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Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in young children and the second leading cause of infant death worldwide. While global circulation has been extensively studied for respiratory viruses such as seasonal influenza, and more recently also in great detail for SARS-CoV-2, a lack of global multi-annual sampling of complete RSV genomes limits our understanding of RSV molecular epidemiology. Here, we capitalise on the genomic surveillance by the INFORM-RSV study and apply phylodynamic approaches to uncover how selection and neutral epidemiological processes shape RSV diversity. Using complete viral genome sequences, we show similar patterns of site-specific diversifying selection among RSVA and RSVB and recover the imprint of non-neutral epidemic processes on their genealogies. Using a phylogeographic approach, we provide evidence for air travel governing the global patterns of RSVA and RSVB spread, which results in a considerable degree of phylogenetic mixing across countries. Our findings highlight the potential of systematic global RSV genomic surveillance for transforming our understanding of global RSV spread., (© 2024. The Author(s).)

Monitoring the real-life effectiveness of respiratory syncytial virus (RSV) products is of major public health importance. This generic protocol for a test-negative design study aims to address currently envisioned approaches for RSV prevention (monoclonal antibodies and vaccines) to study effectiveness of these products among target groups: children, older adults, and pregnant women. The generic protocol approach was chosen to allow for flexibility in adapting the protocol to a specific setting. This protocol includes severe acute respiratory infection (SARI) and acute respiratory infection (ARI), both due to RSV, as end points. These end points can be applied to studies in hospitals, primarily targeting patients with more severe disease, but also to studies in general practitioner clinics targeting ARI., Competing Interests: Potential conflicts of interest. E. P. received a grant from the Finnish Medical Foundation. H. N. is a member of Finnish National Immunization Technical Advisory Group and chairman of Strategic Advisory Group of Experts on Immunization for World Health Organization. E. B. is an employee and shareholder of Pfizer, Inc. R. K. is an employee and shareholder of Sanofi. T. H. has received personal fees from Janssen, Sanofi, and MSD for activities outside the present work. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The risk of respiratory syncytial virus (RSV) hospitalization is highest during the first months of life, but few studies have assessed the population-based rates of hospitalization in monthly age groups of infants., Methods: We determined the average population-based rates of hospitalization with virologically confirmed RSV infections in children ≤15 years of age admitted during the 10-year period of 2008-2018. Testing for RSV was routine in all children hospitalized with respiratory infections, and all RSV-positive children admitted at any time during the study period were included in the analyses., Results: The annual population-based rate of RSV hospitalization was highest in infants 1 month of age (52.0 per 1000 children; 95% CI, 45.2-59.7), followed by infants <1 month of age (34.8 per 1000; 95% CI, 29.2-41.1) and those 2 months of age (32.2 per 1000; 95% CI, 26.9-38.4). In cumulative age groups, the rate of hospitalization was 39.7 per 1000 (95% CI, 36.2-43.4) among infants <3 months of age, 26.8 per 1000 (95% CI, 24.8-29.0) in infants aged <6 months, and 15.8 per 1000 (95% CI, 14.7-17.0) in those <12 months of age., Conclusion: In monthly age groups of infants, the incidence rates of virologically confirmed RSV hospitalization in all infants up to 3 months of age were substantially higher than those reported in earlier studies. These data may be important for improving the estimates of the cost-effectiveness of various interventions to reduce the burden of RSV in young infants., (© 2024 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Several immunization products are currently being developed against respiratory syncytial virus (RSV) for children, pregnant females, and older adults, and some products have already received authorization. Therefore, studies to monitor the effectiveness of these products are needed in the following years. To assist researchers to conduct postmarketing studies, we developed a generic protocol for register-based cohort studies to evaluate immunization product effectiveness against RSV-specific and nonspecific outcomes. To conduct a study on the basis of this generic protocol, the researchers can use any relevant databases or healthcare registers that are available at the study site., Competing Interests: Potential conflicts of interest. E. P. received a grant from the Finnish Medical Foundation. H. N. is a member of the Finnish National Immunization Technical Advisory Group and chair of Strategic Advisory Group of Experts on Immunization for the World Health Organization. E. B. is an employee and shareholder of Pfizer, Inc. R. K. is an employee and shareholder of Sanofi. T. H. has received personal fees from Janssen, Sanofi, and MSD (for activities outside the present work). All other authors have no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: During the first year of life, 1 in 4 infants develops a symptomatic respiratory syncytial virus (RSV) infection, yet only half seek medical attention. The current focus on medically attended RSV therefore underrepresents the true societal burden of RSV. We assessed the burden of nonmedically attended RSV infections and compared with medically attended RSV., Methods: We performed active RSV surveillance until the age of 1 year in a cohort (n = 993) nested within the Respiratory Syncytial Virus Consortium in EUrope (RESCEU) prospective birth cohort study enrolling healthy term-born infants in 5 European countries. Symptoms, medication use, wheezing, and impact on family life were analyzed., Results: For 97 of 120 (80.1%) nonmedically attended RSV episodes, sufficient data were available for analysis. In 50.5% (49/97), symptoms lasted ≥15 days. Parents reported impairment in usual daily activities in 59.8% (58/97) of episodes; worries, 75.3% (73/97); anxiety, 34.0% (33/97); and work absenteeism, 10.8% (10/93). Compared with medically attended RSV (n = 102, 9 hospital admissions), Respiratory Syncytial Virus NETwork (ReSViNET) severity scores were lower (3.5 vs 4.6, P < .001), whereas duration of respiratory symptoms and was comparable., Conclusions: Even when medical attendance is not required, RSV infection poses a substantial burden to infants, families, and society. These findings are important for policy makers when considering the implementation of RSV immunization. Clinical Trials Registration. ClinicalTrials.gov (NCT03627572)., Competing Interests: Potential conflicts of interest. M. A. v. H. has received honoraria for participation in advisory boards from Sanofi and Moderna and acted as a principal investigator in randomized clinical trials for Pfizer. T. H. has received honoraria for lectures or participation in advisory boards or data monitoring committees from Janssen, Sanofi, and MSD. A. J. P. is part of RESCEU (Respiratory Syncytial Virus Consortium in Europe), and his university received grant funding from the European Commission’s Innovative Medicines Initiative for this work. Oxford University has received grant funding from the Medical Research Council, Wellcome Trust, Bill & Melinda Gates Foundation, Serum Institute of India, and AstraZeneca. A. J. P. is a contributor to intellectual property licensed by Oxford University Innovation to AstraZeneca. A. J. P. is chair of the UK Joint Committtee of Vaccination and Immunisation and was a member of the World Health Organization’s Strategic Advisory Group of Experts on Immunization until 2022. S. C. provided clinical study advice or acted as principal investigator for GSK, Pfizer, MedImmune, Ablynx, Gilead, Ark Biosciences, Shionogi, and Janssen/Alios, with fees paid to the University of Edinburgh. F. M.-T. has received honoraria from GSK, Biofabri, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F. M.-T. has also acted as principal investigator in randomized controlled trials of the aforementioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. A. D.-U. has been a subinvestigator for clinical trials sponsored by Pfizer and GSK and observational studies sponsored by Sanofi, with all funds paid to her institution. A. D.-U. has received funding for attending the Asociación Española Pediatría (Pediatric Spanish Association) meeting in 2022. L. J. B. has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. University Medical Center Utrecht (UMCU) has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation. UMCU has received major funding as part of the public-private RESCEU and PROMISE projects, funded by the Innovative Medicines Initiative, in partnership with GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding from Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding (€1000–€25 000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, and Janssen. L. J. B. is the founding chair of the ReSViNET Foundation. J. G. W. has been an investigator for clinical trials sponsored by pharmaceutical companies, including AstraZeneca, Merck, Pfizer, Sanofi, and Janssen, with all funds paid to UMCU. J. G. W participated in the advisory board of Janssen and Sanofi, with fees paid to UMCU. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. 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Background: No overall estimate of respiratory syncytial virus (RSV)-associated hospitalizations in children aged under 5 years has been published for the European Union (EU). We aimed to estimate the RSV hospitalization burden in children aged under 5 years in EU countries and Norway, by age group., Methods: We collated national RSV-associated hospitalization estimates calculated using linear regression models via the RESCEU project for Denmark, England, Finland, Norway, the Netherlands, and Scotland, 2006-2018. Additional estimates were obtained from a systematic review. Using multiple imputation and nearest neighbor matching methods, we estimated overall RSV-associated hospitalizations and rates in the EU., Results: Additional estimates for 2 countries (France and Spain) were found in the literature. In the EU, an average of 245 244 (95% confidence interval [CI], 224 688-265 799) yearly hospital admissions with a respiratory infection per year were associated with RSV in children aged under 5 years, with most cases occurring among children aged under 1 year (75%). Infants aged under 2 months represented the most affected group (71.6 per 1000 children; 95% CI, 66.6-76.6)., Conclusions: Our findings will help support decisions regarding prevention efforts and represent an important benchmark to understand changes in the RSV burden following the introduction of RSV immunization programs in Europe., Competing Interests: Potential conflicts of interest. H. C. reports grants, personal fees, and nonfinancial support from World Health Organization; grants and personal fees from Sanofi Pasteur; grants from Bill and Melinda Gates Foundation, all payments made via the University of Edinburgh; and is a shareholder in the Journal of Global Health, Ltd. J. P. declares that Nivel has received unrestricted research grants regarding the epidemiology of RSV from Sanofi Pasteur and IMI in the past 12 months. X. W. has received research grants from GlaxoSmithKline; and consultancy fees from Pfizer, outside the submitted work. T. H. has received honoraria for lectures and/or participation in advisory boards or data monitoring committees from Janssen, Sanofi Pasteur, Enanta, and MSD. M. B. is an employee of Sanofi Vaccines and may hold stocks in the company. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Nirsevimab is an extended half-life monoclonal antibody to the respiratory syncytial virus (RSV) fusion protein that has been developed to protect infants for an entire RSV season. Previous studies have shown that the nirsevimab binding site is highly conserved. However, investigations of the geotemporal evolution of potential escape variants in recent (ie, 2015-2021) RSV seasons have been minimal. Here, we examine prospective RSV surveillance data to assess the geotemporal prevalence of RSV A and B, and functionally characterise the effect of the nirsevimab binding-site substitutions identified between 2015 and 2021., Methods: We assessed the geotemporal prevalence of RSV A and B and nirsevimab binding-site conservation between 2015 and 2021 from three prospective RSV molecular surveillance studies (the US-based OUTSMART-RSV, the global INFORM-RSV, and a pilot study in South Africa). Nirsevimab binding-site substitutions were assessed in an RSV microneutralisation susceptibility assay. We contextualised our findings by assessing fusion-protein sequence diversity from 1956 to 2021 relative to other respiratory-virus envelope glycoproteins using RSV fusion protein sequences published in NCBI GenBank., Findings: We identified 5675 RSV A and RSV B fusion protein sequences (2875 RSV A and 2800 RSV B) from the three surveillance studies (2015-2021). Nearly all (25 [100%] of 25 positions of RSV A fusion proteins and 22 [88%] of 25 positions of RSV B fusion proteins) amino acids within the nirsevimab binding site remained highly conserved between 2015 and 2021. A highly prevalent (ie, >40·0% of all sequences) nirsevimab binding-site Ile206Met:Gln209Arg RSV B polymorphism arose between 2016 and 2021. Nirsevimab neutralised a diverse set of recombinant RSV viruses, including new variants containing binding-site substitutions. RSV B variants with reduced susceptibility to nirsevimab neutralisation were detected at low frequencies (ie, prevalence <1·0%) between 2015 and 2021. We used 3626 RSV fusion-protein sequences published in NCBI GenBank between 1956 and 2021 (2024 RSV and 1602 RSV B) to show that the RSV fusion protein had lower genetic diversity than influenza haemagglutinin and SARS-CoV-2 spike proteins., Interpretation: The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time., Funding: AstraZeneca and Sanofi., Competing Interests: Declaration of interests DW, CM, BA, AAA, TB, VG, EJK, KMT, and MTE are current employees of and hold stock or stock options in AstraZeneca. MEA and DET are former employees of and hold stock or stock options in AstraZeneca. EB has received honoraria from AstraZeneca and Sanofi for lectures, presentations, speaker bureaus, manuscript writing, or educational events. TH has participated in Data Safety Monitoring Boards and ad-hoc advisory boards for Sanofi, Data Safety Monitoring Boards for Enanta, and ad-hoc advisory boards for Janssen and has received honoraria from Janssen and Merck, Sharp & Dohme (MSD) for lectures at academic meetings. CK has received honoraria from F Hoffmann-La Roche for lectures. FM-T's research activities are supported by grants from Instituto de Salud Carlos III (grant numbers: PI16/01569, PI19/01090, PI22/00406, and CB21/06/00103), GEN-COVID (grant number: IN845D 2020/23), and Grupos de Referencia Competitiva (grant number: IIN607A2021/05), and he has received additional grants to his institution from AstraZeneca and Sanofi; he also received honoraria from GlaxoSmithKline, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as speaker in congresses outside the scope of the submitted work, in addition to travel support from GlaxoSmithKline, MSD, Pfizer, and Sanofi. FM-T has also participated in advisory boards for Pfizer, MSD, Sanofi, and GlaxoSmithKline, and in Data Safety Monitoring Boards for Biofabri; is a member of The European Technical Advisory Group of Experts—WHO Europe and the Spanish Paediatric Infectious Diseases Society; and has also acted as principal investigator in randomised controlled trials for AstraZeneca, Biofabri Seqirus, GlaxoSmithKline, Janssen, MSD, Novavax, Novartis, Pfizer, Roche, Regeneron, and Sanofi Pasteur with honoraria paid to his institution. MCN has received grants from the Bill & Melinda Gates Foundation, European and Developing Countries Clinical Trials, Pfizer, and Sanofi Pasteur; honoraria from Sanofi for lectures presentations, speakers' bureaus, manuscript writing or educational events; payment for expert testimony from Pfizer and Sanofi Pasteur; and is a board member for Gavi vaccine alliance. JMP has received payments to his institution from the Canadian Paediatric Review and Yearly RSV Coordinators Workshop and is an unpaid co-chair of the Ontario Immunization Advisory Committee. PR has received investigator-initiated research grants to his institution from MSD and has received institutional funding from GlaxoSmithKline for local and international lectures and from AstraZeneca, GlaxoSmithKline, MSD, Sanofi, and Pfizer for participation in advisory boards. RTS has received payment or honoraria for lectures for AstraZeneca, Pfizer, and Sanofi Pasteur. CV has received payment or honoraria for lectures from AstraZeneca. LJB has not received personal fees or other personal benefits from pharmaceutical companies. His institution, University Medical Center Utrecht (UMCU), has received major funding (>€100 000 per industrial partner) from AbbVie, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics for investigator-initiated studies. UMCU has received major funding for the RSV-GOLD study from the Bill & Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GlaxoSmithKline, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi Pasteur. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by AstraZeneca and Pfizer. UMCU has received minor funding (€1 000–25 000 per industrial partner) for consultation and invited lectures by AbbVie, AstraZeneca, Ablynx, Bavaria Nordic, MabXience, GlaxoSmithKline, Novavax, Pfizer, Moderna, AstraZeneca, MSD, Sanofi, Genzyme, and Janssen. LJB is the founding chairman of the ReSViNET Foundation. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Respiratory syncytial virus (RSV) causes a considerable disease burden in young children globally, but reliable estimates of RSV-related costs and health-related quality-of-life (HRQoL) are scarce. This study aimed to evaluate the RSV-associated costs and HRQoL effects in infants and their caregivers in four European countries., Methods: Healthy term-born infants were recruited at birth and actively followed up in four European countries. Symptomatic infants were systematically tested for RSV. Caregivers recorded the daily HRQoL of their child and themselves, measured by a modified EQ-5D with Visual Analogue Scale, for 14 consecutive days or until symptoms resolved. At the end of each RSV episode, caregivers reported healthcare resource use and work absenteeism. Direct medical costs per RSV episode were estimated from a healthcare payer's perspective and indirect costs were estimated from a societal perspective. Means and 95% confidence intervals (CI) of direct medical costs, total costs (direct costs + productivity loss) and quality-adjusted life-day (QALD) loss per RSV episode were estimated per RSV episode, as well as per subgroup (medical attendance, country)., Results: Our cohort of 1041 infants experienced 265 RSV episodes with a mean symptom duration of 12.5 days. The mean (95% CI) cost per RSV episode was €399.5 (242.3, 584.2) and €494.3 (317.7, 696.1) from the healthcare payer's and societal perspective, respectively. The mean QALD loss per RSV episode of 1.9 (1.7, 2.1) was independent of medical attendance (in contrast to costs, which also differed by country). Caregiver and infant HRQoL evolved similarly., Conclusion: This study fills essential gaps for future economic evaluations by prospectively estimating direct and indirect costs and HRQoL effects on healthy term infants and caregivers separately, for both medically attended (MA) and non-MA laboratory-confirmed RSV episodes. We generally observed greater HRQoL losses than in previous studies which used non-community and/or non-prospective designs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 'PB reported consulting fees from Pfizer, GSK on 2 occasions for discussions on economic evaluation, for a total of <€3000 combined, paid 100% directly to the University of Antwerp. NH reported grants from Janssen Vaccines & Prevention BV (R-11873) for collection of social contact data relevant for the spread of respiratory pathogens including SARS-CoV-2, RSV, influenza. NH reports consulting fees from Janssen Global Services for participation in advisory board related to RSV disease transmission modelling; payments made to Hasselt University. LB has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding (>€100,000 per industrial partner) for investigator initiated studies from AbbVie, MedImmune, Janssen, the Bill and Melinda Gates Foundation, Nutricia (Danone) and MeMed Diagnostics. UMCU has received major cash or in kind funding as part of the public private partnership IMI-funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer and Sanofi. UMCU has received major funding by Julius Clinical for participating in the INFORM study sponsored by MedImmune. UMCU has received minor funding for participation in trials by Regeneron and Janssen from 2015-2017 (total annual estimate less than €20,000). UMCU received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer, Janssen (total annual estimate less than €20,000). Dr. Bont is the founding chairman of the ReSViNET Foundation. SC reported IMI – RESCEU grant funding (as detailed in manuscript), with fees paid to the University of Edinburgh. FM-T has received honoraria from GSK group of companies, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, Biofabri and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. FM-T has also acted as principal investigator in randomized controlled trials of the above-mentioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. TH has received honoraria for lectures and/or participation in advisory boards or data monitoring committees from Janssen, Sanofi Pasteur, Enanta and MSD. MDS acted until September 2022 on behalf of the University of Oxford as an Investigator on research studies funded or supported by the vaccine manufacturers GlaxoSmithKline, Janssen, AstraZeneca, Novavax, MCM vaccines and Pfizer. He received no direct personal benefit for this work. From September 2022 he has been an employee at Moderna Biotech UK and holds stock options in this company. AJP is a member of AMS and Senior Investigator of NIHR. KK has received fees for interview for expert opinion considering the burden of RSV in older adults with IQVIA (part of Janssen) as well as interview for expert opinion considering the burden of RSV in older adults with Deallus. AD has participated as sub-investigator in clinical trials and observational studies for Novavax, MedImmune, Janssen GSK, Pfizer, Merk, Sharp Donme, ReViral, Enanta Pharmaceuticals. All payments were made to the institution and no direct payment was received. MJP is a member of JCVI and reports stock or stock options for HealthEcore (25% of shares) and PAG BV (100% of shares). All other authors report no potential conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Respiratory syncytial virus (RSV) is a major cause of hospitalisation in infants. The burden of RSV infection in healthy term infants has not yet been established. Accurate health-care burden data in healthy infants are necessary to determine RSV immunisation policy when RSV immunisation becomes available., Methods: We performed a multicentre, prospective, observational birth cohort study in healthy term-born infants (≥37 weeks of gestation) in five sites located in different European countries to determine the health-care burden of RSV. The incidence of RSV-associated hospitalisations in the first year of life was determined by parental questionnaires and hospital chart reviews. We performed active RSV surveillance in a nested cohort to determine the incidence of medically attended RSV infections. The study is registered with ClinicalTrials.gov, NCT03627572., Findings: In total, 9154 infants born between July 1, 2017, and April 1, 2020, were followed up during the first year of life and 993 participated in the nested active surveillance cohort. The incidence of RSV-associated hospitalisations in the total cohort was 1·8% (95% CI 1·6-2·1). There were eight paediatric intensive care unit admissions, corresponding to 5·5% of 145 RSV-associated hospitalisations and 0·09% of the total cohort. Incidence of RSV infection in the active surveillance cohort confirmed by any diagnostic assay was 26·2% (24·0-28·6) and that of medically attended RSV infection was 14·1% (12·3-16·0)., Interpretation: RSV-associated acute respiratory infection causes substantial morbidity, leading to the hospitalisation of one in every 56 healthy term-born infants in high-income settings. Immunisation of pregnant women or healthy term-born infants during their first winter season could have a major effect on the health-care burden caused by RSV infections., Funding: Innovative Medicines Initiative 2 Joint Undertaking, with support from the EU's Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations., Competing Interests: Declaration of interests LJB has regular interaction with pharmaceutical and other industrial partners. He has not received personal fees or other personal benefits. UMCU has received major funding (>€100 000 per industrial partner) for investigator initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD, and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill & Melinda Gates Foundation. UMCU has received major funding as part of the public private partnership IMI-funded RESCEU and PROMISE projects with partners GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer. UMCU received minor funding (€1000–25 000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna, Astrazeneca, MSD, Sanofi, Genzyme, and Janssen. LJB is the founding chairman of the ReSViNET Foundation. SC has provided consultancy or investigator roles in relation to product development for Ablynx, Janssen, MedImmune, AstraZeneca, Pfizer, GSK, Vertex, AbbVie, Valneva, Fibrogen, and Boehringer Ingelheim, with fees paid to the University of Edinburgh. FM-T reports honoraria from GSK group, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses, outside the submitted work; and principal investigator-role in randomised controlled trials for GSK, Pfizer, Sanofi Pasteur, MSD, Seqirus, Biofabri, Janssen, Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. MDS acts as an investigator on behalf of the University of Oxford on research studies funded by vaccine manufacturers including GSK, Janssen, MCM vaccines, Novavax, AtraZeneca, and Pfizer. MDS was an National Institute for Heath and Care Research (NIHR) Senior Investigator and received salary support from the NIHR Oxford Biomedical Research Centre during the course of this work. MDS is currently an employee of Moderna. SBD had received honoraria from MSD and Sanofi Pasteur for taking part in advisory boards and has provided consultancy or investigator roles in relation to product development for Janssen, AstraZeneca, Pfizer, Valneva, MSD, and Sanofi Pasteur with fees paid to St George's University of London. TH has received honoraria for lectures or participation in advisory boards or data monitoring committees from Janssen, Sanofi Pasteur, Enanta, and MSD. BR is a full-time employee of the GSK group and holds shares and restricted shares in the GSK group as part of their employee remuneration. AJP is currently Chair of the Department of Health Social Cares Joint Committee on Vaccination and Immunisation and was previously a member of WHO Scientific Advisory Group for Emergencies and chair of the European Medicine's Agency Scientific Advisory Group on Vaccines. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Respiratory syncytial virus (RSV) imposes a substantial burden on pediatric hospital capacity in Europe. Promising prophylactic interventions against RSV including monoclonal antibodies (mAb) and maternal immunizations (MI) are close to licensure. Therefore, we aimed to evaluate the cost-effectiveness of potential mAb and MI interventions against RSV in infants, for six European countries., Methods: We used a static cohort model to compare costs and health effects of four intervention programs to no program and to each other: year-round MI, year-round mAb, seasonal mAb (October to April), and seasonal mAb plus a catch-up program in October. Input parameters were obtained from national registries and literature. Influential input parameters were identified with the expected value of partial perfect information and extensive scenario analyses (including the impact of interventions on wheezing and asthma)., Results: From the health care payer perspective, and at a price of €50 per dose (mAb and MI), seasonal mAb plus catch-up was cost-saving in Scotland, and cost-effective for willingness-to-pay (WTP) values ≥€20,000 (England, Finland) or €30,000 (Denmark) per quality adjusted life-year (QALY) gained for all scenarios considered, except when using ICD-10 based hospitalization data. For the Netherlands, seasonal mAb was preferred (WTP value: €30,000-€90,000) for most scenarios. For Veneto region (Italy), either seasonal mAb with or without catch-up or MI was preferred, depending on the scenario and WTP value. From a full societal perspective (including leisure time lost), the seasonal mAb plus catch-up program was cost-saving for all countries except the Netherlands., Conclusion: The choice between a MI or mAb program depends on the level and duration of protection, price, availability, and feasibility of such programs, which should be based on the latest available evidence. Future research should focus on measuring accurately age-specific RSV-attributable hospitalizations in very young children., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘PB reports grants from Respiratory Syncytial Virus Consortium in Europe (RESCEU), Innovative Medicines Initiative 2 of the European Commission, Joint Undertaking under grant agreement No 116,019 during the conduct of the study; and grants from Pfizer, GSK, Merck and European Commission IMI project PROMISE, outside the submitted work, but he has not received any personal fees or other personal benefits. LB’s institution, UMCU has received major funding (>€100,000 per industrial partner) for investigator initiated studies from AbbVie, MedImmune, AstraZeneca, Sanofi, Janssen, Pfizer, MSD and MeMed Diagnostics. UMCU has received major funding for the RSV GOLD study from the Bill and Melinda Gates Foundation and major funding as part of the public private partnership IMI-funded projects (RESCEU and PROMISE). UMCU also has received major funding by Julius Clinical for participating in clinical studies sponsored by MedImmune and Pfizer and minor funding (€1,000–25,000 per industrial partner) for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, GSK, Novavax, Pfizer, Moderna. TH declared consultancy fees from Sanofi and Janssen for Ad hoc advisory board meeting and honoraria for Lecture on the burden of RSV in children from Jassen and MSD, outside the submitted work. JvS’s institution, Nivel has received unrestricted research grants from WHO, Sanofi and the Foundation for Influenza Epidemiology for work outside the submitted work. CR declared consultancy fees for Ad hoc advisory board meeting and honoraria for Lecture from Seqirus, MSD, Sanofi, outside of the submitted work. ST was an employee of IVIDATA during the conduct of the study, and her employer received consultancy fees from Sanofi. All other authors report no potential conflicts.’, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results., Competing Interests: Declaration of interests UMCU received minor funding from The Bill & Melinda Gates Medical Research Institute. DMW has received consulting fees from Pfizer, Merck, Affinivax, and Matrivax, unrelated to this manuscript; and is a principal investigator with grant support from Pfizer and Merck to Yale University, unrelated to this manuscript. NIM has regular interaction with pharameutical and other industrial partners: UMC Utrecht has received fees for invited lectures by Abbvie, Merck, and Sanofi. LB has regular interaction with pharmaceutical and other industrial partners. BSG is an inventor of patents for RSV vaccines using the stabilised prefusion F protein. AM has received research grants from National Institutes of Health, Janssen, and Merck institution; fees for participation in advisory boards from Janssen, Sanofi-Pasteur, and Merck; and fees for educational lectures from Sanofi-Pasteur and AstraZeneca. TJR was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. BSG was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UJB was financially supported by the Intramural Program of the National Institute of Allergy & Infectious Diseases, National Institute of Health. UMCU has received major funding (>€100 000 per industrial partner) for investigator-initiated studies from AbbVie, MedImmune, Janssen, Pfizer, the Bill & Melinda Gates Foundation, and MeMed Diagnostics. UMCU has received major cash or in-kind funding as part of the public private partnership IMI-funded RESCEU project from GSK, Novavax, Janssen, AstraZeneca, Pfizer, and Sanofi. UMCU has received major funding by Julius Clinical for participating in the INFORM study sponsored by MedImmune. UMCU has received minor funding for participation in trials by Regeneron and Janssen from 2015-17 (total annual estimate less than €20 000). UMCU received minor funding for consultation and invited lectures by AbbVie, MedImmune, Ablynx, Bavaria Nordic, MabXience, Novavax, Pfizer, and Janssen (total annual estimate less than €20 000). Dr. Bont is the founding chairman of the ReSViNET Foundation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Knowledge on age-specific hospitalizations associated with RSV infection is limited due to limited testing, especially in older children and adults in whom RSV infections are not expected to be severe. Burden estimates based on RSV coding of hospital admissions are known to underestimate the burden of RSV. We aimed to provide robust and reliable age-specific burden estimates of RSV-associated hospital admissions based on data on respiratory infections from national health registers and laboratory-confirmed cases of RSV., Methods: We conducted multiseason regression analysis of weekly hospitalizations with respiratory infection and weekly laboratory-confirmed cases of RSV and influenza as covariates, based on national health registers and laboratory databases across 6 European countries. The burden of RSV-associated hospitalizations was estimated by age group, clinical diagnosis, and presence of underlying medical conditions., Results: Across the 6 European countries, hospitalizations of children with respiratory infections were clearly associated with RSV, with associated proportions ranging from 28% to 60% in children younger than 3 months and we found substantial proportions of admissions to hospital with respiratory infections associated with RSV in children younger than 3 years. Associated proportions were highest among hospitalizations with ICD-10 codes of "bronchitis and bronchiolitis." In all 6 countries, annual incidence of RSV-associated hospitalizations was >40 per 1000 persons in the age group 0-2 months. In age group 1-2 years the incidence rate ranged from 1.3 to 10.5 hospitalizations per 1000. Adults older than 85 years had hospitalizations with respiratory infection associated to RSV in all 6 countries although incidence rates were low., Conclusions: Our findings highlight the substantial proportion of RSV infections among hospital admissions across different ages and may help public health professionals and policy makers when planning prevention and control strategies. In addition, our findings provide valuable insights for health care professionals attending to both children and adults presenting with symptoms of viral respiratory infections., Competing Interests: Potential conflicts of interest . H. C. reports funding for the submitted work also supported meetings and travel. J. P. reports payments to his institution from Sanofi, AstraZeneca, and Fondation de France for other RSV projects. S. T. and M. B. are employees of Sanofi. T. K. F. reports participating in research funded by Pfizer outside the submitted work. T. H. reports personal fees from Janssen outside the submitted work. Y. L. reports grants from World Health Organization and the Wellcome Trust, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infections (RTIs) in young children. High-quality country-specific estimates of bed days and length of stay (LOS) show the population burden of RSV-RTI on secondary care services and the burden among patients, and can be used to inform RSV immunization implementation decisions., Methods: We estimated the hospital burden of RSV-associated RTI (RSV-RTI) in children under 5 years in 7 European countries (Finland, Denmark, Norway, Scotland, England, the Netherlands, and Italy) using routinely collected hospital databases during 2001-2018. We described RSV-RTI admission rates during the first year of life by birth month and assessed their correlation with RSV seasonality in 5 of the countries (except for England and Italy). We estimated average annual numbers and rates of bed days for RSV-RTI and other-pathogen RTI, as well as the hospital LOS., Results: We found that infants born 2 months before the peak month of RSV epidemics more frequently had the highest RSV-RTI hospital admission rate. RSV-RTI hospital episodes accounted for 9.9-21.2 bed days per 1000 children aged <5 years annually, with the median (interquartile range) LOS ranging from 2 days (0.5-4 days) to 4 days (2-6 days) between countries. Between 70% and 89% of these bed days were in infants aged <1 year, representing 40.3 (95% confidence interval [CI], 40.1-40.4) to 91.2 (95% CI, 90.6-91.8) bed days per 1000 infants annually. The number of bed days for RSV-RTI was higher than that for RTIs associated with other pathogens in infants aged <1 year, especially in those <6 months., Conclusions: RSV disease prevention therapies (monoclonal antibodies and maternal vaccines) for infants could help prevent a substantial number of bed days due to RSV-RTI. "High-risk" birth months should be considered when developing RSV immunization schedules. Variation in LOS between countries might reflect differences in hospital care practices., Competing Interests: Potential conflicts of interest. Y. L. reports grants from the World Health Organization (WHO), grants from Wellcome Trust outside the submitted work. A. C. T. reports grants from the European Union (EU) Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 116019 for the RESCEU project during the conduct of the study. M. B. reports an employee of Sanofi Pasteur and may hold shares. T. H. reports grants from the EU Innovative Medicines Initiative 2 Joint Undertaking during the conduct of this study, and personal fees from Sanofi Pasteur and Janssen, outside the submitted work. S. T. reports work as an employee of Sanofi Pasteur. H. C. reports grants from the EU Innovative Medicines Initiative, grants and personal fees from the Bill & Melinda Gates Foundation, and grants and personal fees from WHO, during the conduct of the study. E. B. reports personal fees from AbbVie, Sanofi, and Chiesi, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development., Methods: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400)., Findings: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs)., Interpretation: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented., Funding: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU)., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Although many infants with respiratory syncytial virus (RSV) infection are hospitalized, most infants are treated as outpatients. Limited data are available on the burden of RSV in outpatient infants., Methods: In a prospective study, we enrolled 431 newborn infants and followed them up for a 10-month period (September-June). During each respiratory illness, we examined the infants and obtained nasopharyngeal specimens for the detection of RSV. The parents completed daily symptom diaries throughout the study., Results: Among 408 active participants, the seasonal incidence rate of RSV illness was 328.4 per 1000 (95% confidence interval [CI], 275.2-389.0). Infants with ≥1 sibling had a 1.9-fold higher incidence of RSV illness than those without siblings (95% CI, 1.3-2.8; P < .001). Acute otitis media developed in 103 (76.9%) of 134 infants with RSV infection, and 95 (70.9%) were treated with antibiotics. Nine infants with RSV (6.7%) were hospitalized, for a seasonal incidence rate of RSV hospitalization of 22.1 per 1000 (95% CI, 10.1-41.9)., Conclusions: The outpatient burden of RSV is heavy on infants during the first year of life. Acute otitis media is a frequent complication of RSV, and it should be included in cost-effectiveness analyses of prevention or treatment of RSV infections in infants., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) causes significant morbidity and mortality in infants worldwide. Although prematurity and cardiopulmonary disease are risk factors for severe disease, the majority of infants hospitalized with RSV are previously healthy. Various vaccines and therapeutics are under development and expected to be available in the near future. To inform the use of these new vaccines and therapeutics, it is necessary to determine the burden of RSV disease in Europe. We will prospectively follow-up a birth cohort to obtain incidence data on RSV acute respiratory tract infection (ARTI)., Methods: Multicenter prospective study of a birth cohort consisting of 10 000 healthy infants, recruited during 3 consecutive years. RSV associated hospitalization in the first year of life will be determined by questionnaires and hospital chart reviews. A nested cohort of 1000 infants will be actively followed. In case of ARTI, a respiratory sample will be collected for RSV molecular diagnosis., Results: The primary outcome is the incidence rate of RSV-associated hospitalization in the first year of life. In the active cohort the primary outcome is RSV associated ARTI and MA-ARTI., Conclusions: We will provide key information to fill the gaps in knowledge about the burden of RSV disease in healthy infants., Clinical Trials Registration: NCT03627572., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants. Early detection of RSV can optimize clinical management and minimize use of antibiotics. BinaxNOW RSV (BN) is a rapid antigen detection test that is widely used. We aimed to validate the sensitivity of BN in hospitalized and nonhospitalized infants against the gold standard of molecular diagnosis., Methods: We evaluated the performance of BN in infants with acute respiratory tract infections with different degrees of disease severity. Diagnostic accuracy of BN test results were compared with molecular diagnosis as reference standard., Results: One hundred sixty-two respiratory samples from 148 children from October 2017 to February 2019 were studied. Sixty-six (40.7%) samples tested positive for RSV (30 hospitalizations, 31 medically attended episodes not requiring hospitalization, and 5 nonmedically attended episodes). Five of these samples tested positive with BN, leading to an overall sensitivity of BN of 7.6% (95% confidence interval [CI], 3.3%-16.5%) and a specificity of 100% (95% CI, 96.2%-100%). Sensitivity was low in all subgroups., Conclusions: We found a low sensitivity of BN for point-of-care detection of RSV infection. BinaxNOW RSV should be used and interpreted with caution., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection (RTI) in young children. Registries provide opportunities to explore RSV epidemiology and burden., Methods: We explored routinely collected hospital data on RSV in children aged < 5 years in 7 European countries. We compare RSV-associated admission rates, age, seasonality, and time trends between countries., Results: We found similar age distributions of RSV-associated hospital admissions in each country, with the highest burden in children < 1 years old and peak at age 1 month. Average annual rates of RTI admission were 41.3-112.0 per 1000 children aged < 1 year and 8.6-22.3 per 1000 children aged < 1 year. In children aged < 5 years, 57%-72% of RTI admissions with specified causal pathogen were coded as RSV, with 62%-87% of pathogen-coded admissions in children < 1 year coded as RSV., Conclusions: Our results demonstrate the benefits and limitations of using linked routinely collected data to explore epidemiology and burden of RSV. Our future work will use these data to generate estimates of RSV burden using time-series modelling methodology, to inform policymaking and regulatory decisions regarding RSV immunization strategy and monitor the impact of future vaccines., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: There are scarce data on whether viral load affects the severity of respiratory syncytial virus (RSV) disease in outpatient children., Methods: We analyzed the association between viral load and disease severity among children who participated in a prospective cohort study of respiratory infections. The children were examined and nasal swabs for the detection of RSV were obtained during each respiratory illness. Quantification of RSV load was based on the cycle threshold (Ct) value. For the primary analysis, the children were divided into 2 groups: higher (Ct < 27) and lower viral load (Ct ≥ 27)., Results: Among 201 episodes of RSV infection, children with higher viral load had significantly longer median durations of rhinitis (8 vs 6 days; P = .0008), cough (8 vs 6 days; P = .034), fever (2 vs 1 days; P = .018), and any symptom (10 vs 8 days; P = .024) than those with lower viral load. There were statistically significant negative correlations between the Ct values and durations of all measured symptoms., Conclusions: Our findings support the concept that viral load drives the severity of RSV disease in children. Reducing the viral load by RSV antivirals might provide substantial benefits to outpatient children., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants. While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV. INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age., Methods: The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide. Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years. Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies., Discussion: The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions. Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created.