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EClinicalMedicine Dec 2023Mucosal administration of monoclonal antibodies (mAbs) against respiratory pathogens is a promising alternative for systemic administration because lower doses are...
BACKGROUND
Mucosal administration of monoclonal antibodies (mAbs) against respiratory pathogens is a promising alternative for systemic administration because lower doses are required for protection. Clinical development of mucosal mAbs is a highly active field yet clinical proof-of-concept is lacking.
METHODS
In this investigator-initiated, double-blind, randomized placebo-controlled trial, we evaluated intranasal palivizumab for the prevention of RSV infection in preterm infants (Dutch Trial Register NTR7378 and NTR7403). We randomized infants 1:1 to receive intranasal palivizumab (1 mg/mL) or placebo once daily during the RSV season. Any RSV infection was the primary outcome and RSV hospitalization was the key secondary outcome. The primary outcome was analyzed with a mixed effect logistic regression on the modified intention-to-treat population.
FINDINGS
We recruited 268 infants between Jan 14, 2019 and Jan 28, 2021, after which the trial was stopped for futility following the planned interim analysis. Adverse events were similar in both groups (22/134 (16.4%) palivizumab arm versus 26/134 (19.4%) placebo arm). There were 6 dropouts and 168 infants were excluded from the efficacy analyses due to absent RSV circulation during the SARS-CoV-2 pandemic. Any RSV infection was similar in infants in both groups (18/47 (38.3%) palivizumab arm versus 11/47 (23.4%) placebo arm; aOR 2.2, 95% CI 0.7-6.5).
INTERPRETATION
Daily intranasal palivizumab did not prevent RSV infection in late preterm infants. Our findings have important implications for the clinical development of mucosal mAbs, namely the necessity of timely interim analyses and further research to understand mucosal antibody half-life.
FUNDING
Funded by the Department of Pediatrics, University Medical Centre Utrecht, the Netherlands.
PubMed: 38192587
DOI: 10.1016/j.eclinm.2023.102324 -
The Journal of Infection May 2024This study investigated the prevalence, genetic diversity, and evolution of human respiratory syncytial virus (HRSV) in Barcelona from 2013 to 2023.
OBJECTIVES
This study investigated the prevalence, genetic diversity, and evolution of human respiratory syncytial virus (HRSV) in Barcelona from 2013 to 2023.
METHODS
Respiratory specimens from patients with RTI suspicion at Hospital Universitari Vall d'Hebron were collected from October 2013 to May 2023 for laboratory-confirmation of respiratory viruses. Next-generation sequencing was performed in randomly-selected samples with Illumina technology. Phylogenetic analyses of whole genome sequences were performed with BEAST v1.10.4. Signals of selection and evolutionary pressures were inferred by population dynamics and evolutionary analyses. Mutations in major surface proteins were genetic and structurally characterised, emphasizing those within antigenic epitopes.
RESULTS
Analyzing 139,625 samples, 5.3% were HRSV-positive (3008 HRSV-A, 3882 HRSV-B, 56 HRSV-A and -B, and 495 unsubtyped HRSV), with a higher prevalence observed in the paediatric population. Pandemic-related shifts in seasonal patterns returned to normal in 2022-2023. A total of 198 whole-genome sequences were obtained for HRSV-A (6.6% of the HRSV-A positive samples) belonging to GA2.3.5 lineage. For HRSV-B, 167 samples were sequenced (4.3% of the HRSV-B positive samples), belonging to GB5.0.2, GB5.0.4a and GB5.0.5a. HRSV-B exhibited a higher evolution rate. Post-SARS-CoV-2 pandemic, both subtypes showed increased evolutionary rates and decreased effective population size initially, followed by a sharp increase. Analyses indicated negative selective pressure on HRSV. Mutations in antigenic epitopes, including S276N and M274I in palivizumab-targeted site II, and I206M, Q209R, and S211N in nirsevimab-targeted site Ø, were identified.
DISCUSSION
Particularly in the context of the large-scale use in 2023-2024 season of nirsevimab, continuous epidemiological and genomic surveillance is crucial.
Topics: Humans; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Phylogeny; Child, Preschool; Child; Male; Infant; Evolution, Molecular; Female; Genome, Viral; Middle Aged; Spain; Adolescent; Adult; Genetic Variation; Antibodies, Monoclonal; Aged; Young Adult; Mutation; Whole Genome Sequencing; Antibodies, Viral; Prevalence; High-Throughput Nucleotide Sequencing; Infant, Newborn
PubMed: 38588960
DOI: 10.1016/j.jinf.2024.106153 -
Infectious Diseases and Therapy Jun 2024Respiratory syncytial virus (RSV) is one of the major causes of respiratory tract infections among children. Until recently, the monoclonal antibody palivizumab was the...
INTRODUCTION
Respiratory syncytial virus (RSV) is one of the major causes of respiratory tract infections among children. Until recently, the monoclonal antibody palivizumab was the only RSV prophylaxis available in Japan. In 2024, the bivalent RSV prefusion F protein-based (RSVpreF) vaccine was approved for the prevention of RSV infection in infants by active immunization of pregnant women. In this study, we assessed the cost-effectiveness of a combined strategy of RSVpreF vaccine and palivizumab in Japanese setting.
METHODS
Using a Markov model, we evaluated prevented cases and deaths of medically attended RSV infections from birth to age 11 months for each of the three healthcare settings: inpatient (hospitalization), emergency department visits, and outpatient visits. Incremental cost-effectiveness ratios (ICERs) were calculated from economic outcomes (intervention costs, medication costs, and productivity losses) and quality-adjusted life years (QALYs). Further, we calculated the maximum price of RSVpreF vaccine within which the program would be cost-effective.
RESULTS
In comparison with the current prophylaxis (palivizumab alone), a combined prophylaxis of year-round RSVpreF vaccination of pregnant women and palivizumab prescription for premature infants born in < 32 weeks gestational age (wGA) and all infants with high risk prevented 14,382 medically attended cases of RSV (hospitalization, 7490 cases; emergency department, 2239 cases; outpatient, 4653 cases) and 7 deaths, respectively. From a healthcare payer perspective, when the price of RSVpreF vaccine was equal to or less than ¥23,948 (US $182), a combination prophylaxis was cost-effective under the ICER threshold of ¥5 million per QALY. The other combination prophylaxis of year-round RSVpreF vaccination and palivizumab prescription of premature born in < 32 wGA regardless of risk in infants was a dominant strategy (more effective and less costly).
CONCLUSION
A combined prophylaxis of year-round RSVpreF vaccine and palivizumab could be a cost-effective strategy to protect neonates throughout the infant stage (< 1 years old) in Japan.
PubMed: 38834858
DOI: 10.1007/s40121-024-01000-6 -
Antibodies (Basel, Switzerland) Sep 2023Respiratory Syncytial Virus (RSV) is a significant cause of lower respiratory tract infections in the young, the elderly, and in immunodeficient patients. As such, the...
Respiratory Syncytial Virus (RSV) is a significant cause of lower respiratory tract infections in the young, the elderly, and in immunodeficient patients. As such, the virus represents an important cause of morbidity and mortality worldwide. Development of monoclonal antibodies against RSV has resulted in a commercial prophylaxis, palivizumab (Synagis), and different antibodies that have improved our understanding of the structure of the viral proteins. In this study, a different immunization technique, subtractive immunization, was evaluated for its applicability to develop RSV-specific antibodies. One hybridoma which produced antibodies with the strongest staining of RSV infected cells, ATAC-0025, was selected for further characterization. This antibody belongs to the IgG1 class, has neutralizing capacity and recognizes the envelope F-protein. The antibody has a broad reactivity against a range of RSV reference strains and clinical isolates.
PubMed: 37873859
DOI: 10.3390/antib12040062 -
Nursing For Women's Health Feb 2024Respiratory syncytial virus (RSV) infects nearly all infants in their first year of life and is the leading cause of hospitalization for infants younger than 1 year of...
Respiratory syncytial virus (RSV) infects nearly all infants in their first year of life and is the leading cause of hospitalization for infants younger than 1 year of age in the United States. Historically, the only option for RSV prevention was palivizumab. However, not all infants are eligible for palivizumab, it requires multiple doses per RSV season, and it is costly. In July 2023, the U.S. Food and Drug Administration approved nirsevimab for the prevention of RSV-associated lower respiratory tract infections for all infants. Nirsevimab inhibits RSV from fusing to cellular membranes and thereby neutralizes the virus in the body. Nirsevimab is expected to significantly reduce the health and economic burdens of RSV. This article provides an overview of nirsevimab, potential adverse effects, and implications for nursing practice.
Topics: Infant; Child; Humans; United States; Palivizumab; Respiratory Syncytial Viruses; Antibodies, Monoclonal; Antiviral Agents; Respiratory Syncytial Virus Infections; Hospitalization; Respiratory Tract Infections; Immunization; Antibodies, Monoclonal, Humanized
PubMed: 38070539
DOI: 10.1016/j.nwh.2023.11.002 -
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 -
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 -
The Turkish Journal of Pediatrics May 2024Respiratory syncytial virus (RSV) is one of the most common pathogens causing severe lower respiratory tract disease in infancy and childhood. In newborns, young...
BACKGROUND
Respiratory syncytial virus (RSV) is one of the most common pathogens causing severe lower respiratory tract disease in infancy and childhood. In newborns, young infants, and in infants with co-morbidities, the risk of severe infection is increased. Current protection against severe RSV infection is immunoprophylaxis with the monoclonal antibody palivizumab. The study aimed to assess the effects of palivizumab prophylaxis in the Republic of Montenegro in comparison to the pre-prophylaxis period.
METHODS
The study was conducted in prospective/retrospective single center format in Montenegro in the Clinical Center of Podgorica, for the period 2009-2019.
RESULTS
A total of 104 high-risk infants in the palivizumab prophylaxis program (2014-2019 RSV seasons) and 168 high-risk children without palivizumab prophylaxis (2009-2013 RSV seasons) were enrolled. A total of 51 children (49.0%) received prophylaxis for prematurity, 33 (31.7%) for bronchopulmonary dysplasia (BPD), 13 (12.5%) for hemodynamically significant heart disease/defect (HSCHD), and 7 (6.8%) for "miscellaneous" indications. In the control group most children had prematurity (101, 60.1%), followed by BPD (59, 35.1%), HSCHD (3, 1.8%), and "miscellaneous" (5, 3.4%) conditions. Readmission to the pediatric intensive care units (PICU) due to RSV infection was significantly lower in prophylaxis group (0.0 vs 16.1%, p<0.001). No lethal outcomes were observed in high-risk children with palivizumab prophylaxis compared to 2.4% in the control group.
CONCLUSIONS
The introduction of RSV immunoprophylaxis as well as other new protective treatment strategies for high-risk newborns led to significant improvements in infant and childcare in Montenegro. This is the first report on palivizumab prophylaxis in Montenegro, demonstrating the effectiveness and safety of palivizumab use in clinical settings.
Topics: Palivizumab; Humans; Respiratory Syncytial Virus Infections; Antiviral Agents; Male; Infant; Female; Infant, Newborn; Prospective Studies; Retrospective Studies; Montenegro; Infant, Premature
PubMed: 38814297
DOI: 10.24953/turkjpediatr.2024.4592 -
Nature Communications Apr 2024Currently, only Palivizumab and Nirsevimab that target the respiratory syncytical virus (RSV) fusion protein are licensed for pre-treatment of infants....
Currently, only Palivizumab and Nirsevimab that target the respiratory syncytical virus (RSV) fusion protein are licensed for pre-treatment of infants. Glycoprotein-targeting antibodies may also provide protection against RSV. In this study, we generate monoclonal antibodies from mice immunized with G proteins from RSV-A2 and RSV-B1 strains. These monoclonal antibodies recognize six unique antigenic classes (G0-G5). None of the anti-G monoclonal antibodies neutralize RSV-A2 or RSV-B1 in vitro. In mice challenged with either RSV-A2 line 19 F or RSV-B1, one day after treatment with anti-G monoclonal antibodies, all monoclonal antibodies reduce lung pathology and significantly reduce lung infectious viral titers by more than 2 logs on day 5 post-RSV challenge. RSV dissemination in the lungs was variable and correlated with lung pathology. We demonstrate new cross-protective anti-G monoclonal antibodies targeting multiple sites including conformation-dependent class G0 MAb 77D2, CCD-specific class G1 MAb 40D8, and carboxy terminus of CCD class G5 MAb 7H11, to support development of G-targeting monoclonal antibodies against RSV.
Topics: Humans; Mice; Animals; Antibodies, Monoclonal; Respiratory Syncytial Virus Infections; Antibodies, Viral; Respiratory Syncytial Virus, Human; Viral Fusion Proteins; GTP-Binding Proteins; Respiratory Syncytial Virus Vaccines; Antibodies, Neutralizing
PubMed: 38575575
DOI: 10.1038/s41467-024-47146-2 -
Viruses Nov 2023(1) Background: Palivizumab has been an approved preventative monoclonal antibody for respiratory syncytial virus (RSV) infection for over two decades. However, due to...
(1) Background: Palivizumab has been an approved preventative monoclonal antibody for respiratory syncytial virus (RSV) infection for over two decades. However, due to its high cost and requirement for multiple intramuscular injections, its use has been limited mostly to high-income countries. Following our previous study showing the successful lung deposition of aerosolised palivizumab in lambs, this current study evaluated the "proof-of-principle" effect of aerosolised palivizumab delivered as a therapeutic to neonatal lambs following RSV infection. (2) Methods: Neonatal lambs were intranasally inoculated with RSV-A2 on day 0 (day 3 post-birth) and treated with aerosolised palivizumab 3 days later (day 3 post-inoculation). Clinical symptoms, RSV viral load and inflammatory response were measured post-inoculation. (3) Results: Aerosolised therapeutic delivery of palivizumab did not reduce RSV viral loads in the nasopharynx nor the bronchoalveolar lavage fluid, but resulted in a modest reduction in inflammatory response at day 6 post-inoculation compared with untreated lambs. (4) Conclusions: This proof-of-principle study shows some evidence of aerosolised palivizumab reducing RSV inflammation, but further studies using optimized protocols are needed in order to validate these findings.
Topics: Animals; Sheep; Palivizumab; Respiratory Syncytial Virus Infections; Antiviral Agents; Antibodies, Monoclonal, Humanized; Respiratory Syncytial Virus, Human
PubMed: 38005952
DOI: 10.3390/v15112276