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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 -
Canada Communicable Disease Report =... Jul 2022Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in young children worldwide. Underlying health conditions, especially...
Summary of the National Advisory Committee on Immunization (NACI) statement update on the recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants.
BACKGROUND
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in young children worldwide. Underlying health conditions, especially premature birth, chronic lung disease and congenital heart disease, predispose to severe RSV illness. The only means of prophylaxis against RSV disease is passive prophylaxis with the monoclonal antibody, palivizumab (PVZ) (Synagis). The National Advisory Committee on Immunization (NACI) published a statement for PVZ use in 2003. The purpose of this article is to update previous NACI recommendations for the use of PVZ, taking into consideration recent data on RSV burden of illness, effectiveness of PVZ in infants at risk of more severe RSV disease and economic implications of PVZ use.
METHODS
The NACI Working Group and external experts performed systematic literature reviews on three topics to support updated NACI guidance: 1) RSV burden of disease; 2) PVZ effectiveness; and 3) cost effectiveness of PVZ prophylaxis. Full details and results are presented in the statement and supporting documents.
RESULTS
Respiratory syncytial virus hospitalization (RSVH) rates are highest in children younger than one year of age and especially in the first two months of life. In various populations of infants at risk of severe RSV infection, PVZ prophylaxis is associated with reductions of 38%-86% in the risk of RSVH. Only rare cases of anaphylaxis have been reported after decades of use. Palivizumab is expensive and only cost-saving in rare scenarios.
CONCLUSION
Updated NACI recommendations on use of PVZ for the prevention of complications of RSV in infants are now available.
PubMed: 37426290
DOI: 10.14745/ccdr.v48i78a08 -
Frontiers in Pediatrics 2023Preterm infants born between 33 and 35 weeks of gestational age (wGA) have been considered a "major underserved population" and ineligible to receive palivizumab (PLV),...
BACKGROUND
Preterm infants born between 33 and 35 weeks of gestational age (wGA) have been considered a "major underserved population" and ineligible to receive palivizumab (PLV), the only drug authorized to date for respiratory syncytial virus (RSV) prophylaxis, by current international guidelines. In Italy, such a vulnerable population is currently eligible for prophylaxis, and, in our region, specific risk factors are taken into consideration (SIN score) to target prophylaxis for those at highest risk. Whether the adoption of less or more restrictive eligibility criteria for PLV prophylaxis would translate into differences in bronchiolitis and hospitalization incidence is not known.
MATERIALS AND METHODS
A retrospective analysis was conducted in 296 moderate-to-late preterm infants (born between 33 and 35 weeks) who were being considered for prophylaxis in two epidemic seasons: 2018-2019 and 2019-2020. The study participants were categorized according to both the SIN score and the Blanken risk scoring tool (BRST), which was found to reliably predict RSV-associated hospitalization in preterm infants on the basis of three risk factor variables.
RESULTS
Based on the SIN score, approximately 40% of infants (123/296) would meet the criteria to be eligible for PLV prophylaxis. In contrast, none of the analyzed infants would be considered eligible for RSV prophylaxis on the basis of the BRST. A total of 45 (15.2%) bronchiolitis diagnoses were recorded on average at 5 months of age in the overall population. Almost seven out of 10 (84/123) patients exhibiting ≥3 risk factors to be eligible for RSV prophylaxis according to SIN criteria would not be receiving PLV if they were categorized on the basis of the BRST. Bronchiolitis occurrence in patients with a SIN score ≥3 was approximately 2.2 times more likely than that in patients with a SIN score <3. PLV prophylaxis has been associated with a 91% lower risk of requiring a nasal cannula.
CONCLUSION
Our work further supports the need for targeting late preterm infants for RSV prophylaxis and calls for an appraisal of the current eligibility criteria for PLV treatment. Therefore, adopting less restrictive criteria may ensure a comprehensive prophylaxis of the eligible subjects, thus sparing them from avoidable short- and long-term consequences of RSV infection.
PubMed: 37360357
DOI: 10.3389/fped.2023.1154518 -
Italian Journal of Pediatrics Jun 2023Bronchiolitis is a major cause of hospitalization in infants, particularly in the first six months of life, with approximately 60-80% of admissions due to respiratory...
BACKGROUND
Bronchiolitis is a major cause of hospitalization in infants, particularly in the first six months of life, with approximately 60-80% of admissions due to respiratory syncytial virus (RSV) infection. Currently, no prophylactic options are available for healthy infants. The present study aimed at describing the demographic, clinical, and epidemiological characteristics of infants hospitalized for bronchiolitis in the Apulia region of Italy in 2021.
METHODS
From January to December 2021, data on children aged 0-12 months admitted for bronchiolitis in nine neonatal or pediatric units covering 61% of pediatric beds of hospitals in the Apulia region of Italy were analyzed. Demographic data, comorbidities, need for oxygen support, length of hospital stay, palivizumab administration, and outcomes were collected. For the purpose of the analysis, patients were divided into those aged 0-3 months and > 3 months. A multivariate logistic regression model was used to explore associations between the need for oxygen support and sex, age, comorbidities, history of prematurity, length of hospital stay, and palivizumab administration.
RESULTS
This study included 349 children aged 0-12 months admitted for bronchiolitis, with a peak of hospitalization in November (7.4 cases/1,000 children). Of these patients, 70.5% were RSV positive, 80.2% were aged 0-3 months, and 73.1% required oxygen support. Moreover, 34.9% required observation in the sub-intensive care unit, and 12.9% in the intensive care unit. Of the infants who required intensive care, 96.9% were aged 0-3 months and 78.8% were born at term. Three patients required mechanical ventilation and one, who required Extra Corporeal Membrane Oxygenation, died. Children aged 0-3 months were more likely to show dyspnea, need oxygen support, and have a longer hospital stay.
CONCLUSIONS
The present study showed that almost all of the children who required intensive care support were aged ≤ 3 months and most were born at term. Therefore, this age group remains the highest risk group for severe bronchiolitis. Preventive measures such as single-dose monoclonal antibody immunoprophylaxis, and maternal and childhood vaccination against RSV, may reduce the high public health burden of bronchiolitis.
Topics: Infant, Newborn; Infant; Humans; Child; Palivizumab; Antiviral Agents; Antibodies, Monoclonal, Humanized; Hospitalization; Bronchiolitis; Respiratory Syncytial Virus Infections; Italy
PubMed: 37280662
DOI: 10.1186/s13052-023-01455-2 -
Viruses Apr 2023The respiratory syncytial virus (RSV) causes significant respiratory disease in young infants and the elderly. Immune prophylaxis in infants is currently limited to...
The respiratory syncytial virus (RSV) causes significant respiratory disease in young infants and the elderly. Immune prophylaxis in infants is currently limited to palivizumab, an anti-RSV fusion (F) protein monoclonal antibody (mAb). While anti-F protein mAbs neutralize RSV, they are unable to prevent aberrant pathogenic responses provoked by the RSV attachment (G) protein. Recently, the co-crystal structures of two high-affinity anti-G protein mAbs that bind the central conserved domain (CCD) at distinct non-overlapping epitopes were solved. mAbs 3D3 and 2D10 are broadly neutralizing and block G protein CX3C-mediated chemotaxis by binding antigenic sites γ1 and γ2, respectively, which is known to reduce RSV disease. Previous studies have established 3D3 as a potential immunoprophylactic and therapeutic; however, there has been no similar evaluation of 2D10 available. Here, we sought to determine the differences in neutralization and immunity to RSV Line19F infection which recapitulates human RSV infection in mouse models making it useful for therapeutic antibody studies. Prophylactic (24 h prior to infection) or therapeutic (72 h post-infection) treatment of mice with 3D3, 2D10, or palivizumab were compared to isotype control antibody treatment. The results show that 2D10 can neutralize RSV Line19F both prophylactically and therapeutically, and can reduce disease-causing immune responses in a prophylactic but not therapeutic context. In contrast, 3D3 was able to significantly ( < 0.05) reduce lung virus titers and IL-13 in a prophylactic and therapeutic regimen suggesting subtle but important differences in immune responses to RSV infection with mAbs that bind distinct epitopes.
Topics: Mice; Humans; Animals; Aged; Palivizumab; Antibodies, Viral; Viral Fusion Proteins; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Antibodies, Monoclonal; Epitopes
PubMed: 37243153
DOI: 10.3390/v15051067 -
Vaccine Jun 2023Preventive measures applied during the COVID-19 pandemic have modified the age distribution, the clinical severity and the incidence of Respiratory Syncytial Virus (RSV)...
BACKGROUND
Preventive measures applied during the COVID-19 pandemic have modified the age distribution, the clinical severity and the incidence of Respiratory Syncytial Virus (RSV) hospitalisations during the 2020/21 RSV season. The aim of the present study was to estimate the impact of these aspects on RSV-associated hospitalisations (RSVH) costs stratified by age group between pre-COVID-19 seasons and 2020/21 RSV season.
METHODS
We compared the incidence, the median costs, and total RSVH costs from the national health insurance perspective in children < 24 months of age during the COVID-19 period (2020/21 RSV season) with a pre-COVID-19 period (2014/17 RSV seasons). Children were born and hospitalised in the Lyon metropolitan area. RSVH costs were extracted from the French medical information system (Programme de Médicalisation des Systémes d'Information).
RESULTS
The RSVH-incidence rate per 1000 infants aged < 3 months decreased significantly from 4.6 (95 % CI [4.1; 5.2]) to 3.1 (95 % CI [2.4; 4.0]), and increased in older infants and children up to 24 months of age during the 2020/21 RSV season. Overall, RSVH costs for RSVH cases aged below 2 years old decreased by €201,770 (31 %) during 2020/21 RSV season compared to the mean pre-COVID-19 costs.
CONCLUSIONS
The sharp reduction in costs of RSVH in infants aged < 3 months outweighed the modest increase in costs observed in the 3-24 months age group. Therefore, conferring a temporal protection through passive immunisation to infants aged < 3 months should have a major impact on RSVH costs even if it results in an increase of RSVH in older children infected later in life. Nevertheless, stakeholders should be aware of this potential increase of RSVH in older age groups presenting with a wider range of disease to avoid any bias in estimating the cost-effectiveness of passive immunisation strategies.
Topics: Infant; Child; Humans; Aged; Child, Preschool; Palivizumab; Respiratory Syncytial Virus Infections; Antiviral Agents; Pandemics; COVID-19; Respiratory Syncytial Virus, Human; Hospitalization
PubMed: 37198017
DOI: 10.1016/j.vaccine.2023.05.021