Epidemiolóxico de Galicia. 2023;XXXII(6):1–16. https://www.sergas.es/Saude-publica/Documents/7294/BEG%20XXXII-6.pdf.
- Ranganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: absolute risk reduction, relative risk reduction, and number needed to treat. Perspect Clin Res. 2016;7(1):51–3. doi:10.4103/2229-3485.173773.
- Galician Statistical Institute [Instituto Galego de Estadistica]. 2024. https://www.ige.gal/web/mostrar_seccion.jsp?idioma=gl&codigo=0201.
- Homaira N, Briggs N, Oei JL, Hilder L, Bajuk B, Jaffe A, Omer SB. Association of age at first severe respiratory syncytial virus disease with subsequent risk of severe asthma: a population-based cohort study. J Infect Dis. 2019;220(4):550–6. doi:10.1093/infdis/jiy671.
- Szabo SM, Levy AR, Gooch KL, Bradt P, Wijaya H, Mitchell I. Elevated risk of asthma after hospitalization for respiratory syncytial virus infection in infancy. Paediatr Respir Rev. 2013;13(2):S9–15. doi:10.1016/S1526-0542(12)70161-6.
- de Miguel Diez J, Lopez de Andres A, Jimenez Garcia R. The Minimum Basic Data Set (MBDS), our big data for the epidemiological investigation of respiratory diseases. Arch Bronconeumol (Engl Ed). 2020;56(5):267–8. doi:10.1016/j.arbr.2019.04.022.
- Baldassarre ME, Loconsole D, Centrone F, Caselli D, Martire B, Quartulli L, Acquafredda A, D’Amato G, Maffei G, Latorre G. et al. Hospitalization for bronchiolitis in children aged ≤ 1year, Southern Italy, year 2021: need for new preventive strategies? Ital J Pediatr. 2023;49(1):66. doi:10.1186/s13052-023-01455-2.