Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

Global disease burden of and risk factors for acute lower respiratory infections caused by respiratory syncytial virus in preterm infants and young children in 2019: a systematic review and meta-analysis of aggregated and individual participant data.

BACKGROUND: Infants and young children born prematurely are at high risk of severe acute lower respiratory infection (ALRI) caused by respiratory syncytial virus (RSV). In this study, we aimed to assess the global disease burden of and risk factors for RSV-associated ALRI in infants and young children born before 37 weeks of gestation. METHODS: We conducted a systematic review and meta-analysis of aggregated data from studies published between Jan 1, 1995, and Dec 31, 2021, identified from MEDLINE, Embase, and Global Health, and individual participant data shared by the Respiratory Virus Global Epidemiology Network on respiratory infectious diseases. We estimated RSV-associated ALRI incidence in community, hospital admission, in-hospital mortality, and overall mortality among children younger than 2 years born prematurely. We conducted two-stage random-effects meta-regression analyses accounting for chronological age groups, gestational age bands (early preterm, <32 weeks gestational age [wGA], and late preterm, 32 to <37 wGA), and changes over 5-year intervals from 2000 to 2019. Using individual participant data, we assessed perinatal, sociodemographic, and household factors, and underlying medical conditions for RSV-associated ALRI incidence, hospital admission, and three severity outcome groups (longer hospital stay [>4 days], use of supplemental oxygen and mechanical ventilation, or intensive care unit admission) by estimating pooled odds ratios (ORs) through a two-stage meta-analysis (multivariate logistic regression and random-effects meta-analysis). This study is registered with PROSPERO, CRD42021269742. FINDINGS: We included 47 studies from the literature and 17 studies with individual participant-level data contributed by the participating investigators. We estimated that, in 2019, 1 650 000 (95% uncertainty range [UR] 1 350 000-1 990 000) RSV-associated ALRI episodes, 533 000 (385 000-730 000) RSV-associated hospital admissions, 3050 (1080-8620) RSV-associated in-hospital deaths, and 26 760 (11 190-46 240) RSV-attributable deaths occurred in preterm infants worldwide. Among early preterm infants, the RSV-associated ALRI incidence rate and hospitalisation rate were significantly higher (rate ratio [RR] ranging from 1·69 to 3·87 across different age groups and outcomes) than for all infants born at any gestational age. In the second year of life, early preterm infants and young children had a similar incidence rate but still a significantly higher hospitalisation rate (RR 2·26 [95% UR 1·27-3·98]) compared with all infants and young children. Although late preterm infants had RSV-associated ALRI incidence rates similar to that of all infants younger than 1 year, they had higher RSV-associated ALRI hospitalisation rate in the first 6 months (RR 1·93 [1·11-3·26]). Overall, preterm infants accounted for 25% (95% UR 16-37) of RSV-associated ALRI hospitalisations in all infants of any gestational age. RSV-associated ALRI in-hospital case fatality ratio in preterm infants was similar to all infants. The factors identified to be associated with RSV-associated ALRI incidence were mainly perinatal and sociodemographic characteristics, and factors associated with severe outcomes from infection were mainly underlying medical conditions including congenital heart disease, tracheostomy, bronchopulmonary dysplasia, chronic lung disease, or Down syndrome (with ORs ranging from 1·40 to 4·23). INTERPRETATION: Preterm infants face a disproportionately high burden of RSV-associated disease, accounting for 25% of RSV hospitalisation burden. Early preterm infants have a substantial RSV hospitalisation burden persisting into the second year of life. Preventive products for RSV can have a substantial public health impact by preventing RSV-associated ALRI and severe outcomes from infection in preterm infants. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe.

Prefusion F Protein-Based Respiratory Syncytial Virus Immunization in Pregnancy.

BACKGROUND: Respiratory syncytial virus (RSV), a major cause of illness and death in infants worldwide, could be prevented by vaccination during pregnancy. The efficacy, immunogenicity, and safety of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine in pregnant women and their infants are uncertain. METHODS: In a phase 2b trial, we randomly assigned pregnant women, at 24 through 36 weeks' gestation, to receive either 120 or 240 µg of RSVpreF vaccine (with or without aluminum hydroxide) or placebo. The trial included safety end points and immunogenicity end points that, in this interim analysis, included 50% titers of RSV A, B, and combined A/B neutralizing antibodies in maternal serum at delivery and in umbilical-cord blood, as well as maternal-to-infant transplacental transfer ratios. RESULTS: This planned interim analysis included 406 women and 403 infants; 327 women (80.5%) received RSVpreF vaccine. Most postvaccination reactions were mild to moderate; the incidence of local reactions was higher among women who received RSVpreF vaccine containing aluminum hydroxide than among those who received RSVpreF vaccine without aluminum hydroxide. The incidences of adverse events in the women and infants were similar in the vaccine and placebo groups; the type and frequency of these events were consistent with the background incidences among pregnant women and infants. The geometric mean ratios of 50% neutralizing titers between the infants of vaccine recipients and those of placebo recipients ranged from 9.7 to 11.7 among those with RSV A neutralizing antibodies and from 13.6 to 16.8 among those with RSV B neutralizing antibodies. Transplacental neutralizing antibody transfer ratios ranged from 1.41 to 2.10 and were higher with nonaluminum formulations than with aluminum formulations. Across the range of assessed gestational ages, infants of women who were immunized had similar titers in umbilical-cord blood and similar transplacental transfer ratios. CONCLUSIONS: RSVpreF vaccine elicited neutralizing antibody responses with efficient transplacental transfer and without evident safety concerns. (Funded by Pfizer; ClinicalTrials.gov number, NCT04032093.).

Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.

BACKGROUND: Safe, effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in children younger than 12 years of age. METHODS: A phase 1, dose-finding study and an ongoing phase 2-3 randomized trial are being conducted to investigate the safety, immunogenicity, and efficacy of two doses of the BNT162b2 vaccine administered 21 days apart in children 6 months to 11 years of age. We present results for 5-to-11-year-old children. In the phase 2-3 trial, participants were randomly assigned in a 2:1 ratio to receive two doses of either the BNT162b2 vaccine at the dose level identified during the open-label phase 1 study or placebo. Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-µg doses of BNT162b2. Vaccine efficacy against Covid-19 at 7 days or more after the second dose was assessed. RESULTS: During the phase 1 study, a total of 48 children 5 to 11 years of age received 10 µg, 20 µg, or 30 µg of the BNT162b2 vaccine (16 children at each dose level). On the basis of reactogenicity and immunogenicity, a dose level of 10 µg was selected for further study. In the phase 2-3 trial, a total of 2268 children were randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). At data cutoff, the median follow-up was 2.3 months. In the 5-to-11-year-olds, as in other age groups, the BNT162b2 vaccine had a favorable safety profile. No vaccine-related serious adverse events were noted. One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). Covid-19 with onset 7 days or more after the second dose was reported in three recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3). CONCLUSIONS: A Covid-19 vaccination regimen consisting of two 10-µg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

Epidemiology of Medically Attended Respiratory Syncytial Virus Lower Respiratory Tract Infection in Japanese Children, 2011-2017.

BACKGROUND: The objective was to report critical respiratory syncytial virus (RSV)-related epidemiological and healthcare resource utilization measures among Japanese children stratified by gestational and chronological age groups. METHODS: The JMDC (formerly the Japan Medical Data Center) was used to retrospectively identify infants with or without RSV infection (beginning between 1 February 2011 and 31 January 2016, with follow-up through 31 December 2017). The incidence of RSV medically attended lower respiratory tract infection (MALRI) was captured by flagging hospitalizations, outpatient, and emergency department/urgent care visits with an RSV diagnosis code during the season. RESULTS: Of 113 529 infants and children identified, 17 022 (15%) had an RSV MALRI (14 590 during the season). The RSV MALRI and hospitalization rates in the first 5 months were 14.3/100 child-years (CY) and 6.0/100 CY, respectively (13.4/100 and 5.8/100 CY for full-term infants and 20/100 and 6.8/100 CY for late preterm infants, respectively). Among those with ≥1 type of MALRI event during the RSV season, >80% of children had it by 24 months of chronological age, although this observation differed by prematurity status. Sixty percent of healthcare resource utilization measures started in the outpatient setting. CONCLUSIONS: This study emphasizes the RSV burden in young children and critically highlights the data needed to make decisions about new preventive strategies.

Risk factors for the development of severe or very severe respiratory syncytial virus-related lower respiratory tract infection in Indian infants: A cohort study in Melghat, India.

OBJECTIVES: Respiratory syncytial virus (RSV) is undoubtedly the single most important cause of severe lower respiratory tract infection (LRTI) globally. While new prevention measures in young infants have become available, their use in developing countries is likely many years away. While risk factors for severe or very severe RSV LRTI in impoverished rural areas likely differ to urban areas, there are very few studies, especially those conducted in India, the major country contributing to the global burden of disease. METHODS: Active surveillance for acute LRTI in enrolled infants and children <2 years of age, was conducted through weekly home visits in 93 villages of Melghat, India, from August 2016 to December 2020. Local hospitals and primary health centres were surveyed for admissions of enrolled subjects. Nasopharyngeal swabs were collected from children with severe, or very severe LRTIs and all who died, with RSV testing using nucleic acid tests at ICMR, National Institute of Virology Pune. Risk factors for both RSV associated and non-RSV associated, severe and very severe LRTI were identified through univariate and multivariate logistic regression. RESULTS: There were 483 severe or very severe RSV LRTI cases and 2807 non-RSV severe or very severe LRTI infections in a cohort of 13,318 children. Weight for age z-score ≤-2, the use of kerosene or wood for cooking, obtaining drinking water from a public tap and low gestational age significantly increased the risk of RSV LRTI. A higher wealth score index and water purification were protective. Comparison with non-RSV LRTI showed male sex as an additional risk factor. The analysis highlighted the risk of kerosene use [OR = 17.8 (3.0-104.4) (p ≤ 0.001)] and [OR = 3.4 (0.8-14.4) (p ≤ 0.05)] for RSV and non-RSV LRTIs, respectively. CONCLUSIONS: Nutritional status and environmental air quality are predisposing factors for developing an RSV LRI in young children, factors which are amenable to environmental and behavioural interventions.

Viral Detection by Reverse Transcriptase Polymerase Chain Reaction in Upper Respiratory Tract and Metagenomic RNA Sequencing in Lower Respiratory Tract in Critically Ill Children With Suspected Lower Respiratory Tract Infection.

OBJECTIVES: Viral lower respiratory tract infection (vLRTI) contributes to substantial morbidity and mortality in children. Diagnosis is typically confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) of nasopharyngeal specimens in hospitalized patients; however, it is unknown whether nasopharyngeal detection accurately reflects presence of virus in the lower respiratory tract (LRT). This study evaluates agreement between viral detection from nasopharyngeal specimens by RT-PCR compared with metagenomic next-generation RNA sequencing (RNA-Seq) from tracheal aspirates (TAs). DESIGN: This is an analysis of of a seven-center prospective cohort study. SETTING: Seven PICUs within academic children's hospitals in the United States. PATIENTS: Critically ill children (from 1 mo to 18 yr) who required mechanical ventilation via endotracheal tube for greater than or equal to 72 hours. INTERVENTIONS: We evaluated agreement in viral detection between paired upper and LRT samples. Results of clinical nasopharyngeal RT-PCR were compared with TA RNA-Seq. Positive and negative predictive agreement and Cohen's Kappa were used to assess agreement. MEASUREMENTS AND MAIN RESULTS: Of 295 subjects with paired testing available, 200 (68%) and 210 (71%) had positive viral testing by RT-PCR from nasopharyngeal and RNA-Seq from TA samples, respectively; 184 (62%) were positive by both nasopharyngeal RT-PCR and TA RNA-Seq for a virus, and 69 (23%) were negative by both methods. Nasopharyngeal RT-PCR detected the most abundant virus identified by RNA-Seq in 92.4% of subjects. Among the most frequent viruses detected, respiratory syncytial virus demonstrated the highest degree of concordance (κ = 0.89; 95% CI, 0.83-0.94), whereas rhinovirus/enterovirus demonstrated lower concordance (κ = 0.55; 95% CI, 0.44-0.66). Nasopharyngeal PCR was more likely to detect multiple viruses than TA RNA-Seq (54 [18.3%] vs 24 [8.1%], p ≤ 0.001). CONCLUSIONS: Viral nucleic acid detection in the upper versus LRT reveals good overall agreement, but concordance depends on the virus. Further studies are indicated to determine the utility of LRT sampling or the use of RNA-Seq to determine LRTI etiology.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

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).

Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants, and a need exists for prevention of RSV in healthy infants. Nirsevimab is a monoclonal antibody with an extended half-life that is being developed to protect infants for an entire RSV season with a single intramuscular dose. METHODS: In this trial conducted in both northern and southern hemispheres, we evaluated nirsevimab for the prevention of RSV-associated lower respiratory tract infection in healthy infants who had been born preterm (29 weeks 0 days to 34 weeks 6 days of gestation). We randomly assigned the infants in a 2:1 ratio to receive nirsevimab, at a dose of 50 mg in a single intramuscular injection, or placebo at the start of an RSV season. The primary end point was medically attended RSV-associated lower respiratory tract infection through 150 days after administration of the dose. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after administration of the dose. RESULTS: From November 2016 through November 2017, a total of 1453 infants were randomly assigned to receive nirsevimab (969 infants) or placebo (484 infants) at the start of the RSV season. The incidence of medically attended RSV-associated lower respiratory tract infection was 70.1% lower (95% confidence interval [CI], 52.3 to 81.2) with nirsevimab prophylaxis than with placebo (2.6% [25 infants] vs. 9.5% [46 infants]; P<0.001) and the incidence of hospitalization for RSV-associated lower respiratory tract infection was 78.4% lower (95% CI, 51.9 to 90.3) with nirsevimab than with placebo (0.8% [8 infants] vs. 4.1% [20 infants]; P<0.001). These differences were consistent throughout the 150-day period after the dose was administered and across geographic locations and RSV subtypes. Adverse events were similar in the two trial groups, with no notable hypersensitivity reactions. CONCLUSIONS: A single injection of nirsevimab resulted in fewer medically attended RSV-associated lower respiratory tract infections and hospitalizations than placebo throughout the RSV season in healthy preterm infants. (Funded by AstraZeneca and Sanofi Pasteur; ClinicalTrials.gov number, NCT02878330.).

Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Tobacco smoke exposure, the lower airways microbiome and outcomes of ventilated children.

BACKGROUND: Tobacco smoke exposure increases the risk and severity of lower respiratory tract infections in children, yet the mechanisms remain unclear. We hypothesized that tobacco smoke exposure would modify the lower airway microbiome. METHODS: Secondary analysis of a multicenter cohort of 362 children between ages 31 days and 18 years mechanically ventilated for >72 h. Tracheal aspirates from 298 patients, collected within 24 h of intubation, were evaluated via 16 S ribosomal RNA sequencing. Smoke exposure was determined by creatinine corrected urine cotinine levels ≥30 µg/g. RESULTS: Patients had a median age of 16 (IQR 568) months. The most common admission diagnosis was lower respiratory tract infection (53%). Seventy-four (20%) patients were smoke exposed and exhibited decreased richness and Shannon diversity. Smoke exposed children had higher relative abundances of Serratia spp., Moraxella spp., Haemophilus spp., and Staphylococcus aureus. Differences were most notable in patients with bacterial and viral respiratory infections. There were no differences in development of acute respiratory distress syndrome, days of mechanical ventilation, ventilator free days at 28 days, length of stay, or mortality. CONCLUSION: Among critically ill children requiring prolonged mechanical ventilation, tobacco smoke exposure is associated with decreased richness and Shannon diversity and change in microbial communities. IMPACT: Tobacco smoke exposure is associated with changes in the lower airways microbiome but is not associated with clinical outcomes among critically ill pediatric patients requiring prolonged mechanical ventilation. This study is among the first to evaluate the impact of tobacco smoke exposure on the lower airway microbiome in children. This research helps elucidate the relationship between tobacco smoke exposure and the lower airway microbiome and may provide a possible mechanism by which tobacco smoke exposure increases the risk for poor outcomes in children.

Respiratory Syncytial Virus-Associated Hospitalization Rates among US Infants: A Systematic Review and Meta-Analysis.

BACKGROUND: Although global reviews of infant respiratory syncytial virus (RSV) burden exist, none have summarized data from the United States or evaluated how RSV burden estimates are influenced by variations in study design. METHODS: We performed a systematic literature review and meta-analysis of studies describing RSV-associated hospitalization rates among US infants and examined the impact of key study characteristics on these estimates. RESULTS: We reviewed 3328 articles through 14 August 2020 and identified 25 studies with 31 unique estimates of RSV-associated hospitalization rates. Among US infants <1 year of age, annual rates ranged from 8.4 to 40.8 per 1000 with a pooled rate of 19.4 (95% confidence interval [CI], 17.9-20.9). Study type influenced RSV-associated hospitalization rates (P = .003), with active surveillance studies having pooled rates (11.0; 95% CI, 9.8-12.2) that were half that of studies based on administrative claims (21.4; 19.5-23.3) or modeling approaches (23.2; 20.2-26.2). CONCLUSIONS: Applying our pooled rates to the 2020 US birth cohort suggests that 79 850 (95% CI, 73 680-86 020) RSV-associated infant hospitalizations occur each year. The full range of RSV-associated hospitalization rates identified in our review can better inform future evaluations of RSV prevention strategies. More research is needed to better understand differences in estimated RSV burden across study design.

Anti-SARS-CoV-2 IgA Identifies Asymptomatic Infection in First Responders.

BACKGROUND: Immunoglobulin A (IgA) is an important component of the early immune response to SARS-CoV-2. Prior serosurveys in high-risk groups employing IgG testing alone have provided discordant estimates. The potential added benefit of IgA in serosurveys has not been established. METHODS: Longitudinal serosurvey of first responders (police, emergency medical service providers, fire fighters, and other staff) employing 3 serologic tests (anti-spike IgA, anti-spike IgG, and anti-nucleocapsid IgG) correlated with surveys assessing occupational and nonoccupational risk, exposure to COVID-19, and illnesses consistent with COVID-19. RESULTS: Twelve percent of first responders in Colorado at baseline and 22% at follow-up were assessed as having SARS-CoV-2 infection. Five percent at baseline and 6% at follow-up were seropositive only for IgA. Among those IgA positive only at baseline, the majority (69%) had a positive antibody at follow-up; 45% of those infected at baseline and 33% at follow-up were asymptomatic. At all time points, the estimated cumulative incidence in our study was higher than that in the general population. CONCLUSIONS: First responders are at high risk of infection with SARS-CoV-2. IgA testing identified a significant portion of cases missed by IgG testing and its use as part of serologic surveys may improve retrospective identification of asymptomatic infection.

Coronavirus Disease Spread during Summer Vacation, Israel, 2020.

The relative increase in coronavirus disease incidence during summer 2020 in Israel was most prominent in young children. This finding contrasts with the lower increase in incidence observed in children than in adults during the school attendance period. School closure without lockdown conditions might not be independently effective at reducing spread.

Comparison of the medical burden of COVID-19 with seasonal influenza and measles outbreaks.

AIM: To examine and compare the medical burden of measles, influenza and COVID-19 outbreaks in the city of Bnei Brak, Israel. METHODS: The study was conducted during 2018-2021. The numbers of hospitalisations for these infections and their complications were recorded. Hospitalisation rates were determined by using the number of children residing in Bnei Brak and hospitalised with these infections during the study period as the numerators. The denominators were the estimated paediatric cases of measles, influenza and COVID-19 in Bnei Brak and were calculated under both pragmatic and conservative assumptions. RESULTS: A total of 247, 65 and 32 children were hospitalised with influenza, COVID-19 and measles respectively. Complication rates were higher following measles than after influenza and SARS-CoV-2 infections. Hospitalisation rates were 10% for measles, 0.6%-1.2% for influenza and 0.15% - 0.25% for COVID-19 infections. Relative risks (RR) with 95% confidence intervals (CI) for hospitalisation following measles compared with COVID-19 ranged from 42 (26.3-67.3) to 70.1 (43.8-112.1), while the relative risks for influenza hospitalisation ranged from 2.5 (1.83-3.41) to 8.2 (6.0-11.2), compared with COVID-19 infection. CONCLUSION: Hospitalisation rates and direct medical burdens of measles and influenza were significantly higher than those of COVID-19 infection in children.

Reopening Schools and the Dynamics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infections in Israel: A Nationwide Study.

BACKGROUND: Benefits of school reopening must be weighed against the morbidity and mortality risks and the impact of enhancing spread of coronavirus disease 2019 (COVID-19). We investigated the effects of school reopening and easing of social-distancing restrictions on dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Israel between March and July 2020. METHODS: We examined the nationwide age-wise weekly incidence, prevalence, SARS-CoV-2 polymerase chain reaction tests, their positivity, COVID-19 hospitalizations, and associated mortality. Temporal differences in these parameters following school reopening, school ending, and following easing of restrictions such as permission of large-scale gatherings were examined. RESULTS: Incidence of SARS-CoV-2 infections gradually increased following school reopening in all age groups, with a significantly higher increase in adults than children. Higher rate ratios (RRs) of sample positivity rates 21-27 days following school reopening relative to positivity rates prior to openings were found for the age groups 40-59 (RR, 4.72; 95% CI, 3.26-6.83) and 20-39 (RR, 3.37 [2.51-4.53]) years, but not for children aged 0-9 (RR, 1.46 [.85-2.51]) and 10-19 (RR, .93 [.65-1.34]) years. No increase was observed in COVID-19-associated hospitalizations and deaths following school reopening. In contrast, permission of large-scale gatherings was accompanied by increases in incidence and positivity rates of samples for all age groups, and increased hospitalizations and mortality. CONCLUSIONS: This analysis does not support a major role of school reopening in the resurgence of COVID-19 in Israel. Easing restrictions on large-scale gatherings was the major influence on this resurgence.

The Burden of Respiratory Syncytial Virus in Children Under 2 Years of Age in a Rural Community in Maharashtra, India.

BACKGROUND: Globally, respiratory syncytial virus (RSV) is a common cause of acute lower tract infection (LRTI) in children younger than 2 years of age, but there are scant population-based studies on the burden of RSV illness in rural communities and no community studies in preterm infants. METHODS: Active surveillance of LRTI was performed in the community and hospital setting for the population of 93 tribal villages in Melghat, Central India, over 4 respiratory seasons. A nasopharyngeal swab was obtained from cases presenting as a severe LRTI for molecular analysis of respiratory pathogens including RSVA and B. RESULTS: High rates of RSV-associated LRTI were found in preterm and term infants beyond 6 months of age, extending into the second year of life. Community severe RSV LRTI rates for 0-11 months of age was 22.4 (18.6-27.0)/1000 child-years (CY) and the hospital-associated rate was 14.1 (11.1-17.8)/1000 CY. For preterm infants, these rates were 26.2 (17.8-38.5)/1000 CY and 12.6 (7.2-22.0)/1000 CY. Comparable rates in the first 6 months were 15.9 (11.8-21.4)/1000 CY and 12.9 (9.3-18.0)/1000 CY in term infants and 26.3 (15.4-45.0)/1000 CY and 10.1 (4.2-24.2)/1000 CY for preterms. The single RSV B season had higher incidences of RSV LRTI in every age group than the 2 RSV A seasons in both preterm and term infants. There were 11 deaths, all term infants. CONCLUSIONS: Studies restricted to the healthcare settings significantly underestimate the burden of RSV LRTI and preterm and term infants have comparable burdens of disease in this rural community.

Adult Population Coverage With Influenza Vaccine and Influenza Hospitalization Rates-Is There a Role for Active Outreach to Immunize At-Risk Neighborhoods?

We evaluated whether Denver neighborhoods with elevated rates of adult hospitalizations for laboratory-confirmed influenza had lower adult coverage with influenza vaccine. Overall vaccine coverage was low. Hospitalization rates were associated with demographic and socioeconomic characteristics. Active immunization of at-risk neighborhoods may be necessary to address disparities in influenza hospitalization rates.

Mortality From Respiratory Syncytial Virus in Children Under 2 Years of Age: A Prospective Community Cohort Study in Rural Maharashtra, India.

BACKGROUND: Although respiratory syncytial virus (RSV) is the most important viral cause of lower respiratory tract infection deaths in infants, there are few data on infant community deaths caused by RSV. METHODS: This was an active surveillance of children younger than 2 years of age in 93 villages, 5 primary health centers, and 3 hospitals serving these villages. Village health workers and counselors at the health facilities monitored all lower respiratory tract infections (LRTIs) in consented subjects. Children with severe, or very severe LRTIs and all who died, had nasopharyngeal swabs collected for detection of RSV by molecular methods. RESULTS: In the 12 134 subjects, there were 2064 episodes of severe LRTIs and 1732 of very severe LRTIs, of which 271 and 195, respectively, had RSV. Fifteen of 16 (94%) children with RSV died of LRTIs, 14 in the community and 1 in the hospital. The case fatality ratios for severe RSV LRTIs in the first 6 months of life were 3/52 (7.1%) and 1/36 (2.8%) in the community and hospital, respectively. Of those with very severe LRTIs in the community, 17.6% died. There were no very severe RSV LRTI hospital deaths. The adjusted RSV LRTI mortality rates ranged from 1.0 to 3.0/1000 child-years (CY) overall, and 2.0 to 6.1/1000 CY, accounting for 20% of the LRTI deaths and 10% of the postneonatal infant mortality. CONCLUSIONS: Community deaths from RSV account for the majority of RSV LRTI deaths, and efforts at prevention should be preferentially directed at populations where access to care is limited.

Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI). METHODS: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI). RESULTS: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups. CONCLUSIONS: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts. CLINICAL TRIALS REGISTRATION: NCT02325791.