scholarly journals 998. Forward and Reverse Translational Approaches to Predict Efficacy of the Neutralizing Respiratory Syncytial Virus (RSV) Antibody MK-1654

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S590-S590
Author(s):  
Brian M Maas ◽  
Jos Lommerse ◽  
Nele Plock ◽  
Radha Railkar ◽  
S Y Amy Cheung ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Tract Infection ◽  
Lower Respiratory Tract ◽  
Incidence Rates ◽  
Independent Contractor ◽  
Phase 3 ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
The Relationship

Abstract Background MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody (mAb) with an extended half-life in late development to prevent RSV infection in infants. Neutralizing mAbs, like MK-1654, have great potential for prophylaxis against viral infection. However, well-validated approaches for clinical dose and efficacy predictions are lacking. Methods Summary-level literature data from RSV prevention studies were used in a model-based meta-analysis (MBMA) to describe the relationship between RSV incidence rates and serum neutralizing antibody (SNA) titer. The model was validated using viral challenge experiments in cotton rats and phase 3 RSV-A efficacy results in infants for an anti-RSV F mAb, REGN-2222. A phase 2b human RSV challenge study (HCS) in adults was also conducted with MK-1654. Participants (N=70) received 100, 200, 300, or 900 mg of MK-1564 or placebo and were challenged intranasally with RSV 29 days later. RSV viral load and symptomatic infection were monitored. Data from the HCS were compared to model predictions. The MBMA was used to predict efficacy of MK-1654 in a virtual population of pre- and full- term infants. Results The relationship between SNA titer and RSV incidence rate defined using the viral load data from the cotton rat approximated the relationship identified for infants from the clinical MBMA. The MBMA was quantitatively consistent with the phase 3 efficacy results against RSV A for REGN-2222. In the HCS, RSV nasal viral load measured by RT-qPCR and quantitative culture as well as symptomatic infections were decreased in MK-1654 recipients compared to placebo. Incidence rates of RSV infection in the HCS were also consistent with MBMA predictions. The model-based clinical trial simulations for MK-1654 indicated a high probability of substantial efficacy against RSV-associated medically attended lower respiratory tract infection ( >75% for 5 months) for doses ≥75 mg. Conclusion Our MBMA successfully quantified the relationship between RSV SNA and clinically relevant endpoints, including lower respiratory tract infection in infants. MBMA-based efficacy predictions support continued development of the MK-1654 antibody for the prevention of RSV in infants. Disclosures Brian M. Maas, PharmD, Merck & Co., Inc. (Employee, Shareholder) Jos Lommerse, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Radha Railkar, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Luzelena Caro, PhD, Merck & Co., Inc. (Employee, Shareholder) Jingxian Chen, PhD, Merck & Co., Inc. (Employee, Shareholder) Wen Liu, MPH, Merck & Co., Inc. (Employee, Shareholder) Ying Zhang, PhD, Merck & Co., Inc. (Employee, Shareholder) Qinlei Huang, MS, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Li Qin, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Jie Meng, MSc, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Han Witjes, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Emilie Schindler, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Benjamin Guiastrennec, PharmD, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Francesco Bellanti, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Daniel Spellman, PhD, Merck & Co., Inc. (Employee, Shareholder) Brad Roadcap, MS, Merck & Co., Inc. (Employee, Shareholder) Amy Espeseth, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Aubrey Stoch, MD, Merck & Co., Inc. (Employee, Shareholder) Eseng Lai, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Kalpit A. Vora, PhD, Merck & Co., Inc. (Employee, Shareholder) Antonios O. Aliprantis, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

scholarly journals Presumed Risk Factors and Biomarkers for Severe Respiratory Syncytial Virus Disease and Related Sequelae: Protocol for an Observational Multicenter, Case-Control Study From the Respiratory Syncytial Virus Consortium in Europe (RESCEU)

2020 ◽  
Vol 222 (Supplement_7) ◽  
pp. S658-S665 ◽  
Author(s):  
Kimberley Jefferies ◽  
Simon B Drysdale ◽  
Hannah Robinson ◽  
Elizabeth Ann Clutterbuck ◽  
Luke Blackwell ◽  
...  
Keyword(s):  
Risk Factors ◽  
Respiratory Syncytial Virus ◽  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Disease Severity ◽  
Lower Respiratory Tract ◽  
Viral Pathogen ◽  
Rsv Infection ◽  
Syncytial Virus

Abstract Respiratory syncytial virus (RSV) is the leading viral pathogen associated with acute lower respiratory tract infection and hospitalization in children < 5 years of age worldwide. While there are known clinical risk factors for severe RSV infection, the majority of those hospitalized are previously healthy infants. There is consequently an unmet need to identify biomarkers that predict host response, disease severity, and sequelae. The primary objective is to identify biomarkers of severe RSV acute respiratory tract infection (ARTI) in infants. Secondary objectives include establishing biomarkers associated with respiratory sequelae following RSV infection and characterizing the viral load, RSV whole-genome sequencing, host immune response, and transcriptomic, proteomic, metabolomic and epigenetic signatures associated with RSV disease severity. Six hundred thirty infants will be recruited across 3 European countries: the Netherlands, Spain, and the United Kingdom. Participants will be recruited into 2 groups: (1) infants with confirmed RSV ARTI (includes upper and lower respiratory tract infections), 500 without and 50 with comorbidities; and (2) 80 healthy controls. At baseline, participants will have nasopharyngeal, blood, buccal, stool, and urine samples collected, plus complete a questionnaire and 14-day symptom diary. At convalescence (7 weeks ± 1 week post-ARTI), specimen collection will be repeated. Laboratory measures will be correlated with symptom severity scores to identify corresponding biomarkers of disease severity. Clinical Trials Registration NCT03756766.

scholarly journals Local dornase alfa treatment reduces NETs-induced airway obstruction during severe RSV infection

Thorax ◽  
2017 ◽  
Vol 73 (6) ◽  
pp. 578-580 ◽  
Author(s):  
Bart Cortjens ◽  
Rineke de Jong ◽  
Judith G Bonsing ◽  
Job B M van Woensel ◽  
Adriaan F G Antonis ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Airway Obstruction ◽  
Lower Respiratory Tract ◽  
Neutrophil Extracellular Traps ◽  
Strong Reduction ◽  
Dornase Alfa ◽  
Extracellular Traps ◽  
Rsv Infection ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) infection is characterised by airway obstruction with mucus plugs, containing DNA networks in the form of neutrophil extracellular traps (NETs). We investigated the effect of dornase alfa on histopathological NETs-induced airway obstruction and viral load in an age-relevant calf model of severe bovine RSV disease. As compared with the control animals, dornase alfa treatment resulted in a strong reduction of NETs-induced airway obstruction. Viral load in the lower respiratory tract was not different between the two groups. We conclude that NETs form a relevant target for treatment of airway obstruction in severe RSV disease.

scholarly journals 1013. Predicting RSV Efficacy for MK-1654 in Temperate and Tropical Climates using MBMA and Clinical Trial Simulation to Account for Seasonal Differences in RSV Force-of-Infection

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S597-S598
Author(s):  
Nele Plock ◽  
Jos Lommerse ◽  
Brian M Maas ◽  
Jingxian Chen ◽  
Francesco Bellanti ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tract Infection ◽  
Lower Respiratory Tract ◽  
Epidemiological Data ◽  
Incidence Rates ◽  
Independent Contractor ◽  
Tropical Regions ◽  
Force Of Infection ◽  
Clinical Trial Simulations ◽  
Rsv Infection

Abstract Background MK-1654 is a respiratory syncytial virus (RSV) F glycoprotein neutralizing monoclonal antibody under development to prevent RSV infection in infants. A model-based meta-analysis (MBMA) describing the relationship between RSV serum neutralizing activity (SNA) and clinically relevant endpoints (e.g. incidence rates) in humans, including lower respiratory tract infection (LRI) in infants, was presented previously. This model accounted for variable exposure to RSV over the course of the season through a force-of-infection (FOI) function modulating the overall risk of RSV infection over time. The objective of the current work was to determine whether variations in regional seasonality would impact the efficacy of a clinical trial evaluating MK-1654. Methods A FOI function to describe the degree of RSV exposure as a function of time was created by fitting epidemiological data to a Gaussian function added to a constant baseline value. Clinical trial simulations were conducted using the MBMA to predict seasonal incidence rates (IR) of RSV medically attended lower-respiratory tract infection (MALRI) and efficacies for a range of MK-1654 doses in both temperate and tropical regions. Results Epidemiological data was well captured by the FOI function. Clinical trial simulations indicated that seasonal IRs of RSV were sensitive to differences in the FOI represented by temperate and tropical regions; however, there was no substantial impact on efficacies across MK-1654 dose levels. Consistent with predictions for a temperate climate, MK-1654, when administered at the start of the RSV season in a region with a tropical climate, was also predicted to maintain high efficacy ( > 75%) for the prevention of RSV MALRI for 150 days. Conclusion Simulations indicated that while FOI is a substantial driver of overall RSV incidence rates, MK-1654 efficacy in a late-stage clinical trial is likely to be high, regardless of regional variations in RSV. Disclosures Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Jos Lommerse, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Brian M. Maas, PharmD, Merck & Co., Inc. (Employee, Shareholder) Jingxian Chen, PhD, Merck & Co., Inc. (Employee, Shareholder) Francesco Bellanti, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Li Qin, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Han Witjes, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Philippe Pierrillas, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Radha Railkar, PhD, Merck & Co., Inc. (Employee, Shareholder) Antonios O. Aliprantis, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) Kalpit A. Vora, PhD, Merck & Co., Inc. (Employee, Shareholder) Wei Gao, PhD, Merck & Co., Inc. (Employee, Shareholder) Luzelena Caro, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

Factors associated with severe respiratory syncytial virus disease in hospitalised children: a retrospective analysis

2021 ◽  
pp. archdischild-2021-322435
Author(s):  
Jeremy Anderson ◽  
Michelle Oeum ◽  
Eva Verkolf ◽  
Paul V Licciardi ◽  
Kim Mulholland ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Lower Respiratory Tract ◽  
Severe Disease ◽  
Severe Respiratory Syncytial Virus ◽  
Factors Associated ◽  
Rsv Infection ◽  
Syncytial Virus

BackgroundEarly recognition of children at risk of severe respiratory syncytial virus (RSV) lower respiratory tract infection is important as it informs management decisions. We aimed to evaluate factors associated with severe disease among young children hospitalised with RSV infection.MethodsWe conducted a retrospective cohort study of all children <2 years of age hospitalised for RSV lower respiratory tract infection at a single tertiary paediatric hospital over three RSV seasons (January 2017–December 2019). We classified children as having ‘moderate’ or ‘severe’ disease based on the level of respiratory intervention and used univariable and multivariable regression models to determine factors associated with severe disease.ResultsOf 970 hospitalised children, 386 (40%) were classified as having ‘severe’ and 584 (60%) as having ‘moderate’ RSV disease. On multivariable analyses, age <2 months (OR: 2.3, 95% CI 1.6 to 3.3, p<0.0001), prematurity (OR: 1.6, 95% CI 1.1 to 2.4, p=0.02) and RSV–parainfluenza virus type 3 (PIV3) codetection (OR: 2.6, 95% CI 1.05 to 6.5, p=0.04) were independently associated with severe disease.ConclusionYounger age, prematurity and PIV3 codetection were associated with severe RSV disease in children <2 years of age hospitalised with RSV infection. The association between PIV3 and severe RSV disease is a novel finding and warrants further investigation.

scholarly journals Gene Expression of Nucleic Acid-Sensing Pattern Recognition Receptors in Children Hospitalized for Respiratory Syncytial Virus-Associated Acute Bronchiolitis

2009 ◽  
Vol 16 (6) ◽  
pp. 816-823 ◽  
Author(s):  
Carolina Scagnolari ◽  
Fabio Midulla ◽  
Alessandra Pierangeli ◽  
Corrado Moretti ◽  
Enea Bonci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pattern Recognition ◽  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Pattern Recognition Receptors ◽  
Mrna Levels ◽  
Acute Bronchiolitis ◽  
Expression Levels ◽  
Rsv Infection ◽  
Syncytial Virus

ABSTRACT Given the critical role of pattern recognition receptors (PRRs) in acid nucleic recognition in the initiation of innate immunity and the orchestration of adaptive immunity, the aim of this study was to determine whether any heterogeneity of PRR expression in the airway tracts of infants with respiratory syncytial virus (RSV) infection might explain the broad clinical spectrum of RSV-associated bronchiolitis in infants. For this purpose, the levels of melanoma differentiation-associated protein-5 (MDA-5), retinoic acid inducible gene-1 (RIG-1), and Toll-like receptor 3 (TLR-3), TLR-7, TLR-8, and TLR-9 mRNAs were evaluated, using TaqMan quantitative reverse transcription-PCR, in cells from nasopharyngeal washes collected from 157 infants suffering from acute bronchiolitis whether or not they were associated with respiratory viruses. High interindividual variability was observed in both virus-positive and -negative infants; however, the relative gene expression levels of MDA-5, RIG-1, TLR-7, and TLR-8 were significantly higher in the virus-infected group, whereas the expression levels of TLR-3 and TLR-9 were not significantly different. The differences in the gene expression of MDA-5, RIG-1, TLR-7, and TLR-8 were more evident in infants with RSV infection than in those with bocavirus or rhinovirus infection. In RSV-infected infants, PRR-mRNA levels also were analyzed in relation to interferon protein levels, viral load, clinical severity, days of hospitalization, age, and body weight. A significant positive correlation was observed only between RSV viral load and RIG-1 mRNA levels. These findings provide the first direct evidence that, in infants with respiratory virus-associated bronchiolitis, especially RSV, there are substantial changes in PRR gene expression; this likely is an important determinant of the clinical outcome of bronchiolitis.

Reappraisal of respiratory syncytial virus as an aetiology of severe acute lower respiratory tract infections in children younger than 5 years in Nigeria

2019 ◽  
Vol 113 (8) ◽  
pp. 446-452
Author(s):  
Damilola M Oladele ◽  
Dimeji P Oladele ◽  
Rasheedat M Ibraheem ◽  
Mohammed B Abdulkadir ◽  
Rasaki Adewole Raheem ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Lower Respiratory Tract ◽  
Respiratory Tract Infections ◽  
Preventive Strategy ◽  
Lower Respiratory Tract Infections ◽  
Cross Sectional ◽  
Rsv Infection ◽  
Syncytial Virus ◽  
Tract Infections

Abstract Background Acute lower respiratory tract infections (ALRIs) especially severe ALRIs, constitute a global high burden of morbidity and mortality in children <5 y of age and respiratory syncytial virus (RSV) has been documented to a play a major aetiological role. However, Nigerian reports on severe childhood RSV ALRIs are rare and most reports are old. With recent advances in RSV preventive strategy, arises the need for a recent appraisal of RSV infection in children with severe ALRI. The current study thus set out to determine the prevalence of RSV infection among hospitalized children <5 y of age and describe the related social determinants. Methods We performed a descriptive cross-sectional study conducted over 1 y of 120 children, ages 2–59 months, diagnosed with ALRI. Relevant data were obtained and an antigen detection assay was used for viral studies. Results The prevalence of RSV infection was 34.2% and its peak was in the rainy months. The proportion of infants in the RSV-positive group was significantly higher than that in the RSV-negative group (82.9% vs 54.4%; p=0.002). These findings were largely consistent with those of earlier reports. Conclusions RSV has remained a common cause of severe ALRI in infants, especially during the rainy months in Nigeria. It is thus suggested that more effort be focused towards implementing the current global recommendations for the prevention of RSV-associated LRI, particularly in infants.

scholarly journals 667. Preclinical Pharmacokinetic and Pharmacodynamic Characterization of EDP-938, a Novel and Potent NonFusion Replication Inhibitor of Respiratory Syncytial Virus

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S305-S306
Author(s):  
Li-Juan Jiang ◽  
Lisha Xu ◽  
Meng Huang ◽  
Shucha Zhang ◽  
Yang Li ◽  
...  
Keyword(s):  
Viral Load ◽  
Respiratory Syncytial Virus ◽  
Post Infection ◽  
Human Liver ◽  
Liver Microsomes ◽  
Monkey Model ◽  
Green Monkey ◽  
Rsv Infection ◽  
Syncytial Virus

Abstract Background Respiratory syncytial virus (RSV) infection presents a significant health challenge in young children, elderly and immunocompromised patients. To date, there are no effective treatments available. EDP-938 was designed to meet this unmet medical need and is currently in Phase 2 clinical trials. Herein we report its preclinical pharmacokinetic (PK) and pharmacodynamic (PD) properties. Methods The pharmacokinetics of EDP-938 following single intravenous and oral doses were determined in mice, rats, dogs, and monkeys. In vitro cellular permeability and metabolic stability were assayed using Caco-2 cells and human liver microsomes, respectively. In vivo pharmacodynamic efficacy of EDP-938 was conducted in the African green monkey model, in which animals experimentally challenged with RSV were orally dosed twice daily with 100 mg/kg EDP-938 for 6 days starting 24 hours prior to infection. Results EDP-938 was well absorbed in the preclinical species with oral bioavailability values ranging from 27.1% in dogs, 35.4% in mice, 35.7% in rats, and 39.5% in monkeys, after a single oral dose when formulated in 0.5% methylcellulose. EDP-938 showed a moderate in vitro permeability of 3.6 x 10–6 cm/sec in Caco-2 cells. Based on the outcome of these absorption studies, EDP-938 was projected to have good oral absorption in humans. EDP-938 had low intrinsic clearance of 5 mL/minute/mg in human liver microsomes. Moreover, EDP-938 demonstrated potent antiviral efficacy in an African green monkey model of RSV infection. In untreated monkeys the RSV RNA viral load in the bronchoalveolar lavage fluid peaked at 106 copies/mL on day 5 post-infection, by comparison in animals treated with EDP-938 the viral load was below the limit of detection by day 3 post-infection. The PK/PD modeling suggested that plasma trough concentrations ≥10 × EC90 led to &gt;4-log viral load reduction in EDP-938 treated monkeys. Conclusion The favorable preclinical PK and PD properties of EDP-938 support its further clinical development as a novel treatment for RSV infection. Disclosures All authors: No reported disclosures.

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