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Advanced Science (Weinheim,... Mar 2024Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via...
Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in infants, the immunocompromised, and the elderly. RSV infects the airway epithelium via the apical membrane and almost exclusively sheds progeny virions back into the airway mucus (AM), making RSV difficult to target by systemically administered therapies. An inhalable "muco-trapping" variant of motavizumab (Mota-MT), a potent neutralizing mAb against RSV F is engineered. Mota-MT traps RSV in AM via polyvalent Fc-mucin bonds, reducing the fraction of fast-moving RSV particles in both fresh pediatric and adult AM by ≈20-30-fold in a Fc-glycan dependent manner, and facilitates clearance from the airways of mice within minutes. Intranasal dosing of Mota-MT eliminated viral load in cotton rats within 2 days. Daily nebulized delivery of Mota-MT to RSV-infected neonatal lambs, beginning 3 days after infection when viral load is at its maximum, led to a 10 000-fold and 100 000-fold reduction in viral load in bronchoalveolar lavage and lung tissues relative to placebo control, respectively. Mota-MT-treated lambs exhibited reduced bronchiolitis, neutrophil infiltration, and airway remodeling than lambs receiving placebo or intramuscular palivizumab. The findings underscore inhaled delivery of muco-trapping mAbs as a promising strategy for the treatment of RSV and other acute respiratory infections.
Topics: Humans; Infant; Child; Animals; Sheep; Mice; Aged; Antibodies, Monoclonal; Respiratory Syncytial Virus Infections; Palivizumab; Respiratory Syncytial Viruses; Lung
PubMed: 38225749
DOI: 10.1002/advs.202306729 -
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 -
Research Square Dec 2023Respiratory Syncytial Virus (RSV) is a leading cause of acute respiratory tract infection, with greatest impact on infants, immunocompromised individuals, and older...
Respiratory Syncytial Virus (RSV) is a leading cause of acute respiratory tract infection, with greatest impact on infants, immunocompromised individuals, and older adults. RSV prevalence decreased substantially following the implementation of non-pharmaceutical interventions to mitigate the COVID-19 pandemic but later rebounded with initially abnormal seasonality. The biological and epidemiological factors underlying this altered behavior remain poorly defined. In this retrospective cohort study, we examined RSV epidemiology, clinical severity, and genetic diversity in the years surrounding the COVID-19 pandemic. We found that changes in RSV diagnostic platforms drove increased detections in outpatient settings after 2020 and that hospitalized adults with RSV-A were at higher risk of needing intensive care than those with RSV-B. While the population structure of RSV-A remained unchanged, the population structure of RSV-B shifted in geographically distinct clusters. Mutations in the antigenic regions of the fusion protein suggest convergent evolution with potential implications for vaccine and therapeutic development.
PubMed: 38168164
DOI: 10.21203/rs.3.rs-3712859/v1 -
Hong Kong Medical Journal = Xianggang... Dec 2023
Topics: Child; Humans; Infant; Palivizumab; Cost-Benefit Analysis; Hong Kong; Antiviral Agents; Respiratory Syncytial Virus Infections; Hospitalization
PubMed: 38148655
DOI: No ID Found -
Vaccines Dec 2023Respiratory Syncytial Virus (RSV) poses a severe threat to infants, particularly preterm infants. Palivizumab, the standard preventive prophylaxis, is primarily utilized...
Respiratory Syncytial Virus (RSV) poses a severe threat to infants, particularly preterm infants. Palivizumab, the standard preventive prophylaxis, is primarily utilized in high-risk newborns due to its cost. This study assessed palivizumab's effectiveness in preventing RSV infections in predominantly very preterm infants during their first year of life. Serum samples from a prospective multicentre cohort study in the Netherlands were analyzed to assess RSV infection rates by measuring IgG levels against three RSV proteins: nucleoprotein, pre-fusion, and post-fusion protein. Infants were stratified based on gestational age (GA), distinguishing very preterm (≤32 weeks GA) from moderate/late preterm (>32 to ≤36 weeks GA). In very preterm infants, palivizumab prophylaxis significantly reduced infection rates (18.9% vs. 48.3% in the prophylaxis vs. non-prophylaxis group. Accounting for GA, sex, birth season, and birth weight, the prophylaxis group showed significantly lower infection odds. In infants with >32 to ≤36 weeks GA, the non-prophylaxis group (55.4%) showed infection rates similar to the non-prophylaxis ≤32-week GA group, despite higher maternal antibody levels in the moderate/late preterm infants. In conclusion, palivizumab prophylaxis significantly reduces RSV infection rates in very premature infants. Future research should explore clinical implications and reasons for non-compliance, and compare palivizumab with emerging prophylactics like nirsevimab aiming to optimize RSV prophylaxis and improve preterm infant outcomes.
PubMed: 38140212
DOI: 10.3390/vaccines11121807 -
Vaccines Nov 2023Respiratory syncytial virus (RSV) is a well-known infant pathogen transmitted mainly by droplets. It is a leading cause of upper respiratory tract infections in... (Review)
Review
Respiratory syncytial virus (RSV) is a well-known infant pathogen transmitted mainly by droplets. It is a leading cause of upper respiratory tract infections in children, usually with a mild course of illness. RSV has also been a threat to older people, especially those with underlying medical conditions. For a long time, prevention was limited to passive immunoprophylaxis with palivizumab for high-risk infants. There was a strong need to find other treatment or prevention methods against RSV infections. In addition, after the coronavirus disease 2019 (COVID-19) pandemic, some significant changes in RSV epidemiology have been observed. Researchers noticed the shift in RSV seasonality and age distribution and the increased number of cases in older infants and adults. All of these made the need to find other medical options even stronger. Fortunately, two protein-based vaccines against RSV have successfully passed all phases of clinical trials and have been approved for use by adults and older people. One of them is also approved for infants from birth to 6 months of age (after maternal immunisation during pregnancy) and for pregnant women between 24 and 36 weeks of pregnancy. Also, a new passive immunisation option named nirsevimab (a highly potent monoclonal antibody with a long half-life) is now available for the paediatric group. In this review, we will discuss the previous and current RSV prevention methods in the light of structural discoveries of RSV antigens.
PubMed: 38140201
DOI: 10.3390/vaccines11121797 -
Euro Surveillance : Bulletin Europeen... Dec 2023A monoclonal antibody for universal respiratory syncytial virus prophylaxis in infants has recently been licensed. We share our experiences of integrating nirsevimab...
Early lessons from the implementation of universal respiratory syncytial virus prophylaxis in infants with long-acting monoclonal antibodies, Galicia, Spain, September and October 2023.
A monoclonal antibody for universal respiratory syncytial virus prophylaxis in infants has recently been licensed. We share our experiences of integrating nirsevimab into the regional immunisation programme in Galicia, Spain. After a 3-week hospital-based immunisation campaign with flexible individualised appointments and educational activities, nirsevimab uptake was 97.5% in the high-risk group, 81.4% in the catch-up group and 92.6% in infants born during the campaign. This successful implementation strategy can serve as a model and may inform other countries' programmatic deliberations.
Topics: Infant; Humans; Antibodies, Monoclonal; Palivizumab; Respiratory Syncytial Virus Infections; Spain; Respiratory Syncytial Viruses; Antiviral Agents; Respiratory Syncytial Virus, Human
PubMed: 38062942
DOI: 10.2807/1560-7917.ES.2023.28.49.2300606 -
Journal of the Association of Medical... Nov 2023The introduction of nirsevimab (a respiratory syncytial virus [RSV] monoclonal antibody that can protect for minimum 5 months with a single dose) and RSV maternal...
The introduction of nirsevimab (a respiratory syncytial virus [RSV] monoclonal antibody that can protect for minimum 5 months with a single dose) and RSV maternal vaccines to protect young infants has the potential to dramatically decrease RSV hospitalizations in Canada. However, there remain many unanswered questions before optimal use of these products can be assured.
PubMed: 38058503
DOI: 10.3138/jammi-2023-05-31 -
Paediatric Drugs Mar 2024Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in children, and is associated with long-term pulmonary sequelae...
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection (LRTI) in children, and is associated with long-term pulmonary sequelae for up to 30 years after infection. The mainstay of RSV management is supportive therapy such as supplemental oxygen. Palivizumab (Synagis™-AstraZeneca), a monoclonal antibody targeting the RSV F protein site II, has been licensed for the prevention of RSV in high-risk groups since 1998. There has been recent promising progress in preventative strategies that include vaccines and long-acting, high-potency monoclonal antibodies. Nirsevimab (Beyfortus™-AstraZeneca/Sanofi), a monoclonal antibody with an extended half-life, has recently been registered in the European Union and granted licensure by the US Food and Drug Administration. Furthermore, a pre-fusion sub-unit protein vaccine has been granted licensure for pregnant women, aimed at protecting their young infants, following established safety and efficacy in clinical trials (Abrysvo™-Pfizer). Also, multiple novel antiviral therapeutic options are in early phase clinical trials. The next few years have the potential to change the landscape of LRTI through improvements in the prevention and management of RSV LRTI. Here, we discuss these new approaches, current research, and clinical trials in novel therapeutics, monoclonal antibodies, and vaccines against RSV infection in infants and children.
Topics: Pregnancy; United States; Child; Infant; Female; Humans; Respiratory Syncytial Virus Infections; Palivizumab; Antibodies, Monoclonal; European Union; Vaccines
PubMed: 38032456
DOI: 10.1007/s40272-023-00606-6 -
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