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Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in children. We aimed to assess the safety and efficacy of an anti-RSV monoclonal antibody (motavizumab) in healthy term (≥36 weeks' gestational age) infants for the prevention of medically attended RSV acute lower respiratory tract infections. This phase 3, double-blind, placebo-controlled, randomised trial enrolled healthy Native American infants aged 6 months or younger who were born at 36 weeks' gestational age in southwestern USA, on the Navajo Nation, the White Mountain Apache reservation, and the San Carlos Apache Indian reservation. Participants were randomly assigned (2:1) to receive either five monthly intramuscular doses of motavizumab (15 mg/kg) or placebo. They were followed up for 150 days after the first dose, and the primary endpoints were respiratory admission to hospital with a positive result for RSV by RT-PCR and death caused by RSV. Participants were followed up for medically attended wheezing until they reached age 3 years. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00121108. During the autumn seasons (October to December) between 2004 and 2007, 2127 infants of the 2596 infants enrolled were randomly assigned to receive either motavizumab (1417) or placebo (710). After ITT analysis, motavizumab resulted in an 87% relative reduction (relative risk [RR] 0·13, 95% CI 0·08–0·21) in the proportion of infants admitted to hospital with RSV (21 [2%] of 1417 participants who received motavizumab; 80 [11%] of 710 participants who received placebo, p<0·0001). Serious adverse events were less common in particpants taking motavizumab (212 [15%]) than particpants on placebo (148 [21%]). Six deaths occurred in study participants (motavizumab, n=4 [0·3%]; placebo, n=2 [0·3%]); none were deemed to be related to the study product. Hypersensitivity events were more common in patients given motavizumab (208 [14·7%]) than in placebo recipients (87 [12·3%]; p=0·14). There was no effect on rates of medically attended wheezing in children aged 1–3 years (190 [14·9%] of participants randomly assigned to receive motavizumab vs 90 [14·0%] participants randomly assigned to receive placebo). To our knowledge, this is the only trial of an anti-RSV antibody to prevent serious RSV disease in healthy term infants. Motavizumab significantly reduced the RSV-associated inpatient and outpatient burden and set a benchmark for the efficacy of RSV prevention strategies. The findings do not support a direct, generalisable, causal association between RSV lower respiratory tract infection and subsequent long-term wheezing in term infants. MedImmune.

Introduction To avoid the need for reconstitution required by lyophilized palivizumab, a liquid formulation was developed. This study assessed the safety and antidrug antibodies (ADA) of the liquid formulation of palivizumab compared with the lyophilized formulation. Methods This phase 4, randomized, double-blind, multicenter study included children with chronic lung disease of prematurity who were ≤24 months of age and children born prematurely with a gestational age of ≤35 weeks who were ≤6 months of age at randomization. Subjects were randomized 1:1 to 15 mg/kg of either liquid or lyophilized palivizumab administered via intramuscular injection every 30 days for a total of 5 injections. Safety was assessed based on serious adverse events (SAEs). ADA to palivizumab was assessed using blood collected at baseline and at a time point between study days 240 and 300. Results A total of 413 subjects were included in the analyses. The incidence of SAEs reported was 8.5% with liquid palivizumab and 5.9% with lyophilized palivizumab; none were deemed drug-related. The reported SAEs were consistent with expected conditions in this pediatric age group; there was no increase in respiratory syncytial virus (RSV) disease with liquid palivizumab. At study days 240–300, antipalivizumab antibodies were detected in none of the subjects in the liquid palivizumab group and in 1 subject in the lyophilized group. The true ADA percent positive, based on the upper limit of the 95% confidence interval (CI), was <1.5% for both treatments combined. Conclusion The frequency of detection of ADAs was low. The true ADA percent positive for both treatment groups combined based on the upper limit of the 95% CI was <1.5%. The type and frequency of SAEs reported were as expected, and there was no evidence of an increase in RSV disease with liquid palivizumab.

Abstract Background Influenza is responsible for significant morbidity and mortality and more effective therapeutics are needed. MEDI8852 is a human IgG1 kappa monoclonal antibody that binds to the conserved stalk region of the influenza hemagglutinin protein neutralizing both seasonal and pandemic influenza A strains. MEDI8852 is being developed to treat patients hospitalized with influenza A. The primary objective of this study was to evaluate the safety of MEDI8852 administered either alone or with oseltamivir (OS) in outpatient adults with acute, uncomplicated influenza A. Methods Subjects aged 18 to 65 years with onset of influenza symptoms ≤ 5 days prior to dosing were enrolled. Subjects were randomized into 4 cohorts: Cohort 1: 750 mg MEDI8852 (single intravenous infusion) + 75 mg OS (orally twice a day for 5 days); Cohort 2: 3,000 mg MEDI8852 + 75 mg OS; Cohort 3: placebo + 75 mg OS; or Cohort 4: 3,000 mg MEDI8852. Subjects were followed through Day 10 for solicited symptoms (SS), through Day 28 for adverse events (AEs) and through Day 101 for serious AEs (SAEs) and AEs of special interest (AESIs). Viral shedding was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) through Day 7. Results 126 subjects (31 in Cohort 1; 31 in Cohort 2; 32 in Cohort 3; and 32 in Cohort 4) were enrolled at sites in United States (2015–16) and South Africa (2016). More AEs were reported in the total MEDI8852 group (Cohorts 1, 2 and 4 combined: 39/93, 41.9%) than in placebo group (10/32, 31.3%). Related AEs were similar across the 2 groups (14/93, 15.1% total MEDI8852 group; 5/32, 15.6% placebo group). Most AEs were Grade 1 or Grade 2. The most common AE was bronchitis (11/93, 11.8%; 1/32, 3.1%). One subject in Cohort 2 had a related SAE (and AESI) of Grade 3 infusion-related reaction, which resolved with treatment. There were no deaths or discontinuations due to an AE. Median (range) time to resolution of SS were similar across groups (93/94, 111.3 [92.4, 130.8] hours; 32/32, 108.8 [71.2, 161.8] hours). Median (range) decreases in viral shedding (log10 viral copies/mL) were similar across groups (-3.6 [-6.2. 0.5]; -3.4 [-5.9, 0.9]). Conclusion MEDI8852 has an acceptable safety profile in adults with acute, uncomplicated influenza A. These results support the continued development of MEDI8852 for the treatment of influenza A. Disclosures O. Ali, MedImmune: Employee, Salary; T. Takas, MedImmune: Employee and Shareholder, Salary and stock; A. C. Nyborg, MedImmune: Employee, Salary; K. M. Jensen, MedImmune: Employee and Shareholder, Salary and stock; F. Dubovsky, MedImmune: Employee and Shareholder, Salary and stock; R. Mallory, MedImmune: Employee, Salary

Abstract Background RSV is the most common cause of lower respiratory tract infection (LRTI) among infants making prevention of RSV disease a public health priority. A significant unmet need exists for RSV prevention in healthy infants. Our goal is to develop a mAb with an extended half-life (t½) capable of protecting infants for an entire RSV season by using a single intramuscular (IM) dose. This study was conducted to evaluate the safety profile, pharmacokinetics (PK), RSV neutralizing antibody titers, and anti-drug antibody (ADA) responses for MEDI8897 in healthy preterm infants born between 32 and 35 weeks gestational age. Methods Infants were randomized 4:1 to receive a single IM injection of MEDI8897 10mg (n = 8), 25mg (n = 31), 50mg (n = 32) or placebo (n = 18) and followed for 360 days. Enrollment occurred during the 2,015 RSV seasons in the US, South Africa, and Chile. Blood was collected at multiple timepoints. Infants who met criteria for a medically-attended (MA) LRTI had nasal swabs obtained for RSV testing by RT-PCR. Results A total of 85/89 (95.5%) infants completed the study. Adverse events (AEs) were reported in 17/18 (94.4%) placebo and 66/71 (93.0%) MEDI8897 recipients. Five serious AEs (three LRTIs, two febrile seizures) were reported in three MEDI8897 recipients. No events were consistent with hypersensitivity reactions. The estimated MEDI8897 serum t½ ranged from 62.5 to 72.9 days. On day 151, 87% of the infants who received the 50mg dose of MEDI8897 had serum concentrations above the target EC90 level of 6.8 µg/ml, and 93.3% showed a ≥3-fold rise from baseline in serum anti-RSV neutralizing antibody titers. ADA was detected in 28.2% of MEDI8897 recipients, but when present was not associated with any safety findings. ADA was detected at day 361 only in 26.5% of subjects. MA-LRTI was reported in 5 (7%) MEDI8897 recipients through 150 days after dosing. The one subject with an MA-LRTI caused by RSV had received a 10mg dose of MEDI8897. Conclusion In healthy preterm infants, the safety profile of MEDI8897 was favorable. The extended t½ of MEDI8897 with the corresponding increase in RSV neutralizing antibody levels was confirmed and supports protection from RSV disease during a typical 5-month season with a single 50mg IM dose. This study was sponsored by MedImmune. Disclosures J. B. Domachowske, Medimmune: Investigator, Research grant; Regeneron: Investigator, Research grant; Pfizer: Investigator, Research grant; Glaxo Smith Kline: Investigator, Research grant; Novavax: Investigator, Research grant; Janssen: Investigator, Research grant; A. Khan, MedImmune: Employee and Shareholder, Salary and stock; M. T. Esser, MedImmune: Employee and Shareholder, Salary and stock; K. M. Jensen, MedImmune: Employee and Shareholder, Salary and stock; T. Takas, MedImmune: Employee and Shareholder, Salary and stock; T. Villafana, MedImmune: Employee and Shareholder, Salary and stock; F. Dubovsky, MedImmune: Employee and Shareholder, Salary and stock; M. P. Griffin, MedImmune: Employee and Shareholder, Salary and stock

This volume provides an opportunity for readers to deepen their understanding of practice-based education and broaden and critically appraise their strategies for engaging with practice-based education theory.

Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment (\"waitlist\"), placebo treatment alone (\"limited\") and, placebo treatment \"augmented\" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. ClinicalTrials.gov NCT01573312.

Cell‐to‐cell heterogeneity is a feature of the tumor necrosis factor (TNF)‐stimulated inflammatory response mediated by the transcription factor NF‐κB, motivating an exploration of the underlying sources of this noise. Here, we combined single‐transcript measurements with computational models to study transcriptional noise at six NF‐κB‐regulated inflammatory genes. In the basal state, NF‐κB‐target genes displayed an inverse correlation between mean and noise characteristic of transcriptional bursting. By analyzing transcript distributions with a bursting model, we found that TNF primarily activated transcription by increasing burst size while maintaining burst frequency for gene promoters with relatively high basal histone 3 acetylation (AcH3) that marks open chromatin environments. For promoters with lower basal AcH3 or when AcH3 was decreased with a small molecule drug, the contribution of burst frequency to TNF activation increased. Finally, we used a mathematical model to show that TNF positive feedback amplified gene expression noise resulting from burst size–mediated transcription, leading to a subset of cells with high TNF protein expression. Our results reveal potential sources of noise underlying intercellular heterogeneity in the TNF‐mediated inflammatory response. SYNOPSIS Single‐cell transcript measurements show that TNF stimulation primarily increases transcriptional burst size at NF‐κB target genes. Chromatin measurements and mathematical modeling are used to explore the sources and consequences of TNF‐mediated bursting. NF‐κB‐target genes display an inverse correlation between mean and noise characteristic of transcriptional bursting. TNF primarily activates transcription by increasing burst size while maintaining burst frequency for promoters with relatively high basal histone 3 acetylation. The contribution of burst frequency to TNF activation increases when basal AcH3 at target promoters is reduced. Mathematical modeling shows that TNF positive feedback amplification of gene expression noise can produce a subset of cells with high TNF protein expression. Graphical Abstract Single‐cell transcript measurements show that TNF stimulation primarily increases transcriptional burst size at NF‐κB target genes. Chromatin measurements and mathematical modeling are used to explore the sources and consequences of TNF‐mediated bursting.

Mature super-Earths and sub-Neptunes are predicted to be ≃ Jovian radius when younger than 10 Myr. Thus, we expect to find 5–15 R ⊕ planets around young stars even if their older counterparts harbor none. We report the discovery and validation of TOI 1227b, a 0.85 ± 0.05 R J (9.5 R ⊕) planet transiting a very-low-mass star (0.170 ± 0.015 M ⊙) every 27.4 days. TOI 1227's kinematics and strong lithium absorption confirm that it is a member of a previously discovered subgroup in the Lower Centaurus Crux OB association, which we designate the Musca group. We derive an age of 11 ± 2 Myr for Musca, based on lithium, rotation, and the color–magnitude diagram of Musca members. The TESS data and ground-based follow-up show a deep (2.5%) transit. We use multiwavelength transit observations and radial velocities from the IGRINS spectrograph to validate the signal as planetary in nature, and we obtain an upper limit on the planet mass of ≃0.5 M J. Because such large planets are exceptionally rare around mature low-mass stars, we suggest that TOI 1227b is still contracting and will eventually turn into one of the more common <5 R ⊕ planets.