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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.)

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8-8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9-1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Respiratory syncytial virus-associated acute respiratory infection (RSV-ARI) constitutes a substantial disease burden in older adults aged ≥65 years. We aimed to identify all studies worldwide investigating the disease burden of RSV-ARI in this population. We estimated the community incidence, hospitalization rate, and in-hospital case-fatality ratio (hCFR) of RSV-ARI in older adults, stratified by industrialized and developing regions, using data from a systematic review of studies published between January 1996 and April 2018 and 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burdens in older adults with RSV-ARI in the community and in hospitals for that year. We estimated the number of in-hospital deaths due to RSV-ARI by combining hCFR data with hospital admission estimates from hospital-based studies. In 2015, there were about 1.5 million episodes (95% confidence interval [CI], .3 million-6.9 million) of RSV-ARI in older adults in industrialized countries (data for developing countries were missing), and of these, approximately 14.5% (214 000 episodes; 95% CI, 100 000-459 000) were admitted to hospitals. The global number of hospital admissions for RSV-ARI in older adults was estimated at 336 000 hospitalizations (uncertainty range [UR], 186 000-614 000). We further estimated about 14 000 in-hospital deaths (UR, 5000-50 000) related to RSV-ARI globally. The hospital admission rate and hCFR were higher for those aged ≥65 years than for those aged 50-64 years. The disease burden of RSV-ARI among older adults is substantial, with limited data from developing countries. Appropriate prevention and management strategies are needed to reduce this burden., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We estimated the prevalence of human immunodeficiency virus (HIV) disclosure in children from a prospective observational cohort study conducted at clinical sites in Brazil, Mexico, and Peru. Fewer than half of the children in this study knew their HIV status, which highlights the need for better strategies for disclosure that are age and culturally appropriate.

Progress in tuberculosis clinical research is hampered by a lack of reliable biomarkers that predict progression from latent to active tuberculosis, and subsequent cure, relapse, or failure. Regional Prospective Observational Research in Tuberculosis (RePORT) International represents a consortium of regional cohorts (RePORT India, RePORT Brazil, and RePORT Indonesia) that are linked through the implementation of a Common Protocol for data and specimen collection, and are poised to address this critical research need. Each RePORT network is designed to support local, in-country tuberculosis-specific data and specimen biorepositories, and associated research. Taken together, the expected results include greater global clinical research capacity in high-burden settings, and increased local access to quality data and specimens for members of each network and their domestic and international collaborators. Additional networks are expected to be added, helping to spur tuberculosis treatment and prevention research around the world., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Unlabelled: Introduction: We hypothesized that nutritional deficiency would be common in a cohort of postpartum, human immunodeficiency virus (HIV)-infected women and their infants., Methods: Weight and height, as well as blood concentrations of retinol, α-tocopherol, ferritin, hemoglobin, and zinc, were measured in mothers after delivery and in their infants at birth and at 6-12 weeks and six months of age. Retinol and α-tocopherol levels were quantified by high performance liquid chromatography, and zinc levels were measured by atomic absorption spectrophotometry. The maternal body mass index during pregnancy was adjusted for gestational age (adjBMI)., Results: Among the 97 women 19.6% were underweight. Laboratory abnormalities were most frequently observed for the hemoglobin (46.4%), zinc (41.1%), retinol (12.5%) and ferritin (6.5%) levels. Five percent of the women had mean corpuscular hemoglobin concentrations < 31g/dL. The most common deficiency in the infants was α-tocopherol (81%) at birth; however, only 18.5% of infants had deficient levels at six months of age. Large percentages of infants had zinc (36.8%) and retinol (29.5%) deficiencies at birth; however, these percentages decreased to 17.5% and 18.5%, respectively, by six months of age. No associations between infant micronutrient deficiencies and either the maternal adjBMI category or maternal micronutrient deficiencies were found., Conclusions: Micronutrient deficiencies were common in HIV-infected women and their infants. Micronutrient deficiencies were less prevalent in the infants at six months of age. Neither underweight women nor their infants at birth were at increased risk for micronutrient deficiencies.

Objective: To describe temporal management and outcome trends among HIV-1-infected pregnant women and their infants enrolled in the NISDI Perinatal and LILAC cohorts., Methods: A prospective cohort of 1548 HIV-1-infected pregnant women and their 1481 singleton live-born infants was analyzed. Participants were enrolled at 24 Latin American and Caribbean sites and followed-up for at least 6 months postpartum. Variables were compared by 2-year enrollment periods from September 27, 2002, to June 30, 2009, using logistic and linear regression modeling., Results: Antiretroviral (ARV) use during pregnancy remained high (99.0%). ARVs became increasingly used for treatment (P<0.001). Regimens containing 2 nucleoside reverse transcriptase inhibitors plus a protease inhibitor became more common in later years (P<0.001). The proportion of women with viral loads below 1000 copies/mL at hospital discharge after delivery (HD) increased over time (P=0.0031). Median CD4 lymphocyte counts also rose at HD, from 441 cell/mm(3) to 515 cells/mm(3) (P<0.05). Elective cesarean deliveries increased from 30.5% to 42.0% (P=0.018). Most infants received ARV prophylaxis (99.7%). Few infants were breastfed (0.5%) or became infected with HIV-1 (1.2%)., Conclusion: The results indicate that national HIV-1 treatment and transmission prevention policies are effective among patients with healthcare access in the region., (Copyright © 2013. Published by Elsevier Ireland Ltd.)

Background: Maternal human immunodeficiency virus (HIV) coinfection has been associated with increased hepatitis C virus (HCV) mother-to-child transmission (MTCT). We hypothesized that HCV/HIV-coinfected women with well-controlled HIV disease would not have increased HCV MTCT., Methods: The NISDI Perinatal and LILAC cohorts enrolled HIV-infected pregnant women and their infants in Latin America and the Caribbean. This substudy evaluated the HCV infection status of mothers at participating sites and their live born, singleton infants who had a 6-month postnatal visit by December 31, 2008. Mothers who were anti-HCV-positive, or who had CD4 counts (cells/mm(3)) <200 with detectable HCV RNA, were considered HCV-infected. All HCV-infected women were tested for HCV RNA. Infants with HCV RNA were considered HCV-infected., Results: Of 1042 enrolled women, 739 (71%) mother-infant pairs met the inclusion criteria. Of the 739 women, 67 (9%) were anti-HCV-positive and 672 anti-HCV-negative [68 (10%) with CD4 counts <200; of these, 3 (4.4%) were HCV RNA-positive]. Therefore, our study population comprised 70 HCV-infected (47 with HCV RNA) and 669 HCV-uninfected women (and their infants). Factors associated with maternal HCV infection included unemployment (odds ratio [OR] = 2.58); tobacco (OR = 1.73) or marijuana (OR = 3.88) use during pregnancy; enrollment HIV viral load ([VL] copies/mL) ≥10 000 (OR = 2.27); HIV clinical disease stage C (OR = 2.12); and abnormal alanine aminotransferase (OR = 4.24) or aspartate aminotransferase (OR = 11.98). Four of 47 infants (8.5%) born to HCV-viremic women were HCV-infected, and all 4 mothers had HIV VL <1000 at hospital discharge after delivery., Conclusions: HCV MTCT among HIV/HCV-coinfected women with well-controlled HIV disease may be lower than reported in other coinfected populations. Studies with longer infant follow-up are needed.

Objective: To evaluate respiratory morbidity (RM) in HIV-exposed newborns according to mode of delivery., Methods: The NISDI Perinatal/LILAC prospective cohort studies enrolled HIV-infected pregnant women and their newborns in Latin America and the Caribbean. Associations between RM and delivery mode or other characteristics were evaluated., Results: Between September 2002 and December 2009, 1630 women were enrolled, and 1443 mother-infant pairs met the inclusion criteria. There were 561 vaginal (VD), 269 cesarean before labor and membrane rupture (SCS) for preventing mother-to-child transmission (SCS-PMTCT), 248 other SCS, and 365 cesarean after labor and/or ruptured membranes (NSCS) deliveries. In total, 108 (7.5%) newborns had RM: 49 had respiratory distress syndrome (RDS), 39 had transient tachypnea (TTN), and 28 had other events (7 newborns had >1 RM event). Delivery mode was associated with RDS (P<0.005) and TTN (P<0.001). The proportion with RDS and TTN was lowest for VD (1.6% and 0.5%, respectively), highest for NSCS (4.9% and 4.7%), and intermediate for SCS-PMTCT (3.0% and 2.6%). Newborns with RDS or TTN were hospitalized longer (median +1day) than those without. A minority required ventilatory support (RDS, 24.5%-28.6%; TTN, 2.6%-15.4%)., Conclusions: SCS-PMTCT is relatively safe for newborns of HIV-infected women., (Copyright © 2011 International Federation of Gynecology and Obstetrics. All rights reserved.)

Objectives: To describe laboratory abnormalities among HIV-infected women and their infants with standard and increased lopinavir/ritonavir (LPV/r) dosing during the third trimester of pregnancy., Methods: We evaluated data on pregnant women from NISDI cohorts (2002-2009) enrolled in Brazil, who received at least 28 days of LPV/r during the third pregnancy trimester and gave birth to singleton infants., Results: 164 women received LPV/r standard dosing [(798/198 or 800/200 mg/day) (Group 1)] and 70 increased dosing [(> 800/200 mg/day) (Group 2)]. Group 1 was more likely to have advanced clinical disease and to use ARVs for treatment, and less likely to have CD4 counts > 500 cells/mm³. Mean plasma viral load was higher in Group 2. There were statistically significant, but not clinically meaningful, differences between groups in mean AST, ALT, cholesterol, and triglycerides. The proportion of women with Grade 3 or 4 adverse events was very low, with no statistically significant differences between groups in severe adverse events related to ALT, AST, total bilirubin, cholesterol, or triglycerides. There were statistically significant, but not clinically meaningful, differences between infant groups in ALT and creatinine. The proportion of infants with Grade 3 or 4 adverse events was very low, and there were no statistically significant differences in severe adverse events related to ALT, AST, BUN, or creatinine., Conclusion: The proportions of women and infants with severe laboratory adverse events were very low. Increased LPV/r dosing during the third trimester of pregnancy appears to be safe for HIV-infected women and their infants.

Background: Approximately 800,000 children die each year due to pneumococcal disease and >90% of these deaths occur in developing countries where few children have access to life-saving serotype-based vaccines. Understanding the serotype epidemiology of invasive pneumococcal disease (IPD) among children is necessary for vaccine development and introduction policies. The aim of this study was to systematically estimate the global and regional distributions of serotypes causing IPD in children <5 years of age., Methods and Findings: We systematically reviewed studies with IPD serotype data among children <5 years of age from the published literature and unpublished data provided by researchers. Studies conducted prior to pneumococcal conjugate vaccine (PCV) introduction, from 1980 to 2007, with ≥12 months of surveillance, and reporting ≥20 serotyped isolates were included. Serotype-specific proportions were pooled in a random effects meta-analysis and combined with PD incidence and mortality estimates to infer global and regional serotype-specific PD burden. Of 1,292, studies reviewed, 169 were included comprising 60,090 isolates from 70 countries. Globally and regionally, six to 11 serotypes accounted for ≥70% of IPD. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) were the most common globally; and based on year 2000 incidence and mortality estimates these seven serotypes accounted for >300,000 deaths in Africa and 200,000 deaths in Asia. Serotypes included in both the 10- and 13-valent PCVs accounted for 10 million cases and 600,000 deaths worldwide., Conclusions: A limited number of serotypes cause most IPD worldwide. The serotypes included in existing PCV formulations account for 49%-88% of deaths in Africa and Asia where PD morbidity and mortality are the highest, but few children have access to these life-saving vaccines. Please see later in the article for the Editors' Summary.

A prospective study in three Egyptian villages (A, B and C) having a high prevalence of hepatitis C virus (HCV) infection examined incidence of community-acquired HCV infection in children; 2852 uninfected infants were prospectively followed from birth for up to 5.5 years. Fifteen seroconverted for either HCV antibodies and/or HCV-RNA (incidence of 0.53%). Ten had both anti-HCV and HCV-RNA; four had only anti-HCV; and one had HCV-RNA in the absence of antibody. The incidence rate at all ages was 2.7/1000 person-years (PY). It was 3.8/1000 PY during infancy and 2.0/1000 PY for the 1-5-years age group. Hospitalization and low birth weight increased the risk of infection; while living in village B, the family having a higher socioeconomic status, and advanced maternal education were protective. Six of eight HCV-infected infants reported iatrogenic exposures (e.g. hospitalization, therapeutic injections, ear piercing) prior to infection whereas only 2/7 children older than 1 year reported these exposures. Having an HCV-positive mother was the only other reported risk in two of these older children. The virus cleared in six (40%) children by the end of follow-up. Health education targeting iatrogenic exposures and focusing on risk factors could reduce HCV infection in children in high-risk populations., (Copyright 2010 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.)

Background: We assessed the infant feeding choices of HIV-1-infected women in rural Tamil Nadu, India, and risk factors for mother-to-child transmission of HIV-1., Methods: The study population comprised live born infants of HIV-1-infected women from the antenatal clinics of 2 public hospitals in rural Tamil Nadu, India who were enrolled in a prospective cohort study. All women enrolled in the cohort were offered antiretroviral prophylaxis and infant feeding counseling based on WHO/UNAIDS/UNICEF training materials. Infant study visits were scheduled at birth (within the first 24 hours of life), at 1 week, 1 month, and 2 months after birth, and then every 2 months between 4 and 12 months of age., Results: One-third of women did not breast-feed their infants. Of those who initiated breast-feeding, the median duration of breast-feeding was approximately 3 months. Among those infants who initiated breast-feeding, the proportion exclusively breast-feeding declined from approximately 70% during the first week of life to 0% by the 8 month visit. The observed rate of mother-to-child transmission of HIV-1 in the entire cohort was 6.5% (95% CI: 1.4%-17.9%). The observed HIV-1 incidence among breast-fed infants was 0% (95% CI: 0%-8.9%)., Conclusion: The overall transmission rate was relatively low, suggesting effectiveness of antiretroviral transmission prophylaxis. The infant feeding choices made may reflect knowledge gained through the educational program and infant feeding counseling provided. Ensuring HIV-1-infected women receive appropriate HIV-1 treatment (for those who meet criteria for treatment) and access to known efficacious interventions to prevent mother-to-child transmission of HIV-1, are essential.

A prospective cohort study of the incidence and risk factors for hepatitis C virus (HCV) infection was performed in 2171 pregnant women in three rural Egyptian villages who were HCV antibody (anti-HCV) and RNA (HCV-RNA) negative at baseline. During an average of 2.2 years follow up, 25 incident cases were observed, giving an estimated HCV incidence of 5.2/1000 person-years (PY). The infection rate correlated with community anti-HCV prevalence in pregnant women, while the perinatal incidence rate of 11.2/1000 PY was almost five times that of the non-perinatal rate (2.3/1000 PY). The data suggested iatrogenic perinatal risk factors were associated with infection in one village, while health education reduced infections in another. Among the 25 incident cases, eight were HCV-RNA negative when they were first found to be anti-HCV positive and one-third of the 15 viraemic cases with follow-up data available cleared their HCV-RNA after an average of 1.3 years. None of the 25 incident cases were jaundiced or had symptoms of hepatitis but elevated serum alanine aminotransferase levels confirmed hepatitis in nine. Our data suggest that asymptomatic HCV infections frequently occurred during the perinatal period but often cleared and that educating medical personnel on safe practices possibly reduced HCV transmission.

Background: The authors assessed acceptance and safety of, and adherence to, perinatal HIV-1 transmission prophylaxis at 2 public hospitals in rural Tamil Nadu, India., Methods: Eligible HIV-1-infected women were offered zidovudine (ZDV) beginning at 28-weeks gestation until delivery. Their infants received ZDV for 6 weeks. A subsequent revision to the protocol added 1 dose of nevirapine (NVP) for mother and infant., Results: Sixty of 67 women (90%) met inclusion criteria for the cohort study. Thirty-four of 36 eligible women and all 19 eligible live born infants received prophylaxis on study. Infant, but not maternal, adherence to ZDV varied by antiretroviral prophylaxis group (those receiving combined prophylaxis with ZDV and NVP had lower median adherence) (P = .02). Neutropenia (usually transient) was the most common severe adverse event. Only 1 of 5 women with neutropenia possibly related to ZDV permanently discontinued ZDV. ZDV was not discontinued for any infant., Conclusion: With the exception of neutropenia, usually transient and always without clinical consequences, long-term ZDV (with or without NVP prophylaxis) is well tolerated.

Background: Acute viral hepatitis is less frequent in Egypt than serum antibody levels suggest. Because acute viral hepatitis has a wide clinical spectrum, we tested the hypothesis that many cases are undetected because of mild illness caused by initial, early-childhood exposure to hepatitis viruses., Methods: During active case detection among 20,000 inhabitants of rural villages in Egypt, we screened 1715 symptomatic patients for serum alanine aminotransferase (ALT) levels. Viral hepatitis markers were tested in 47 subjects who had ALT levels that were least twice the normal level., Results: Of the 47 individuals tested, 4 children aged 3-5 years had immunoglobulin M (IgM) antibodies to hepatitis A virus (anti-HAV IgM). One also had a possible false-positive result to a test for IgM antibodies to hepatitis E virus. None had serological evidence of acute hepatitis B virus (HBV) infection or hepatitis C virus (HCV) infection. However, 33 of the remaining 43 had active HCV infection, having both antibodies to HCV (anti-HCV) and HCV RNA. Four others anti-HCV without HCV RNA, and 2 others had seroconversion to anti-HCV during follow-up. Two patients who were positive for hepatitis B surface antigen had chronic HBV infection. Only 3 with elevated ALT levels had no evidence of acute or chronic infections with known hepatitis viruses. Immunoglobulin G antibodies to hepatitis E virus was detected in 40 patients., Conclusion: Active surveillance covering approximately 50,000 person-years detected only 4 cases of acute HAV infection. Almost all persons with mild symptoms and elevated ALT levels had serological evidence of chronic viral hepatitis, most often associated with HCV. Many of these cases were probably "flare-ups" of HCV infection or incidental illness in patients with chronic HCV infection, but some could have been caused by difficult-to-confirm initial HCV infections. Although serological evidence for exposures was highly prevalent, hepatitis viruses seldom caused acute viral hepatitis in these communities.

Prevalence and risk factors for hepatitis C virus (HCV) infection were studied in 2,587 pregnant women from three rural Egyptian villages in the Nile Delta being admitted to a prospective cohort study of maternal-infant transmission; 408 (15.8%) had antibodies to HCV (anti-HCV) and 279 (10.8%) also had HCV-RNA. Fewer than 1% gave a history of jaundice or liver disease. Risk factors for anti-HCV included increasing age, low socioeconomic status and a history of blood transfusion or injection therapy for schistosomiasis. Sub-analyses after stratification of subjects by village revealed risks associated with specific venues for medical care, having a previous delivery attended by a traditional birth assistant (TBA), receiving medical care in a temporary clinic located in a mosque, overnight admission to a private doctor's clinic, and circumcision by a TBA or a 'health barber'. Our results suggest HCV causes very little detected illness in young adult Egyptian women and some sources of HCV transmission in rural Egypt in the past were associated with the provision of medical care and varied by location. Prevention should be focused on providing appropriate resources and health education should be given to formal and informal health care providers and should be sufficiently broad to adjust for local variations in exposures.

Hepatitis E virus (HEV) is enterically transmitted and causes self-limiting acute viral hepatitis (AVH) primarily in less developed countries. A prospective cohort study to assess incidence of, and risk factors for, seroconversion to HEV (anti-HEV) was conducted in two Egyptian villages with a 67.7% anti-HEV prevalence. Nine hundred and nineteen villagers who were initially anti-HEV-negative were followed for 10.7 months. Thirty-four (3.7%) had strong anti-HEV serologic responses at follow-up giving an estimated anti-HEV incidence of 41.6/1,000 person-years. No significant associations were found between anti-HEV seroincidence and demographic and socioeconomic factors, source of water, household plumbing or sanitation, hand and vegetable washing, ownership of animals, jaundice and many other variables. None of the seroconverting subjects gave a history compatible with AVH during the interval. We hypothesize that both zoonotic and anthroponotic transmission of avirulent (possibly genotype-3) HEV is occurring extensively in these rural villages. An alternative explanation for the lack of morbidity among anti-HEV incident cases could be initial asymptomatic infections occur during early childhood with subsequent antibody titer boosting without illness upon re-exposure to the virus.

The epidemiology of hepatitis E virus (HEV), an enterically-transmitted cause of acute viral hepatitis (AVH), is not fully understood. During outbreaks on the Indian subcontinent and elsewhere, HEV causes severe AVH with mortality rates around 20% during pregnancy. In Egypt, where prevalence of HEV antibodies (anti-HEV) in rural communities is very high, severe HEV-caused AVH in pregnant women has not been reported. This study examined a cohort of 2,428 pregnant women in the Nile Delta to assess prevalence of, and risk factors for, anti-HEV and correlated these with history of liver disease. Anti-HEV prevalence was 84.3%. Several risk factors associated with anti-HEV included older age, many siblings, not using soap to wash produce and frequent contact with cats. History of jaundice and liver disease was rare and not increased in those having anti-HEV. Our results confirm Egypt's high HEV endemicity and show that almost all women of childbearing age in these communities had prior HEV exposures without a history of liver disease. Reasons for the lack of clinical hepatitis remain unclear but could be the result of early childhood HEV exposures, producing long-lasting immunity and/or modify subsequent responses to exposure. Alternatively, the predominant HEV strain(s) in Egypt are less virulent than those in South Asia.