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The Lancet. Child & Adolescent Health Mar 2023In a phase 2b trial and the phase 3 MELODY trial, nirsevimab, an extended half-life, monoclonal antibody against respiratory syncytial virus (RSV), protected healthy... (Meta-Analysis)
Meta-Analysis
Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials.
BACKGROUND
In a phase 2b trial and the phase 3 MELODY trial, nirsevimab, an extended half-life, monoclonal antibody against respiratory syncytial virus (RSV), protected healthy infants born preterm or at full term against medically attended RSV lower respiratory tract infection (LRTI). In the MEDLEY phase 2-3 trial in infants at higher risk for severe RSV infection, nirsevimab showed a similar safety profile to that of palivizumab. The aim of the current analysis was to assess the efficacy of nirsevimab using a weight-banded dosing regimen in infants born between 29 weeks gestational age and full term.
METHODS
Infants enrolled in the phase 2b and MELODY trials were randomised (2:1) to receive a single intramuscular injection of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) or placebo before the RSV season. Infants in MEDLEY were randomised (2:1) to receive one dose of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) followed by four monthly placebo doses, or five once-a-month intramuscular doses of palivizumab. We report a prespecified pooled efficacy analysis assessing the weight-banded dosing regimen proposed on the basis of the phase 2b and MELODY trials, in addition to extrapolated efficacy in infants with chronic lung disease, congenital heart disease, or extreme preterm birth (<29 weeks' gestational age) based on pharmacokinetic data from the phase 2-3 MEDLEY safety trial. For the pooled efficacy analysis, the primary endpoint was incidence of medically attended RSV LRTI through 150 days post-dose. The secondary efficacy endpoint was number of admissions to hospital for medically attended RSV LRTI. The incidence of very severe RSV LRTI was an exploratory endpoint, defined as cases of hospital admission for medically attended RSV LRTI that required supplemental oxygen or intravenous fluids. We also did a prespecified exploratory analysis of medically attended LRTI of any cause (in the investigator's judgement) and hospital admission for respiratory illness of any cause (defined as any upper respiratory tract infection or LRTI leading to hospital admission). Post hoc exploratory analyses of outpatient visits and antibiotic use were also done. Nirsevimab serum concentrations in MEDLEY were assessed using population pharmacokinetic methods and the pooled data from the phase 2b and MELODY trials. An exposure target was defined on the basis of an exposure-response analysis. To successfully demonstrate extrapolation, more than 80% of infants in MEDLEY had to achieve serum nirsevimab exposures at or above the predicted efficacious target.
FINDINGS
Overall, 2350 infants (1564 in the nirsevimab group and 786 in the placebo group) in the phase 2b and MELODY trials were included in the pooled analysis. Nirsevimab showed efficacy versus placebo with respect to the primary endpoint of medically attended RSV LRTI (19 [1%] nirsevimab recipients vs 51 [6%] placebo recipients; relative risk reduction [RRR] 79·5% [95% CI 65·9-87·7]). Consistent efficacy was shown for additional endpoints of RSV LRTI hospital admission (nine [1%] nirsevimab recipients vs 21 [3%] placebo recipients; 77·3% [50·3-89·7]) and very severe RSV (five [<1%] vs 18 [2%]; 86·0% [62·5-94·8]). Nirsevimab recipients had fewer hospital admissions for any-cause respiratory illness (RRR 43·8% [18·8-61·1]), any-cause medically attended LRTI (35·4% [21·5-46·9]), LRTI outpatient visits (41·9% [25·7-54·6]), and antibiotic prescriptions (23·6% [3·8-39·3]). Among infants with chronic lung disease, congenital heart disease, or extreme preterm birth in MEDLEY, nirsevimab serum exposures were similar to those found in the pooled data; exposures were above the target in more than 80% of the overall MEDLEY trial population (94%), including infants with chronic lung disease (94%) or congenital heart disease (80%) and those born extremely preterm (94%).
INTERPRETATION
A single dose of nirsevimab protected healthy infants born at term or preterm from medically attended RSV LRTI, associated hospital admission, and severe RSV. Pharmacokinetic data support efficacy extrapolation to infants with chronic lung disease, congenital heart disease, or extreme prematurity. Together, these data suggest that nirsevimab has the potential to change the landscape of infant RSV disease by reducing a major cause of infant morbidity and the consequent burden on caregivers, clinicians, and health-care providers.
FUNDING
AstraZeneca and Sanofi.
Topics: Female; Infant; Infant, Newborn; Humans; Palivizumab; Premature Birth; Antiviral Agents; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Respiratory Tract Infections; Heart Defects, Congenital; Lung Diseases; Randomized Controlled Trials as Topic
PubMed: 36634694
DOI: 10.1016/S2352-4642(22)00321-2 -
Frontiers in Immunology 2022Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of... (Review)
Review
Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of outpatient visits, which result in a huge economic and healthcare burden. Most hospitalizations happen in otherwise healthy infants, highlighting the need to protect all infants against RSV. Moreover, there is evidence on the association between early-life RSV respiratory illness and recurrent wheezing/asthma-like symptoms As such, RSV is considered a global health priority. However, despite this, the only prevention strategy currently available is palivizumab, a monoclonal antibody (mAb) indicated in a subset of preterm infants or those with comorbidities, hence leaving the majority of the infant population unprotected against this virus. Therefore, development of prevention strategies against RSV for all infants entering their first RSV season constitutes a large unmet medical need. The aim of this review is to explore different immunization approaches to protect all infants against RSV. Prevention strategies include maternal immunization, immunization of infants with vaccines, immunization of infants with licensed mAbs (palivizumab), and immunization of infants with long-acting mAbs (e.g., nirsevimab, MK-1654). Of these, palivizumab use is restricted to a small population of infants and does not offer a solution for all-infant protection, whereas vaccine development in infants has encountered various challenges, including the immaturity of the infant immune system, highlighting that future pediatric vaccines will most likely be used in older infants (>6 months of age) and children. Consequently, maternal immunization and immunization of infants with long-acting mAbs represent the two feasible strategies for protection of all infants against RSV. Here, we present considerations regarding these two strategies covering key areas which include mechanism of action, "consistency" of protection, RSV variability, duration of protection, flexibility and optimal timing of immunization, benefit for the mother, programmatic implementation, and acceptance of each strategy by key stakeholders. We conclude that, based on current data, immunization of infants with long-acting mAbs might represent the most effective approach for protecting all infants entering their first RSV season.
Topics: Aged; Antibodies, Monoclonal; Antiviral Agents; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Palivizumab; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 35572550
DOI: 10.3389/fimmu.2022.880368 -
American Family Physician Jan 2017Bronchiolitis is a common lower respiratory tract infection in infants and young children, and respiratory syncytial virus (RSV) is the most common cause of this... (Review)
Review
Bronchiolitis is a common lower respiratory tract infection in infants and young children, and respiratory syncytial virus (RSV) is the most common cause of this infection. RSV is transmitted through contact with respiratory droplets either directly from an infected person or self-inoculation by contaminated secretions on surfaces. Patients with RSV bronchiolitis usually present with two to four days of upper respiratory tract symptoms such as fever, rhinorrhea, and congestion, followed by lower respiratory tract symptoms such as increasing cough, wheezing, and increased respiratory effort. In 2014, the American Academy of Pediatrics updated its clinical practice guideline for diagnosis and management of RSV bronchiolitis to minimize unnecessary diagnostic testing and interventions. Bronchiolitis remains a clinical diagnosis, and diagnostic testing is not routinely recommended. Treatment of RSV infection is mainly supportive, and modalities such as bronchodilators, epinephrine, corticosteroids, hypertonic saline, and antibiotics are generally not useful. Evidence supports using supplemental oxygen to maintain adequate oxygen saturation; however, continuous pulse oximetry is no longer required. The other mainstay of therapy is intravenous or nasogastric administration of fluids for infants who cannot maintain their hydration status with oral fluid intake. Educating parents on reducing the risk of infection is one of the most important things a physician can do to help prevent RSV infection, especially early in life. Children at risk of severe lower respiratory tract infection should receive immunoprophylaxis with palivizumab, a humanized monoclonal antibody, in up to five monthly doses. Prophylaxis guidelines are restricted to infants born before 29 weeks' gestation, infants with chronic lung disease of prematurity, and infants and children with hemodynamically significant heart disease.
Topics: Antiviral Agents; Bronchiolitis, Viral; Child, Preschool; Humans; Infant; Palivizumab; Practice Guidelines as Topic; Respiratory Syncytial Virus Infections; Risk Factors
PubMed: 28084708
DOI: No ID Found -
The New England Journal of Medicine Mar 2022
Randomized Controlled Trial
Topics: Antibodies, Monoclonal, Humanized; Antiviral Agents; Chronic Disease; Heart Diseases; Humans; Infant; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Injections, Intramuscular; Lung Diseases; Palivizumab; Respiratory Syncytial Virus Infections
PubMed: 35235733
DOI: 10.1056/NEJMc2112186 -
Infectious Diseases and Therapy Mar 2021Respiratory syncytial virus (RSV) disease is a significant cause of morbidity and socioeconomic burden worldwide among young children. The majority of RSV-associated... (Review)
Review
Respiratory syncytial virus (RSV) disease is a significant cause of morbidity and socioeconomic burden worldwide among young children. The majority of RSV-associated lower respiratory tract infections (LRTI) and mortality occurs in developing countries and is associated with various sociodemographic risk factors. Independent risk factors for severe RSV disease include age and premature birth. While RSV mortality in developed countries is lower relative to developing countries, high-risk infants with comorbidities experience higher rates of mortality. RSV LRTI is often severe and is associated with hospitalization, increased need for intensive care unit admission and mechanical ventilation, long-term complications, and caregiver stress and loss of work productivity. Overall, these factors translate to higher health care resource utilization and costs and should be factored into the consideration for RSV prophylaxis. Multiple vaccine candidates and long-acting monoclonal antibodies are in various stages of clinical development. Currently, palivizumab is the only approved RSV immunoprophylaxis available for use in specific high-risk pediatric populations. This review will discuss the socioeconomic impact and health care resource utilization of RSV-related hospitalization (RSVH) as well as various sociodemographic risk factors that can be used to identify children at high risk of developing severe RSV disease.
PubMed: 33656651
DOI: 10.1007/s40121-020-00390-7 -
The Cochrane Database of Systematic... Nov 2021Respiratory viruses are the leading cause of lower respiratory tract infection (LRTI) and hospitalisation in infants and young children. Respiratory syncytial virus... (Review)
Review
BACKGROUND
Respiratory viruses are the leading cause of lower respiratory tract infection (LRTI) and hospitalisation in infants and young children. Respiratory syncytial virus (RSV) is the main infectious agent in this population. Palivizumab is administered intramuscularly every month during five months in the first RSV season to prevent serious RSV LRTI in children. Given its high cost, it is essential to know if palivizumab continues to be effective in preventing severe RSV disease in children.
OBJECTIVES
To assess the effects of palivizumab for preventing severe RSV infection in children.
SEARCH METHODS
We searched CENTRAL, MEDLINE, three other databases and two trials registers to 14 October 2021, together with reference checking, citation searching and contact with study authors to identify additional studies. We searched Embase to October 2020, as we did not have access to this database for 2021.
SELECTION CRITERIA
We included randomised controlled trials (RCTs), including cluster-RCTs, comparing palivizumab given at a dose of 15 mg/kg once a month (maximum five doses) with placebo, no intervention or standard care in children 0 to 24 months of age from both genders, regardless of RSV infection history. DATA COLLECTION AND ANALYSIS: We used Cochrane's Screen4Me workflow to help assess the search results. Two review authors screened studies for selection, assessed risk of bias and extracted data. We used standard Cochrane methods. We used GRADE to assess the certainty of the evidence. The primary outcomes were hospitalisation due to RSV infection, all-cause mortality and adverse events. Secondary outcomes were hospitalisation due to respiratory-related illness, length of hospital stay, RSV infection, number of wheezing days, days of supplemental oxygen, intensive care unit length of stay and mechanical ventilation days.
MAIN RESULTS
We included five studies with a total of 3343 participants. All studies were parallel RCTs, assessing the effects of 15 mg/kg of palivizumab every month up to five months compared to placebo or no intervention in an outpatient setting, although one study also included hospitalised infants. Most of the included studies were conducted in children with a high risk of RSV infection due to comorbidities like bronchopulmonary dysplasia and congenital heart disease. The risk of bias of outcomes across all studies was similar and predominately low. Palivizumab reduces hospitalisation due to RSV infection at two years' follow-up (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.30 to 0.64; 5 studies, 3343 participants; high certainty evidence). Based on 98 hospitalisations per 1000 participants in the placebo group, this corresponds to 43 (29 to 62) per 1000 participants in the palivizumab group. Palivizumab probably results in little to no difference in mortality at two years' follow-up (RR 0.69, 95% CI 0.42 to 1.15; 5 studies, 3343 participants; moderate certainty evidence). Based on 23 deaths per 1000 participants in the placebo group, this corresponds to 16 (10 to 27) per 1000 participants in the palivizumab group. Palivizumab probably results in little to no difference in adverse events at 150 days' follow-up (RR 1.09, 95% CI 0.85 to 1.39; 3 studies, 2831 participants; moderate certainty evidence). Based on 84 cases per 1000 participants in the placebo group, this corresponds to 91 (71 to 117) per 1000 participants in the palivizumab group. Palivizumab probably results in a slight reduction in hospitalisation due to respiratory-related illness at two years' follow-up (RR 0.78, 95% CI 0.62 to 0.97; 5 studies, 3343 participants; moderate certainty evidence). Palivizumab may result in a large reduction in RSV infection at two years' follow-up (RR 0.33, 95% CI 0.20 to 0.55; 3 studies, 554 participants; low certainty evidence). Based on 195 cases of RSV infection per 1000 participants in the placebo group, this corresponds to 64 (39 to 107) per 1000 participants in the palivizumab group. Palivizumab also reduces the number of wheezing days at one year's follow-up (RR 0.39, 95% CI 0.35 to 0.44; 1 study, 429 participants; high certainty evidence).
AUTHORS' CONCLUSIONS
The available evidence suggests that prophylaxis with palivizumab reduces hospitalisation due to RSV infection and results in little to no difference in mortality or adverse events. Moreover, palivizumab results in a slight reduction in hospitalisation due to respiratory-related illness and may result in a large reduction in RSV infections. Palivizumab also reduces the number of wheezing days. These results may be applicable to children with a high risk of RSV infection due to comorbidities. Further research is needed to establish the effect of palivizumab on children with other comorbidities known as risk factors for severe RSV disease (e.g. immune deficiencies) and other social determinants of the disease, including children living in low- and middle-income countries, tropical regions, children lacking breastfeeding, living in poverty, or members of families in overcrowded situations.
Topics: Child; Child, Preschool; Hospitalization; Humans; Infant; Infant, Newborn; Length of Stay; Palivizumab; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses
PubMed: 34783356
DOI: 10.1002/14651858.CD013757.pub2 -
The New England Journal of Medicine Apr 2023
Topics: Humans; Infant; Infant, Newborn; Antibodies, Monoclonal, Humanized; Antiviral Agents; Hospitalization; Infant, Premature; Palivizumab; Respiratory Syncytial Virus Infections; Term Birth; Infant, Newborn, Diseases
PubMed: 37018470
DOI: 10.1056/NEJMc2214773 -
JAMA Network Open Feb 2023Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection in children younger than 5 years; effective prevention strategies are... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infection in children younger than 5 years; effective prevention strategies are urgently needed.
OBJECTIVE
To compare the efficacy and safety of monoclonal antibodies for the prevention of RSV infection in infants and children.
DATA SOURCES
In this systematic review and network meta-analysis, PubMed, Embase, CENTRAL, and ClinicalTrials.gov were searched from database inception to March 2022.
STUDY SELECTION
Randomized clinical trials that enrolled infants at high risk of RSV infection to receive a monoclonal antibody or placebo were included. Keywords and extensive vocabulary related to monoclonal antibodies, RSV, and randomized clinical trials were searched.
DATA EXTRACTION AND SYNTHESIS
The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was used. Teams of 2 reviewers independently performed literature screening, data extraction, and risk of bias assessment. The Grading of Recommendations, Assessments, Developments, and Evaluation approach was used to rate the certainty of evidence. A random-effects model network meta-analysis was conducted using a consistency model under the frequentist framework.
MAIN OUTCOMES AND MEASURES
The main outcomes were all-cause mortality, RSV-related hospitalization, RSV-related infection, drug-related adverse events, intensive care unit admission, supplemental oxygen use, and mechanical ventilation use.
RESULTS
Fifteen randomized clinical trials involving 18 395 participants were eligible; 14 were synthesized, with 18 042 total participants (median age at study entry, 3.99 months [IQR, 3.25-6.58 months]; median proportion of males, 52.37% [IQR, 50.49%-53.85%]). Compared with placebo, with moderate- to high-certainty evidence, nirsevimab, palivizumab, and motavizumab were associated with significantly reduced RSV-related infections per 1000 participants (nirsevimab: -123 [95% CI, -138 to -100]; palivizumab: -108 [95% CI, -127 to -82]; motavizumab: -136 [95% CI, -146 to -125]) and RSV-related hospitalizations per 1000 participants (nirsevimab: -54 [95% CI, -64 to -38; palivizumab: -39 [95% CI, -48 to -28]; motavizumab: -48 [95% CI, -58 to -33]). With moderate-certainty evidence, both motavizumab and palivizumab were associated with significant reductions in intensive care unit admissions per 1000 participants (-8 [95% CI, -9 to -4] and -5 [95% CI, -7 to 0], respectively) and supplemental oxygen use per 1000 participants (-59 [95% CI, -63 to -54] and -55 [95% CI, -61 to -41], respectively), and nirsevimab was associated with significantly reduced supplemental oxygen use per 1000 participants (-59 [95% CI, -65 to -40]). No significant differences were found in all-cause mortality and drug-related adverse events. Suptavumab did not show any significant benefits for the outcomes of interest.
CONCLUSIONS AND RELEVANCE
In this study, motavizumab, nirsevimab, and palivizumab were associated with substantial benefits in the prevention of RSV infection, without a significant increase in adverse events compared with placebo. However, more research is needed to confirm the present conclusions, especially for safety and cost-effectiveness.
Topics: Male; Infant; Child; Humans; Antibodies, Monoclonal; Palivizumab; Respiratory Syncytial Viruses; Network Meta-Analysis; Respiratory Syncytial Virus Infections; Respiratory Tract Infections; Oxygen; Randomized Controlled Trials as Topic
PubMed: 36800182
DOI: 10.1001/jamanetworkopen.2023.0023 -
American Family Physician Jul 2023Bronchiolitis is the most common lower respiratory tract infection in young children. Respiratory syncytial virus (RSV) is the most common viral cause of bronchiolitis.... (Review)
Review
Bronchiolitis is the most common lower respiratory tract infection in young children. Respiratory syncytial virus (RSV) is the most common viral cause of bronchiolitis. RSV is spread through respiratory droplets, and the number of cases varies with season. For most patients, standard precautions (e.g., hand hygiene, surface cleaning, avoiding contact with sick individuals) are recommended. However, prophylaxis with palivizumab may be considered for infants at high risk. Initial symptoms occur after an incubation period of four to six days and include rhinorrhea, congestion, sneezing, and fever. Signs of lower respiratory tract involvement may follow and include cough, tachypnea, retractions, difficulty feeding, and accessory muscle use. Diagnosis is typically clinical; routine use of radiography or viral testing is not recommended. Treatment of RSV bronchiolitis is mainly supportive. Oxygen saturation should be maintained above 90%. Hydration and nutrition should be maintained by nasogastric or intravenous routes, if needed. Therapies such as bronchodilators, epinephrine, nebulized hypertonic saline, corticosteroids, antibiotics, and chest physiotherapy are not recommended. Although most episodes of RSV bronchiolitis are self-limited, some children have an increased risk of asthma later in life.
Topics: Child; Child, Preschool; Humans; Infant; Bronchiolitis; Bronchodilator Agents; Palivizumab; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses
PubMed: 37440737
DOI: No ID Found -
Early Human Development Nov 2022Respiratory Syncytial Virus (RSV) is the main cause of lower respiratory tract infections (LRTIs) in newborns in the first two years of life. RSV disease has a... (Review)
Review
Respiratory Syncytial Virus (RSV) is the main cause of lower respiratory tract infections (LRTIs) in newborns in the first two years of life. RSV disease has a traditional seasonal trend, with an onset and offset, duration and peak. Prematurity, male gender, bronchopulmonary dysplasia (BPD), critical congenital cardiovascular disorders (CCHD), neuromuscular diseases, congenital and inherited airways anatomical anomalies are the main risk factors for increased severity of this infection. RSV infection is associated with negative long-term respiratory outcomes, with excess of morbidity, resulting in reduced quality of life of the infected children and representing a burden for the healthcare costs and resources. Despite all the efforts, prevention remains, to date, the most effective strategy to reduce RSV-related morbidity. Among the current prevention strategies, strict hygiene, breastfeeding and passive immunization with the monoclonal antibody Palivizumab are the cornerstone. In the next future, it is likely that new possibilities of prevention will add, including use of more potent and longer-acting monoclonal antibodies, implementation of maternal vaccination in pregnancy, and active immunization in children. The purpose of this review is to provide an overview of the main current and future prevention strategies against RSV.
Topics: Child; Pregnancy; Female; Infant, Newborn; Male; Humans; Infant; Respiratory Syncytial Viruses; Quality of Life; Palivizumab; Respiratory Syncytial Virus Infections; Immunization, Passive; Antibodies, Monoclonal
PubMed: 36174288
DOI: 10.1016/j.earlhumdev.2022.105666