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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 -
Journal of Paediatrics and Child Health Dec 2020Respiratory syncytial virus (RSV) continues to be a significant source of morbidity and mortality in both adults and children. Natural infection confers incomplete...
Respiratory syncytial virus (RSV) continues to be a significant source of morbidity and mortality in both adults and children. Natural infection confers incomplete protection, permitting recurrent episodes. Treatment remains limited to supportive care. Initial endeavours to develop a vaccine resulted in an unexpected enhancement of RSV disease and increased recipient mortality. Current proposed strategies to prevent RSV infection rely on the principles of active and passive immunisation and utilise the highly conserved RSV F-protein. Maternal vaccines administered in pregnancy may provide protection; trials are ongoing. Palivizumab, a monoclonal antibody, has a moderate preventative efficacy. A similar newer longer lasting formulation appears promising. A number of other novel options are being developed and are undergoing assessment. Progress has been made, with more vaccine candidates under consideration. We are edging closer to an effective solution to prevent RSV infection. If successful, the impact on paediatric morbidity, mortality, workload and cost will be substantial.
Topics: Adult; Antiviral Agents; Child; Female; Humans; Immunization; Palivizumab; Pregnancy; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus, Human
PubMed: 33089944
DOI: 10.1111/jpc.15232 -
Jornal de Pediatria 2023Despite the global impact of the Respiratory Syncytial Virus (RSV) infection in children, only one monoclonal antibody (Palivizumab) has been approved for clinical use.... (Review)
Review
OBJECTIVES
Despite the global impact of the Respiratory Syncytial Virus (RSV) infection in children, only one monoclonal antibody (Palivizumab) has been approved for clinical use. However, advances in the knowledge of RSV immunology may enable the development of safe and effective new vaccines and monoclonal antibodies in a few years. The purpose of this review is to summarize available data on approved and developing passive and active immunizations against RSV in childhood and pregnancy.
DATA SOURCE
A non-systematic review of RSV immunoprophylaxis in childhood and pregnancy was carried out in PubMed, path.org and clinical trial registries, without language restrictions, up to September 2022.
DATA SYNTHESIS
Three monoclonal antibodies and 17 active immunization candidates are under development in phase 1 to 3 clinical studies. Regarding the first group, Nirsevimab is a monoclonal antibody with a prolonged half-life whose approval for clinical use is expected in the next months. Among the vaccines under development, six techniques are being used: protein subunit, viral particles, live attenuated virus, recombinant viral vector, chimeric, and mRNA. The first two approaches are being tested primarily in pregnancy, while the others are being developed for the pediatric population.
CONCLUSIONS
The approval of extended half-life monoclonal antibodies is the next expected advance in RSV prevention, although the costs may be a barrier to the implementation. Regarding active immunizations, maternal and infant vaccination are complementary strategies and there are many promising candidates in clinical studies using different platforms.
Topics: Infant; Pregnancy; Female; Child; Humans; Respiratory Syncytial Virus Vaccines; Palivizumab; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Immunization, Passive; Antibodies, Monoclonal
PubMed: 36402228
DOI: 10.1016/j.jped.2022.10.004 -
International Journal of Molecular... Apr 2021Respiratory syncytial virus (RSV) represents the main cause of acute respiratory tract infections in children worldwide and is the leading cause of hospitalization in... (Review)
Review
Respiratory syncytial virus (RSV) represents the main cause of acute respiratory tract infections in children worldwide and is the leading cause of hospitalization in infants. RSV infection is a self-limiting condition and does not require antibiotics. However hospitalized infants with clinical bronchiolitis often receive antibiotics for fear of bacteria coinfection, especially when chest radiography is performed due to similar radiographic appearance of infiltrate and atelectasis. This may lead to unnecessary antibiotic prescription, additional cost, and increased risk of development of resistance. Despite the considerable burden of RSV bronchiolitis, to date, only symptomatic treatment is available, and there are no commercially available vaccines. The only licensed passive immunoprophylaxis is palivizumab. The high cost of this monoclonal antibody (mAb) has led to limiting its prescription only for high-risk children: infants with chronic lung disease, congenital heart disease, neuromuscular disorders, immunodeficiencies, and extreme preterm birth. Nevertheless, it has been shown that the majority of hospitalized RSV-infected children do not fully meet the criteria for immune prophylaxis. While waiting for an effective vaccine, passive immune prophylaxis in children is mandatory. There are a growing number of RSV passive immunization candidates under development intended for RSV prevention in all infants. In this review, we describe the state-of-the-art of palivizumab's usage and summarize the clinical and preclinical trials regarding the development of mAbs with a better cost-effectiveness ratio.
Topics: Antiviral Agents; Humans; Infant; Palivizumab; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses
PubMed: 33918185
DOI: 10.3390/ijms22073703 -
American Journal of Perinatology Sep 2020Infections caused by respiratory viruses in neonates during their stay in the neonatal intensive care unit (NICU) are more frequent than generally suspected. Respiratory... (Review)
Review
Infections caused by respiratory viruses in neonates during their stay in the neonatal intensive care unit (NICU) are more frequent than generally suspected. Respiratory syncytial virus (RSV), a highly contagious pathogen, is the most common etiologic agent, and it carries a high risk of nosocomial spread. During the RSV season, overcrowding of the NICU, shortage of staff, and unrestricted visitors are factors predisposing outbreaks. Since signs and symptoms of RSV infections are no specific, a high index of suspicion is essential to prevent or limit epidemics. The etiologic agent should be confirmed and polymerase chain reaction (PCR) is the gold-standard test. Shedding of the virus by infected preterm infants is prolonged and RSV lasts for several hours on countertops and other surfaces. The first case should be isolated and strict cohorting must be instituted. Compliance with hand washing must be warranted. Wearing gowns and gloves may help. The severity of nosocomial RSV infections tends to be higher than that of those community acquired. There is no uniform recommendation to start palivizumab during hospital stay of premature and high-risk infants. The use of this monoclonal antibody to stop or limit the spread of outbreaks is controversial. It is recommended by some professional organizations and not by others but its use during large outbreaks in infants at risk who share the room with infected neonates is not uncommon. KEY POINTS: · During peak community epidemic, NICU outbreaks of RSV infections are not uncommon.. · High index of suspicion is essential as initial signs are nonspecific in preterm neonates.. · Isolation and cohorting, strict hand washing, gowns, gloves, and eventually palivizumab are main tools for management..
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antiviral Agents; Cross Infection; Disease Outbreaks; Humans; Infant, Newborn; Infection Control; Intensive Care Units, Neonatal; Palivizumab; Respiratory Syncytial Virus Infections
PubMed: 32898879
DOI: 10.1055/s-0040-1714081 -
Pharmacology & Therapeutics Apr 2021RSV infection of the lower respiratory tract in infants is the leading cause of pediatric hospitalizations and second to malaria in causing infant deaths worldwide. RSV... (Review)
Review
RSV infection of the lower respiratory tract in infants is the leading cause of pediatric hospitalizations and second to malaria in causing infant deaths worldwide. RSV also causes substantial morbidity in immunocompromised and elderly populations. The only available therapeutic is a prophylactic drug called Palivizumab that is a humanized monoclonal antibody, given to high-risk infants. However, this intervention is expensive and has a limited impact on annual hospitalization rates caused by RSV. No vaccine is available, nor are efficacious antivirals to treat an active infection, and there is still no consensus on how infants with bronchiolitis should be treated during hospital admission. In this comprehensive review, we briefly outline the function of the RSV proteins and their suitability as therapeutic targets. We then discuss the most promising drug candidates, their inhibitory mechanisms, and whether they are in the process of clinical trials. We also briefly discuss the reasons for some of the failures in RSV therapeutics and vaccines. In summary, we provide insight into current antiviral development and the considerations toward producing licensed antivirals and therapeutics.
Topics: Antiviral Agents; Clinical Trials as Topic; Humans; Respiratory Syncytial Virus Infections
PubMed: 33121940
DOI: 10.1016/j.pharmthera.2020.107712 -
Neonatal Network : NN Apr 2024Respiratory syncytial virus (RSV) is the leading cause of hospitalization in infancy in the United States. Nearly all infants are infected by 2 years of age, with...
Respiratory syncytial virus (RSV) is the leading cause of hospitalization in infancy in the United States. Nearly all infants are infected by 2 years of age, with bronchiolitis requiring hospitalization often occurring in previously healthy children and long-term consequences of severe disease including delayed speech development and asthma. Incomplete passage of maternal immunity and a high degree of genetic variability within the virus contribute to morbidity and have also prevented successful neonatal vaccine development. Monoclonal antibodies reduce the risk of hospitalization from severe RSV disease, with palivizumab protecting high-risk newborns with comorbidities including chronic lung disease and congenital heart disease. Unfortunately, palivizumab is costly and requires monthly administration of up to five doses during the RSV season for optimal protection.Rapid advances in the past two decades have facilitated the identification of antibodies with broad neutralizing activity and allowed manipulation of their genetic code to extend half-life. These advances have culminated with nirsevimab, a monoclonal antibody targeting the Ø antigenic site on the RSV prefusion protein and protecting infants from severe disease for an entire 5-month season with a single dose. Four landmark randomized controlled trials, the first published in July 2020, have documented the efficacy and safety of nirsevimab in healthy late-preterm and term infants, healthy preterm infants, and high-risk preterm infants and those with congenital heart disease. Nirsevimab reduces the risk of RSV disease requiring medical attention (number needed to treat [NNT] 14-24) and hospitalization (NNT 33-63) with rare mild rash and injection site reactions. Consequently, the Centers for Disease Control and Prevention has recently recommended nirsevimab for all infants younger than 8 months of age entering or born during the RSV season and high-risk infants 8-19 months of age entering their second season. Implementing this novel therapy in this large population will require close multidisciplinary collaboration. Equitable distribution through minimizing barriers and maximizing uptake must be prioritized.
Topics: Humans; Infant, Newborn; Antibodies, Monoclonal, Humanized; Antiviral Agents; Heart Defects, Congenital; Infant, Premature; Palivizumab; Respiratory Syncytial Virus Infections; United States; Randomized Controlled Trials as Topic
PubMed: 38599778
DOI: 10.1891/NN-2023-0056 -
Sheng Wu Gong Cheng Xue Bao = Chinese... Jun 2022Since the palivizumab for respiratory syncytial virus was approved in 1998, therapeutic antibodies against infectious diseases have been widely used in clinical... (Review)
Review
Since the palivizumab for respiratory syncytial virus was approved in 1998, therapeutic antibodies against infectious diseases have been widely used in clinical treatment. Since the outbreak of COVID-19, plenty of neutralizing antibodies were developed and transferred into clinical trials, holding enormous promise for the treatment of COVID-19 under the context of emergency use authorization. This review summarizes the clinical progress of these drugs, in order to provide a reference for the research and development of neutralizing antibody drugs for the future.
Topics: Antibodies, Neutralizing; Antibodies, Viral; COVID-19; Humans; Neutralization Tests; SARS-CoV-2
PubMed: 35786461
DOI: 10.13345/j.cjb.220118 -
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