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Background: The mRNA-1345 vaccine demonstrated efficacy against respiratory syncytial virus (RSV) disease with acceptable safety in adults aged ≥60 years in the ConquerRSV trial. Here, humoral immunogenicity results from the trial are presented., Methods: This phase 2/3 trial randomly assigned adults (≥60 years) to mRNA-1345 50-µg encoding prefusion F (preF) glycoprotein (n = 17 793) vaccine or placebo (n = 17 748). RSV-A and RSV-B neutralizing antibody (nAb) and preF binding antibody (bAb) levels at baseline and day 29 postvaccination were assessed in a per-protocol immunogenicity subset (PPIS; mRNA-1345, n = 1515; placebo, n = 333)., Results: Day 29 nAb geometric mean titers (GMTs) increased 8.4-fold against RSV-A and 5.1-fold against RSV-B from baseline. Seroresponses (4-fold rise from baseline) in the mRNA-1345 groups were 74.2% and 56.5% for RSV-A and RSV-B, respectively. Baseline GMTs were lower among participants who met the seroresponse criteria than those who did not. mRNA-1345 induced preF bAbs at day 29, with a pattern similar to nAbs. Day 29 antibody responses across demographic and risk subgroups were generally consistent with the overall PPIS., Conclusions: mRNA-1345 enhanced RSV-A and RSV-B nAbs and preF bAbs in adults (≥60 years) across various subgroups, including those at risk for severe disease, consistent with its demonstrated efficacy in the prevention of RSV disease., Clinical Trials Registration: NCT05127434., Competing Interests: Potential conflicts of interest. G. P. M. reports funding from Moderna, Merck, Sanofi, Pfizer, Universidad Nacional de San Martín, Medicago, GSK, and Cassara. C. J. A. D. reports receiving grants from the Medical Research Council and Wellcome, a consultancy for Synarigen, and is a member of the data and safety monitoring board at Oxford University. J. G., L. L., J. D., A. K., S. M., W. H., H. Z., S. K. S., F. P., N. L., C. A. S., E. W., J. M. M., and R. D. are employees of Moderna, Inc., and may hold stock/stock options in the company. N. L. C., K. S., and J. E. T. are consultants for Moderna, Inc. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV) presents a global health concern. A lipid nanoparticle-encapsulated mRNA-based RSV vaccine (mRNA-1345) that encodes the membrane-anchored RSV prefusion-stabilized F glycoprotein is under clinical investigation., Methods: This phase 1 dose escalation study was based on a randomized, observer-blind, placebo-controlled design, and it assessed the safety and immunogenicity of mRNA-1345 in healthy adults aged 18 to 49 years. Participants were randomized to receive 1 dose of mRNA-1345 (50, 100, or 200 µg) or placebo or 3 doses of mRNA-1345 (100 µg) or placebo 56 days apart., Results: mRNA-1345 was well tolerated at all dose levels. The most common solicited adverse reactions were pain, headache, fatigue, myalgia, or chills, which were all generally mild to moderate. At 1 month postinjection, a single injection of mRNA-1345 boosted RSV neutralizing antibody titers (geometric mean fold rise: RSV-A, 20.0-23.5; RSV-B, 11.7-16.0) and RSV prefusion binding antibody concentrations (geometric mean fold rise, 16.1-21.8), with no apparent dose response. Antibody levels remained above baseline through 6 months. Sequential doses of 100 µg were well tolerated but did not further boost antibody levels., Conclusions: A single mRNA-1345 injection demonstrated an acceptable safety profile in younger adults and induced a durable neutralizing antibody response, supporting its continued development., Clinical Trials Registration: ClinicalTrials.gov NCT04528719., Competing Interests: Potential conflicts of interest. C. A. S., R. M., A. K., R. D., L. W., L. E. A., S. S.-G., K. S., and S. K. S. are employees of Moderna, Inc, and may hold stock/stock options in the company. A. A. and G. L. C. were Moderna, Inc, employees at the time of study conduct. 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: An mRNA-based respiratory syncytial virus (RSV) vaccine, mRNA-1345, is under clinical investigation to address RSV disease burden in older adults., Methods: Based on a randomized, observer-blind, placebo-controlled design, this phase 1 dose-ranging study evaluated the safety, reactogenicity, and immunogenicity of mRNA-1345 in adults aged 65 to 79 years. Participants were randomized to receive 1 dose of mRNA-1345 (12.5, 25, 50, 100, or 200 µg) or placebo and matched mRNA-1345 booster or placebo at 12 months., Results: Overall, 298 participants received the first injection and 247 received the 12-month booster injection. mRNA-1345 was generally well tolerated after both injections, with the most frequently reported solicited adverse reactions being injection site pain, fatigue, headache, arthralgia, and myalgia. Reactogenicity was higher after the booster injection but with severity, time to onset, and duration similar to the first injection. A single mRNA-1345 injection boosted RSV-A and RSV-B neutralizing antibody titers and prefusion F binding antibody (preF bAb) concentrations at 1 month (geometric mean fold rises: RSV-A, 10.2-16.5; RSV-B, 5.3-12.5; preF bAb, 7.2-12.1). RSV antibody levels remained above baseline through 12 months, indicating immune persistence. A 12-month booster injection also increased RSV-A and RSV-B neutralizing antibody titers and preF bAb concentrations; titers after booster injection were numerically lower than those after the first dose, with overlapping 95% CIs., Conclusions: mRNA-1345 was well tolerated and immunogenic following a single injection and a 12-month booster., Clinical Trials Registration: NCT04528719 (ClinicalTrials.gov)., Competing Interests: Potential conflicts of interest. C. A. S., R. M., A. K., R. D., L. W., C. A. P., J. G., E. W., R. G., A. K. S., C. R., S. K. S., and G. L. C. are employees of Moderna, Inc, and may hold stock/stock options 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) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV) represents a global health concern, including in older adults. This study assessed the safety and immunogenicity of mRNA-1345, an investigational mRNA RSV vaccine, in adults aged ≥60 years of Japanese descent., Methods: In this phase 1, randomized, observer-blind, placebo-controlled study, participants were randomized to receive one injection of mRNA-1345 100 μg or placebo. Solicited local and systemic adverse reactions (ARs) were collected within 7 days following injection. Unsolicited adverse events (AEs) were collected up to 28 days after injection; AEs of special interest, medically attended AEs, and serious AEs were collected through end of study. Immunogenicity was assessed at baseline and months 1, 2, 3, and 6 following injection., Results: Twenty-five adults of Japanese descent aged ≥60 years received one injection of mRNA-1345 100 μg (n = 21) or placebo (n = 4). mRNA-1345 was well-tolerated; the most common local and systemic solicited ARs were injection site pain, and fatigue and myalgia, respectively, which were generally mild to moderate and transient. No serious AEs were reported. Neutralizing (nAb) and binding (bAb) antibodies were detectable at baseline, consistent with prior RSV exposure. mRNA-1345 boosted RSV nAb titers and preF bAb concentrations 1 month post-injection (geometric mean fold rise: RSV-A nAb, 11.2; RSV-B nAb, 6.6; preF bAb, 9.1). Titers among mRNA-1345 recipients remained above baseline through 6 months., Conclusions: mRNA-1345 100 μg was well-tolerated among older adults of Japanese descent and induced nAbs and bAbs which were durable through 6 months, supporting its continued development., Trial Registration: ClinicalTrials.gov, NCT04528719., Competing Interests: Declaration of competing interest Archana Kapoor, Alana K. Simorellis, Caroline Reuter, Catherine A. Panozzo, Christine A. Shaw, Eleanor Wilson, Grace L. Chen, Hanako Mihara, Jaya Goswami, Lauren Wilson, Rakesh Dhar, Ruiting Guo, Runa Mithani, and Sonia K. Stoszek are employees of Moderna, Inc., and hold stock/stock options in the company. Anthony Mills received research funding from Janssen Pharmaceuticals. Sonia K. Stoszek received travel fees, gifts, and others from Moderna, Inc. David Fitz-Patrick received research funding from Pfizer., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: There is limited evidence regarding the proportion of wheeze in young children attributable to respiratory syncytial virus lower respiratory tract infections (RSV-LRTI) occurring early in life. This cohort study prospectively determined the population attributable risk (PAR) and risk percent (PAR%) of wheeze in 2-<6-year-old children previously surveilled in a primary study for RSV-LRTI from birth to their second birthday (RSV-LRTI<2Y)., Methods: From 2013 to 2021, 2-year-old children from 8 countries were enrolled in this extension study (NCT01995175) and were followed through quarterly surveillance contacts until their sixth birthday for the occurrence of parent-reported wheeze, medically-attended wheeze or recurrent wheeze episodes (≥4 episodes/year). PAR% was calculated as PAR divided by the cumulative incidence of wheeze in all participants., Results: Of 1395 children included in the analyses, 126 had documented RSV-LRTI<2Y. Cumulative incidences were higher for reported (38.1% vs. 13.6%), medically-attended (30.2% vs. 11.8%) and recurrent wheeze outcomes (4.0% vs. 0.6%) in participants with RSV-LRTI<2Y than those without RSV-LRTI<2Y. The PARs for all episodes of reported, medically-attended and recurrent wheeze were 22.2, 16.6 and 3.1 per 1000 children, corresponding to PAR% of 14.1%, 12.3% and 35.9%. In univariate analyses, all 3 wheeze outcomes were strongly associated with RSV-LRTI<2Y (all global P < 0.01). Multivariable modeling for medically-attended wheeze showed a strong association with RSV-LRTI after adjustment for covariates (global P < 0.0001)., Conclusions: A substantial amount of wheeze from the second to sixth birthday is potentially attributable to RSV-LRTI<2Y. Prevention of RSV-LRTI<2Y could potentially reduce wheezing episodes in 2-<6-year-old children., Competing Interests: E.L., A.T., B.A., E.C., J.A.C., I.D., S.G., J.H.K., R.M., M.O.O., S.K.S. and R.A.C. are/were employees of GSK. E.L., B.A., I.D., S.G., J.H.K., S.K.S. and R.A.C. hold/held GSK shares. S.A.M. declares receiving GSK funding to his institution for the conduct of the study, grants to his institution from Bill & Melinda Gates Foundation, GSK, Pfizer, and MinervaX, clinical trial funding to institution from Novavax, Merck, Providence Therapeutics, Gritstone bio, and ImmunityBio, and GSK payment honoraria for lectures. He was also Chair of Data Safety Monitoring Board for PATH (rotavirus vaccine) and CAPRISA (HIV monoclonal antibody). J.M.L. received GSK funding to Dalhousie University, received grants or contracts from GSK, Pfizer, Merck, and Moderna, and consulting fees from GSK. The author declares other financial or nonfinancial interests as expert panelist for the Canadian Agency for Drugs and Technologies in Health (CADTH) review of nirsevimab. T.P. received grants from GSK. M.R. is a national coordinator and/or principal investigator for several clinical trials sponsored by GSK and other vaccine manufacturers and received grants from GSK to his institution. J.A.E. received research support to her institution from AstraZeneca, GSK, Merck, and Pfizer, and is a consultant for AstraZeneca, AbbVie, Shanghai Ark Biopharmaceutical Co., GSK, Pfizer, Sanofi Pasteur, and Shionogi. N.P.K. received research support to her institution from GSK, and grants/contracts to her institution from Pfizer, Sanofi Pasteur, Merck, and CSL Seqirus. M.P.R. received support from Demedica. SKS received funding from GSK for attending conferences. Other authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We conducted a global comprehensive literature review of observational studies reporting RSV incidence in adults and determined current evidence gaps., Methods: PubMed and Embase were searched for English-language publications (2000-2022) and congress abstracts (2019-2021) reporting RSV incidence rates/cumulative incidence. Cross-sectional studies, case series, and other designs estimating only RSV frequency were excluded. The search included all geographic areas; data were extracted by age group and underlying condition where available., Results: 528 potentially relevant records were identified, of which 37 primary studies were relevant to this review. Most evidence was from high-income regions. Approximately two-thirds of the studies reported RSV incidence in the hospital setting. Fifteen studies included or focused exclusively on RSV incidence in adult populations with underlying conditions. Studies varied in their measurement and presentation of incidence. RSV incidence estimates were highly variable within and between geographic regions. Overall, RSV incidence tended to increase with age and was highest in adults with underlying conditions., Conclusion: Estimates of RSV incidence are highly variable across populations and geographies. Further population-based studies with well-defined consistent case definitions and surveillance strategies are needed for accurate and comparable estimates of RSV incidence, particularly in the geographic regions identified by the gap analysis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in infants. This phase 1/2, observer-blind, randomized, controlled study assessed the safety and immunogenicity of an investigational chimpanzee-derived adenoviral vector RSV vaccine (ChAd155-RSV, expressing RSV F, N, and M2-1) in infants., Methods: Healthy 6- to 7-month-olds were 1:1:1-randomized to receive 1 low ChAd155-RSV dose (1.5 × 1010 viral particles) followed by placebo (RSV&#95;1D); 2 high ChAd155-RSV doses (5 × 1010 viral particles) (RSV&#95;2D); or active comparator vaccines/placebo (comparator) on days 1 and 31. Follow-up lasted approximately 2 years., Results: Two hundred one infants were vaccinated (RSV&#95;1D: 65; RSV&#95;2D: 71; comparator: 65); 159 were RSV-seronaive at baseline. Most solicited and unsolicited adverse events after ChAd155-RSV occurred at similar or lower rates than after active comparators. In infants who developed RSV infection, there was no evidence of vaccine-associated enhanced respiratory disease (VAERD). RSV-A neutralizing titers and RSV F-binding antibody concentrations were higher post-ChAd155-RSV than postcomparator at days 31, 61, and end of RSV season 1 (mean follow-up, 7 months). High-dose ChAd155-RSV induced stronger responses than low-dose, with further increases post-dose 2., Conclusions: ChAd155-RSV administered to 6- to 7-month-olds had a reactogenicity/safety profile like other childhood vaccines, showed no evidence of VAERD, and induced a humoral immune response. Clinical Trials Registration. NCT03636906., Competing Interests: Potential conflicts of interest. V. N., Y. Z., W. P., D. F., I. D., A. G. L., R. M., S. K. S., and N. V. are or were employees of GSK during the conduct of the study. I. D., W. P., and S. K. S. hold GSK shares/stocks. R. M. and S. K. S. hold stock/stock options in Moderna. B. T., E. J. A., B. S. C., E. C. D., H. S., J. D. C., J. M. M. A., K. L., M. M. M.-P., M. R., S. N. F., F. B.-A., and T. P. report grants and/or other support from GSK for the conduct of the study. J. M. L. reports grants from GSK paid to her institution for the conduct of the study and holds the CIHR-GSK Chair in Pediatric Vaccinology at Dalhousie University. B. T. reports grants from GSK, Merck, and Pfizer for other trials. C. e. reports support for scientific meetings from GSK and ViiV and advisory consultancy fees from GSK. E. J. A. has consulted for Pfizer, Sanofi Pasteur, GSK, Janssen, Moderna, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Novavax, Sanofi Pasteur, Janssen, and Micron; he serves on a safety monitoring board for Kentucky BioProcessing and Sanofi Pasteur; serves on a data adjudication board for WCG and ACI Clinical; and his institution has also received funding from the National Institutes of Health to conduct clinical trials of COVID-19 vaccines. B. S. C. reports grants for other vaccine trials from GSK and MSD paid to his institution. E. C. D. performs contract work for the Eskisehir Osmangazi University funded by GSK, Sanofi Pasteur, and Pfizer. E. K. reports honoraria for lectures from GSK, MSD, AstraZeneca, Sanofi, and Pfizer. E. L.-M. reports grants from Centro de Estudios en Infectología Pediátrica. F. M.-T. reports grants from Janssen, MSD, and AstraZeneca; personal fees from Ablynx, GSK, Pfizer, MSD, Sanofi Pasteur, Novavax, Seqirus, and Biofabri; nonfinancial support from GSK, Pfizer, MSD, and Seqirus; and trial fees paid to his institution from these different companies (except Biofabri). H. S. reports personal fees and trial fees paid to his institution from MSD, Seqirus, Pfizer, Janssen, and Sanofi Pasteur. I. S. C. has received payment to his institution from GSK for the conduct of the study, by contract approved by the corresponding ethical committees and health authorities, and for trials of other vaccine manufacturers, and has received grants and/or honoraria as a consultant/advisor/speaker or for attending conferences and practical courses from GSK and other vaccine manufacturers. J. D. C. is a member of the Committee on Infectious Diseases of the American Academy of Pediatrics and reports funds paid to his university to study RSV vaccines. J. D.-D. reports grants from GSK, MSD, and Sanofi Pasteur paid to his institution. J. M. M. A. reports fees for medical meetings from GSK and Pfizer. K. L. reports grants from ReViral and Shionogi. M. M.-P. reports grants from MSD, Roche, GSK, Janssen, Takeda, and Syneos. M. R. reports grants for other vaccine trials from GSK and other vaccine manufacturers paid to his institution. S. N. F. reports fees paid to his institution for attending meetings, advisory boards, and/or grants for clinical trials from AstraZeneca/Medimmune, GSK, J&J, Pfizer, Sanofi, Seqirus, Sandoz, Valneva, Novavax, and Merck. X. S.-L. reports grants from Cevaxin Vaccine Research Center. F. B.-A. reports consultancy fees from GSK, Pfizer, and MSD and grants from MSD. 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: Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality among older adults. An mRNA-based RSV vaccine, mRNA-1345, encoding the stabilized RSV prefusion F glycoprotein, is under clinical investigation., Methods: In this ongoing, randomized, double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive one dose of mRNA-1345 (50 μg) or placebo. The two primary efficacy end points were the prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms and with at least three signs or symptoms. A key secondary efficacy end point was the prevention of RSV-associated acute respiratory disease. Safety was also assessed., Results: Overall, 35,541 participants were assigned to receive the mRNA-1345 vaccine (17,793 participants) or placebo (17,748). The median follow-up was 112 days (range, 1 to 379). The primary analyses were conducted when at least 50% of the anticipated cases of RSV-associated lower respiratory tract disease had occurred. Vaccine efficacy was 83.7% (95.88% confidence interval [CI], 66.0 to 92.2) against RSV-associated lower respiratory tract disease with at least two signs or symptoms and 82.4% (96.36% CI, 34.8 to 95.3) against the disease with at least three signs or symptoms. Vaccine efficacy was 68.4% (95% CI, 50.9 to 79.7) against RSV-associated acute respiratory disease. Protection was observed against both RSV subtypes (A and B) and was generally consistent across subgroups defined according to age and coexisting conditions. Participants in the mRNA-1345 group had a higher incidence than those in the placebo group of solicited local adverse reactions (58.7% vs. 16.2%) and of systemic adverse reactions (47.7% vs. 32.9%); most reactions were mild to moderate in severity and were transient. Serious adverse events occurred in 2.8% of the participants in each trial group., Conclusions: A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older. (Funded by Moderna; ConquerRSV ClinicalTrials.gov number, NCT05127434.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Various case definitions of respiratory syncytial virus lower respiratory tract infection (RSV-LRTI) are currently proposed. We assessed the performance of 3 clinical case definitions against the World Health Organization definition recommended in 2015 (WHO 2015)., Methods: In this prospective cohort study conducted in 8 countries, 2401 children were followed up for 2 years from birth. Suspected LRTIs were detected via active and passive surveillance, followed by in-person clinical evaluation including single timepoint respiratory rate and oxygen saturation (by pulse oximetry) assessment, and nasopharyngeal sampling for RSV testing by polymerase chain reaction. Agreement between case definitions was evaluated using Cohen's κ statistics., Results: Of 1652 suspected LRTIs, 227 met the WHO 2015 criteria for RSV-LRTI; 73 were classified as severe. All alternative definitions were highly concordant with the WHO 2015 definition for RSV-LRTI (κ: 0.95-1.00), but less concordant for severe RSV-LRTI (κ: 0.47-0.82). Tachypnea was present for 196/226 (86.7%) WHO 2015 RSV-LRTIs and 168/243 (69.1%) LRTI/bronchiolitis/pneumonia cases, clinically diagnosed by nonstudy physicians. Low oxygen saturation levels were observed in only 55/226 (24.3%) WHO 2015 RSV-LRTIs., Conclusions: Three case definitions for RSV-LRTI showed high concordance with the WHO 2015 definition, while agreement was lower for severe RSV-LRTI. In contrast to increased respiratory rate, low oxygen saturation was not a consistent finding in RSV-LRTIs and severe RSV-LRTIs. This study demonstrates that current definitions are highly concordant for RSV-LRTIs, but a standard definition is still needed for severe RSV-LRTI., Clinical Trial Registration: NCT01995175., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Background: There are limited data describing adverse infant outcomes in infants born to women with a low risk of complications during pregnancy, such as those who may be enrolled in maternal immunization trials. This retrospective study estimated incidence proportions of infant outcomes in different cohorts of liveborn infants in England between 2005 and 2017., Methods: The incidence proportions of 10 infant outcomes were calculated for liveborn infants from pregnancies represented in the Clinical Practice Research Datalink (CPRD) Mother-Baby Link (MBL) and linkage to Hospital Episode Statistics (HES). Three infant cohorts were designed: (1) the all pregnancies infants cohort (N = 185,119), (2) the all pregnancies with a gestational age (GA) ≥ 24 weeks infants cohort (N = 183,869), and (3) the low-risk pregnancies infants cohort (LR infants cohort, N = 121,871), which included pregnancies with a GA ≥ 24 weeks and no diagnosis of predefined high-risk medical conditions until 24 weeks GA., Results: The most common adverse infant outcome in the three infant cohorts was macrosomia (e.g., 1,085.9/10,000 live births in the LR infants cohort), followed by minor congenital anomalies (e.g., 800.6/10,000 in the LR infants cohort), very low/low birth weight (e.g., 400.6/10,000 in the LR infants cohort), and major congenital anomalies (e.g., 270.4/10,000 in the LR infants cohort). The incidence proportions for early-onset sepsis, very low/low birth weight, and minor and major congenital anomalies were lower in the LR infants than in the other cohorts (non-overlapping confidence intervals [CIs]). The incidence proportions of neonatal death, infant death, late-onset sepsis, macrosomia, small for GA, and large for GA were similar between cohorts (overlapping CIs)., Conclusions: This study generated background rates of adverse infant outcomes from liveborn infants of all and low-risk pregnancies represented in the CPRD Pregnancy Register MBL and linkage to HES. The results indicate lower incidence proportions of several adverse infant outcomes in infants from low-risk pregnancies compared to all pregnancies, illustrating the importance of considering maternal risk factors. These background rates may facilitate the interpretation of safety data from maternal immunization trials and of pharmacovigilance data from maternal vaccines. They may also be of interest for other interventions studied in pregnant women., (© 2023. The Author(s).)

Background: The true burden of lower respiratory tract infections (LRTIs) due to respiratory syncytial virus (RSV) remains unclear. This study aimed to provide more robust, multinational data on RSV-LRTI incidence and burden in the first 2 years of life., Methods: This prospective, observational cohort study was conducted in Argentina, Bangladesh, Canada, Finland, Honduras, South Africa, Thailand, and United States. Children were followed for 24 months from birth. Suspected LRTIs were detected via active (through regular contacts) and passive surveillance. RSV and other viruses were detected from nasopharyngeal swabs using PCR-based methods., Results: Of 2401 children, 206 (8.6%) had 227 episodes of RSV-LRTI. Incidence rates (IRs) of first episode of RSV-LRTI were 7.35 (95% confidence interval [CI], 5.88-9.08), 5.50 (95% CI, 4.21-7.07), and 2.87 (95% CI, 2.18-3.70) cases/100 person-years in children aged 0-5, 6-11, and 12-23 months. IRs for RSV-LRTI, severe RSV-LRTI, and RSV hospitalization tended to be higher among 0-5 month olds and in lower-income settings. RSV was detected for 40% of LRTIs in 0-2 month olds and for approximately 20% of LRTIs in older children. Other viruses were codetected in 29.2% of RSV-positive nasopharyngeal swabs., Conclusions: A substantial burden of RSV-LRTI was observed across diverse settings, impacting the youngest infants the most. Clinical Trials Registration. NCT01995175., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Maternal characteristics like medical history and health-related risk factors can influence the incidence of pregnancy outcomes and pregnancy-related events of interest (EIs). Data on the incidence of these endpoints in low-risk pregnant women are needed for appropriate external safety comparisons in maternal immunization trials. To address this need, this study estimated the incidence proportions of pregnancy outcomes and pregnancy-related EIs in different pregnancy cohorts (including low-risk pregnancies) in England, contained in the Clinical Practice Research Datalink (CPRD) Pregnancy Register linked to Hospital Episode Statistics (HES) between 2005 and 2017., Methods: The incidence proportions of 7 pregnancy outcomes and 15 EIs were calculated for: (1) all pregnancies (AP) represented in the CPRD Pregnancy Register linked to HES (AP cohort; N = 298 155), (2) all pregnancies with a gestational age (GA) ≥ 24 weeks (AP24+ cohort; N = 208 328), and (3) low-risk pregnancies (LR cohort; N = 137 932) with a GA ≥ 24 weeks and no diagnosis of predefined high-risk medical conditions until 24 weeks GA., Results: Miscarriage was the most common adverse pregnancy outcome in the AP cohort (1 379.5 per 10 000 pregnancies) but could not be assessed in the other cohorts because these only included pregnancies with a GA ≥ 24 weeks, and miscarriages with GA ≥ 24 weeks were reclassified as stillbirths. Preterm delivery (< 37 weeks GA) was the most common adverse pregnancy outcome in the AP24+ and LR cohorts (742.9 and 680.0 per 10 000 pregnancies, respectively). Focusing on the cohorts with a GA ≥ 24 weeks, the most common pregnancy-related EIs in the AP24+ and LR cohorts were fetal/perinatal distress or asphyxia (1 824.3 and 1 833.0 per 10 000 pregnancies), vaginal/intrauterine hemorrhage (799.2 and 729.0 per 10 000 pregnancies), and labor protraction/arrest disorders (752.4 and 774.5 per 10 000 pregnancies)., Conclusions: This study generated incidence proportions of pregnancy outcomes and pregnancy-related EIs from the CPRD for different pregnancy cohorts, including low-risk pregnancies. The reported incidence proportions of pregnancy outcomes and pregnancy-related EIs are largely consistent with external estimates. These results may facilitate the interpretation of safety data from maternal immunization trials and the safety monitoring of maternal vaccines. They may also be of interest for any intervention studied in populations of pregnant women., (© 2022. The Author(s).)

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.)