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The Journal of Biological Chemistry Nov 2023Synthetic cytokine receptors can modulate cellular functions based on an artificial ligand to avoid off-target and/or unspecific effects. However, ligands that can...
Synthetic cytokine receptors can modulate cellular functions based on an artificial ligand to avoid off-target and/or unspecific effects. However, ligands that can modulate receptor activity so far have not been used clinically because of unknown toxicity and immunity against the ligands. Here, we developed a fully synthetic cytokine/cytokine receptor pair based on the antigen-binding domain of the respiratory syncytial virus-approved mAb Palivizumab as a synthetic cytokine and a set of anti-idiotype nanobodies (AIP) as synthetic receptors. Importantly, Palivizumab is neither cross-reactive with human proteins nor immunogenic. For the synthetic receptors, AIP were fused to the activating interleukin-6 cytokine receptor gp130 and the apoptosis-inducing receptor Fas. We found that the synthetic cytokine receptor AIPgp130 was efficiently activated by dimeric Palivizumab single-chain variable fragments. In summary, we created an in vitro nonimmunogenic full-synthetic cytokine/cytokine receptor pair as a proof of concept for future in vivo therapeutic strategies utilizing nonphysiological targets during immunotherapy.
Topics: Humans; Palivizumab; Receptors, Artificial; Receptors, Cytokine; Cytokines; Respiratory Syncytial Virus Infections; Ligands; Respiratory Syncytial Virus, Human; Antiviral Agents
PubMed: 37734558
DOI: 10.1016/j.jbc.2023.105270 -
Drug, Healthcare and Patient Safety 2023Respiratory Syncytial Virus (RSV) is a major global cause of childhood morbidity and mortality. Palivizumab, a monoclonal antibody that provides passive immunity against... (Review)
Review
Respiratory Syncytial Virus (RSV) is a major global cause of childhood morbidity and mortality. Palivizumab, a monoclonal antibody that provides passive immunity against RSV, is currently licensed for prophylactic use in specific "high-risk" populations, including congenital heart disease, bronchopulmonary dysplasia and prematurity. Available research suggests palivizumab use in these high-risk populations can lead to a reduction in RSV-related hospitalization. However, palivizumab has not been demonstrated to reduce mortality, adverse events or length of hospital stay related to RSV. In this article, we review the management of RSV, indications for palivizumab prophylaxis, the safety, cost-effectiveness and efficacy of this preventative medication, and emerging therapeutics that could revolutionize future prevention of this significant pathogen.
PubMed: 37720805
DOI: 10.2147/DHPS.S348727 -
PloS One 2023Since the last Italian cost-utility assessment of palivizumab in 2009, new data on the burden of respiratory syncytial virus (RSV) and an International Risk Scoring Tool...
A new cost-utility analysis assessing risk factor-guided prophylaxis with palivizumab for the prevention of severe respiratory syncytial virus infection in Italian infants born at 29-35 weeks' gestational age.
Since the last Italian cost-utility assessment of palivizumab in 2009, new data on the burden of respiratory syncytial virus (RSV) and an International Risk Scoring Tool (IRST) have become available. The objective of this study was to provide an up-to-date cost-utility assessment of palivizumab versus no prophylaxis for the prevention of severe RSV infection in otherwise healthy Italian infants born at 29-31 weeks' gestational age (wGA) infants and those 32-35wGA infants categorized as either moderate- or high-risk of RSV-hospitalization (RSVH) by the IRST. A decision tree was constructed in which infants received palivizumab or no prophylaxis and then could experience: i) RSVH; ii) emergency room medically-attended RSV-infection (MARI); or, iii) remain uninfected/non-medically attended. RSVH cases that required intensive care unit admission could die (0.43%). Respiratory morbidity was considered in all surviving infants up to 18 years of age. Hospitalization rates were derived from Italian data combined with efficacy from the IMpact-RSV trial. Palivizumab costs were calculated from vial prices (50mg: €490.37 100mg: €814.34) and Italian birth statistics combined with a growth algorithm. A lifetime horizon and healthcare and societal costs were included. The incremental cost-utility ratio (ICUR) was €14814 per quality-adjusted life year (QALY) gained in the whole population (mean: €15430; probability of ICUR being <€40000: 0.90). The equivalent ICURs were €15139 per QALY gained (€15915; 0.89) for 29-31wGA infants and €14719 per QALY gained (€15230; 0.89) for 32-35wGA infants. The model was most sensitive to rates of long-term sequelae, utility scores, palivizumab cost, and palivizumab efficacy. Palivizumab remained cost-effective in all scenario analyses, including a scenario wherein RSVH infants received palivizumab without a reduction in long-term sequelae and experienced a 6-year duration of respiratory morbidity (ICUR: €27948 per QALY gained). In conclusion, palivizumab remains cost-effective versus no prophylaxis in otherwise healthy Italian preterm infants born 29-35wGA. The IRST can help guide cost-effective use of palivizumab in 32-35wGA infants.
Topics: Infant, Newborn; Infant; Humans; Palivizumab; Respiratory Syncytial Virus Infections; Cost-Benefit Analysis; Gestational Age; Antiviral Agents; Infant, Premature; Antibodies, Monoclonal, Humanized; Risk Factors; Respiratory Syncytial Virus, Human; Hospitalization; Italy
PubMed: 37561741
DOI: 10.1371/journal.pone.0289828 -
The Lancet Regional Health. Western... Oct 2023Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV...
Safety, efficacy and pharmacokinetics of palivizumab in off-label neonates, infants, and young children at risk for serious respiratory syncytial virus infection: a multicenter phase II clinical trial.
BACKGROUND
Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV antibody (palivizumab) in these patients is not indicated at present in Japan.
METHODS
This first-in-the-world multicenter, uncontrolled, open-label, phase II clinical trial was carried out between 28 July 2019 and 24 September 2021 at seven medical institutions in Japan to investigate the efficacy, safety, and pharmacokinetics of palivizumab in 23 subjects recruited from among neonates, infants, or children aged 24 months or younger who had any of the following conditions: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. At least four continuous doses of palivizumab were administered intramuscularly at 15 mg/kg at intervals of 30 days.
FINDINGS
Twenty-three enrolled subjects completed the study. No subject required hospitalization for RSV. Adverse events (AE) did not notably differ from the event terms described in the latest interview form. Five severe AEs required unplanned hospitalization, but resolved without RSV infection. Therapeutically effective concentrations of palivizumab were maintained throughout the study period.
INTERPRETATION
Palivizumab might be well tolerated and effective in preventing serious respiratory symptoms and hospitalization due to severe RSV infection, indicating the prophylactic use in the pediatric patients included in this study.
FUNDING
Japan Agency for Medical Research and Development (AMED), grant numbers 19lk0201097h0001 (to MM), 20lk0201097h0002 (to MM), 21lk0201097h0003 (to MM), and 22lk0201097h0004 (to MM). AMED did not have any role in the execution of this study, analysis and interpretation of the data, or the decision to submit the results.
PubMed: 37554997
DOI: 10.1016/j.lanwpc.2023.100847 -
Journal of the Pediatric Infectious... Aug 2023In children with congenital heart disease and/or chronic lung disease entering their second respiratory syncytial virus (RSV) season, 200 mg nirsevimab had a similar...
In children with congenital heart disease and/or chronic lung disease entering their second respiratory syncytial virus (RSV) season, 200 mg nirsevimab had a similar safety profile to that of palivizumab and resulted in nirsevimab serum exposures associated with efficacy in healthy infants, supporting efficacy in this population at risk of severe RSV disease.
Topics: Infant; Child; Humans; Antibodies, Monoclonal; Antiviral Agents; Seasons; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human; Lung Diseases
PubMed: 37466917
DOI: 10.1093/jpids/piad052 -
American Journal of Perinatology May 2024Palivizumab is a humanized monoclonal antibody approved for the prevention of serious lower respiratory tract infection (LRTI) caused by respiratory syncytial virus...
OBJECTIVE
Palivizumab is a humanized monoclonal antibody approved for the prevention of serious lower respiratory tract infection (LRTI) caused by respiratory syncytial virus (RSV) in infants and young children at high risk of RSV disease. This systematic review summarized evidence on the effectiveness and safety of palivizumab when used in approved populations.
STUDY DESIGN
A systematic review of Phase III trials and observational studies was conducted according to the population, intervention, comparator, outcome, timing, setting (PICOTS) approach (PROSPERO, CRD42021281380). Target populations consisted of infants with a history of premature birth (≤35-week gestational age) and children aged <2 years with bronchopulmonary dysplasia (BPD) or with hemodynamically significant congenital heart disease (hs-CHD). Outcomes of interest included RSV-related hospitalization, admission to intensive care unit (ICU), requirement for mechanical ventilation, treatment-related adverse events (AEs), and RSV-related deaths. Information sources were literature search (Ovid MEDLINE and Embase), pragmatic searches, and snowballing (covering the period up to 07 September 2021).
RESULTS
A total of 60 sources were included (5 Phase III trials and 55 observational studies). RSV-related hospitalization rates following palivizumab prophylaxis in Phase III trials were 1.8% in premature infants and 7.9% in children with BPD, which were significantly lower than rates in placebo arms. In the real-world setting, similar hospitalization rates were found (0.7-4.0% in premature infants [16 studies] and 0-5.5% in patients with BPD [10 studies]) with ICU admission reported in 0 to 33.3% of patients hospitalized for RSV. In Phase III trials, RSV-related mortality rates were 0.2 and 0.3%, while AEs occurred in 11% of premature and/or BPD patients and 7.2% of hs-CHD patients, consisting mainly of injection site reaction, fever, and diarrhea. Similar results were found in observational studies.
CONCLUSION
This systematic review supports the effectiveness and safety of palivizumab in the indicated populations.
KEY POINTS
· Systematic review supports the positive benefit-risk profile of palivizumab in the indicated populations.. · Real-world safety and effectiveness of palivizumab are consistent with Phase III trials results.. · Palivizumab reduces RSV-related hospitalizations, ICU admissions, and need for mechanical ventilation..
Topics: Humans; Palivizumab; Respiratory Syncytial Virus Infections; Antiviral Agents; Infant; Infant, Newborn; Infant, Premature; Hospitalization; Bronchopulmonary Dysplasia; Heart Defects, Congenital; Respiration, Artificial; Respiratory Tract Infections; Observational Studies as Topic; Clinical Trials, Phase III as Topic
PubMed: 36452969
DOI: 10.1055/a-1990-2633 -
American Journal of Perinatology Oct 2023In 2014, the American Academy of Pediatrics (AAP) changed its policy on the use of respiratory syncytial virus immunoprophylaxis (RSV-IP) so that RSV-IP was no longer... (Observational Study)
Observational Study
OBJECTIVE
In 2014, the American Academy of Pediatrics (AAP) changed its policy on the use of respiratory syncytial virus immunoprophylaxis (RSV-IP) so that RSV-IP was no longer recommended for use among infants without other medical conditions born >29 weeks of gestational age (wGA). This study examines 10-year trends in RSV-IP and RSV hospitalizations among term infants and preterm infants born at 29 to 34 wGA, including the 5 RSV seasons before and 5 RSV seasons after the AAP guidance change.
STUDY DESIGN
A retrospective observational cohort study of a convenience sample of infants less than 6 months of age during RSV season (November-March) born between July 1, 2008, and June 30, 2019, who were born at 29 to 34 wGA (preterm) or >37 wGA (term) in the IBM MarketScan Commercial and Multi-State Medicaid databases. We excluded infants with medical conditions that would independently qualify them for RSV-IP. We identified RSV-IP utilization along with RSV and all-cause bronchiolitis hospitalizations during each RSV season. A difference-in-difference model was used to determine if there was a significant change in the relative rate of RSV hospitalizations following the 2014 policy change.
RESULTS
There were 53,535 commercially insured and 85,099 Medicaid-insured qualifying preterm infants and 1,111,670 commercially insured and 1,492,943 Medicaid-insured qualifying term infants. Following the 2014 policy change, RSV-IP utilization decreased for all infants, while hospitalization rates tended to increase for preterm infants. Rate ratios comparing preterm to term infants also increased. The relative rate for RSV hospitalization for infants born at 29 to 34 wGA increased significantly for both commercially and Medicaid-insured infants (1.95, 95% CI: 1.67-2.27, <0.001; 1.70, 95% CI: 1.55-1.86, <0.001, respectively). Findings were similar for all-cause bronchiolitis hospitalizations.
CONCLUSION
We found that the previously identified increase in RSV hospitalization rates among infants born at 29 to 34 wGA persisted for at least 5 years following the policy change.
KEY POINTS
· Immunoprophylaxis rates decreased after the 2014 American Academy of Pediatrics guidelines update.. · Rate of RSV hospitalization increased among preterm infants after the 2014 AAP guidelines update.. · Increase in RSV hospitalization persisted for at least 5 years after AAP guidelines update..
Topics: Infant; Female; Infant, Newborn; Humans; Child; United States; Infant, Premature; Respiratory Syncytial Virus Infections; Antiviral Agents; Retrospective Studies; Hospitalization; Gestational Age; Respiratory Syncytial Virus, Human; Bronchiolitis; Palivizumab
PubMed: 34704241
DOI: 10.1055/s-0041-1736581