Summary of study A multi-country randomized, placebo-controlled trial of the safety, immunogenicity and efficacy of respiratory syncytial virus (RSV) F-protein nanoparticle vaccine was undertaken in 4,636 pregnant women and their infants. RSV F-protein vaccine was safe and immunogenic in the pregnant women inducing anti-F IgG, palivizumab-competing antibodies and RSV neutralizing antibodies that were transferred to the fetus. Although the primary endpoint of prevention of RSV-specific medically-significant lower respiratory tract infection (MS-LRTI) was not met per protocol criteria for efficacy (i.e. 97.52% lower bound >30%), vaccine efficacy was 39.4% (97.52% CI: -1.0, 63.7%; p=0.0278) in infants 0-90 days age. Furthermore, there was a 58.8% (95% CI 31.9, 75.0%) lower rate of RSV LRTI with severe hypoxemia (secondary endpoint) through to 90 days of age in the expanded intent-to-treat analysis. The number of women needed to be vaccinated to prevent RSV-specific MS-LRTI or LRTI with severe hypoxemia in their infants through to 180 days of life were 88 and 82, respectively. Background RSV is the dominant cause of severe lower respiratory tract infection (LRTI) in infants, with most severe disease concentrated in younger-age infants. Methods Healthy, pregnant women between 28 and 36 weeks gestation, with expected delivery near the start of the RSV season, were randomized to a single intramuscular dose of nanoparticle RSV F-protein vaccine, or placebo in a 2:1 ratio. Their infants were followed for 180 days for medically-significant LRTI (MS-LRTI), LRTI with severe hypoxemia and/or LRTI- hospitalization. RSV detection was performed centrally by PCR. Safety evaluation continued until 364 days age. Results 4,636 women were randomized, with 4,579 live births. Over the first 90 days of life, efficacy against RSV-MS-LRTI was 39.4% (97.52%CI: -1.0, 63.7%; p=0.0278) and 41.4% (95%CI: 5.3, 61.2%) in the per protocol and expanded intent-to-treat (eITT) analyses, respectively. There was a lower rate (efficacy 58.8%; 95%CI 31.9, 75.0% in eITT analysis; not adjusted for multiplicity) of RSV-LRTI with severe hypoxemia in infants of vaccinees through 90 days age. Pneumonia reported as a serious adverse events was 49.4% less common in infants of vaccinees (2.6%) than placebo-recipients through 364 days age. Conclusions Maternal vaccination with RSV F-nanoparticle vaccine was safe and immunogenic. The prespecified primary endpoint success criterion (efficacy 97.5% lower bound ≥30%) was not achieved. However, maternal immunization was associated with reduced risk of RSV-confirmed MS-LRTI and LRTI with severe hypoxemia in early infancy. Trial Registration Number ClinicalTrials.Gov: NCT02624947. Funding statement Funded by Novavax, with supporting grant from the Bill and Melinda Gates Foundation.

BACKGROUNDWhether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODSIn 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 proteinbased (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. RESULTSAt 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). CONCLUSIONSRSVpreF 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.

Background Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine. Methods In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases. Results A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%). Conclusions The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697 .)

Rationale: The development of early lung disease in patients with cystic fibrosis (CF) remains poorly defined. Objective: Determine whether asymptomatic infants with CF have evidence for changes in airway structure when assessed by highresolution computed tomography, and whether airway structure correlates with airway function in this age group. Methods: Thirteen infants with CF (8-33 mo) and 13 control infants (7-25 mo) were evaluated. Airway wall and lumen areas were measured from three 1-mm-thick cross-sectional images obtained from upper, middle, and lower lobes during a respiratory pause with the lungs inflated to an airway pressure of 20 cm H 2 O. Lung tissue density was measured from images obtained during a respiratory pause at FRC. Forced expiratory flows were measured by the rapid thoracic compression technique in 11 infants with CF. Results: Airway wall area increased more per unit increase in airway size, whereas airway lumen area increased less per unit increase in airway size in the CF than in the control group. Among infants with CF, a greater ratio of wall to lumen area correlated with lower airway function. In addition, lung density at relaxed (passive) FRC was lower for infants with CF than for control infants (0.38 vs. 0.43 g/ml; p Ͻ 0.02). Conclusions: Our results indicate that infants with CF have thickened airway walls, narrowed airway lumens, and air trapping, when assessed by high-resolution computed tomography, and measurements of airway structure correlated with airway function. Keywords: airway structure; high-resolution computed tomography; lung disease Our understanding of the early pulmonary pathophysiology of cystic fibrosis (CF) has greatly expanded over the last two decades. Measurements of lung function have demonstrated the presence of airway obstruction in infants with CF without respiratory symptoms (1-4), and bronchoalveolar lavage has demonstrated that airway inflammation can be present even among infants with CF without respiratory symptoms (5, 6). Despite these advancements, our current knowledge about structural changes in the lungs of infants with CF is very limited and has primarily been obtained from autopsy studies. Lungs of newborns with CF have essentially normal histology; however, autopsied lungs from severely affected infants with CF can dem- onstrate bronchiectasis as early as age 6 mo (7, 8). The availability of autopsied lungs of infants is currently very limited, and those obtained are most likely atypical of the general CF population. In adults and cooperative older children, high-resolution computed tomography (HRCT) has emerged as a powerful technique to assess lung structure in vivo (9, 10). Evaluations of adults with asthma, chronic obstructive pulmonary disease, or emphysema have demonstrated changes in lung structure on CT images, and quantitative measures of airway size, wall thickness, and parenchymal tissue density, as well as measures of pulmonary function have been consistent with histologic findings (11-15). Studies using CT imaging of older chi...

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Background Family histories of atopy, as well as histories of atopic dermatitis and food allergy, are important risk factors for an infant to have asthma. Although atopic sensitization appears to contribute to the development of asthma, it is unclear when the airways become involved with the atopic process and whether airway function relates to the atopic characteristics of the infant. Objective We sought to evaluate whether atopic infants without prior episodes of wheezing have increased expired nitric oxide (eNO) levels and heightened airway reactivity. Methods Infants with eczema were recruited, and atopic status was defined by specific IgE levels to foods or aeroallergens and total IgE levels. eNO, forced expiratory flow at 75% exhaled volume (FEF75), and airway reactivity to inhaled methacholine were measured in sedated infants. Airway reactivity was quantified by using the provocative concentration to decrease FEF75 by 30%. Results Median age for the 114 infants evaluated was 10.7 months (range, 2.6–19.1 months). Infants sensitized to egg or milk compared with infants sensitized to neither egg nor milk had lower flows (FEF75: 336 vs 285 mL/s, P < .003) and lower lnPC30 (mg/mL) provocative concentrations to decrease FEF75 by 30% (−0.6 vs −1.2, P < .02) but no difference in eNO levels. Infants with total serum IgE levels of greater than 20 IU/mL had higher eNO levels compared with infants with IgE levels of 20 IU/mL or less (14.6 vs 11.2 ppb, P < .023) but no difference in forced flows or airway reactivity. Conclusions Our findings suggest that atopic characteristics of the infant might be important determinants of the airway physiology of forced expiratory flows, airway reactivity, and eNO.

Background-Childhood asthma is most often characterized by recurrent wheezing, airway hyperreactivity, and atopy; however, our understanding of these relationships from early in life remains unclear. Respiratory illnesses and atopic sensitization early in life may produce an interaction between innate and acquired immune responses leading to airway inflammation and heightened airway reactivity.

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