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Vaccine Jan 2017Respiratory syncytial virus (RSV) remains a significant cause of morbidity and mortality in infants and young children, immunocompromised patients and the elderly.... (Review)
Review
Respiratory syncytial virus (RSV) remains a significant cause of morbidity and mortality in infants and young children, immunocompromised patients and the elderly. Despite the high disease burden, an effective and safe vaccine is lacking, although several candidates are currently in development. Current treatment for RSV infection remains largely supportive and RSV-specific options for prophylaxis are limited to palivizumab. In the past few years, novel therapeutic options including nanobodies, polyclonal and monoclonal antibodies have emerged and there are several products in preclinical and Phase-I, -II or -III clinical trials. The major target for antiviral drug development is the surface fusion (F) glycoprotein, which is crucial for the infectivity and pathogenesis of the virus. Solving the structures of the two conformations of the RSV F protein, the prefusion and postfusion forms, has revolutionized RSV research. It is now known that prefusion F is highly superior in inducing neutralizing antibodies. In this section we will review the stages of development and availability of different antibodies directed against RSV for the prevention and also for treatment of acute RSV infections. Some of these newer anti-RSV agents have shown enhanced potency, are being explored through alternative routes of administration, have improved pharmacokinetic profiles with an extended half-life, and may reduce design and manufacturing costs. Management strategies will require targeting not only high-risk populations (including adults or immunocompromised patients), but also previously healthy children who, in fact, represent the majority of children hospitalized with RSV infection. Following treated patients longitudinally is essential for determining the impact of these strategies on the acute disease as well as their possible long-term benefits on lung morbidity.
Topics: Antibodies, Monoclonal; Antibodies, Viral; Antiviral Agents; Clinical Trials as Topic; Humans; Immunization, Passive; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses
PubMed: 27692523
DOI: 10.1016/j.vaccine.2016.09.026 -
Infectious Diseases and Therapy Feb 2023The highly contagious respiratory syncytial virus (RSV) is responsible for up to approximately 50,000 hospitalisations during each RSV season in children aged under... (Review)
Review
Preventing Respiratory Syncytial Virus in Children in France: A Narrative Review of the Importance of a Reinforced Partnership Between Parents, Healthcare Professionals, and Public Health Authorities.
The highly contagious respiratory syncytial virus (RSV) is responsible for up to approximately 50,000 hospitalisations during each RSV season in children aged under 5 years in France, with the burden greatest in infants younger than 1 year who were born at term. There is a need for a strategy to universally protect young children from RSV infection, and thereby reduce the pressure that RSV places every year on RSV-infected children, their parents, and French healthcare systems. Potential strategies currently undergoing clinical investigation include passive immunisation via maternal vaccination or administration of long-acting monoclonal antibodies at or soon after birth, followed by vaccination later in infancy or childhood. An ongoing partnership and collaboration between parents, public health authorities, and frontline primary healthcare will need to be reinforced once these new RSV prevention strategies are available, to facilitate their use and ensure that all children receive adequate protection from the start of their first RSV season.
PubMed: 36520324
DOI: 10.1007/s40121-022-00737-2 -
Breathe (Sheffield, England) Dec 2021https://bit.ly/3ikzwZD.
https://bit.ly/3ikzwZD.
PubMed: 35035568
DOI: 10.1183/20734735.0110-2021 -
Acta Medica Academica Aug 2020This review addresses differences in respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI) between industrialized and developing countries and... (Review)
Review
This review addresses differences in respiratory syncytial virus (RSV) lower respiratory tract illness (LRTI) between industrialized and developing countries and provides observations associated with the dissimilar consequences of viral infection in both environments. RSV LRTI is an important cause of morbidity and mortality in infants worldwide. Its burden is highest in developing countries, where most hospitalizations and mortality occur. Palivizumab has been approved for disease prevention in premature infants in numerous countries but its cost and requirement for several doses hampers its routine use. The significant gap between low- and high-income countries in mortality rates stresses the need to identify specific risk factors for RSV LRTI prevention in different populations. CONCLUSION: RSV LTRI continues to be a serious problem for industrialised and developing countries, although mortality occurs preferentially in the latter. Several vaccines and monoclonal antibodies to prevent severe disease are advancing steadily in late phase trials. The next decade may witness a change in the landscape of RSV infections in young infants.
Topics: Antiviral Agents; Asthma; Bronchiolitis, Viral; Coinfection; Developing Countries; Drug Costs; Global Burden of Disease; Hospitalization; Humans; Infant, Premature; Palivizumab; Pneumonia; Respiratory Syncytial Virus Infections
PubMed: 33189124
DOI: 10.5644/ama2006-124.297 -
Frontiers in Immunology 2023Nirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion...
INTRODUCTION
Nirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion protein, with established efficacy in preventing RSV-associated lower respiratory tract infection in infants for the duration of a typical RSV season. Previous studies suggest that nirsevimab confers protection via direct virus neutralization. Here we use preclinical models to explore whether fragment crystallizable (Fc)-mediated effector functions contribute to nirsevimab-mediated protection.
METHODS
Nirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897*-TM (i.e., MEDI8897* without Fc effector functions) binding to Fc γ receptors (FcγRs) was evaluated using surface plasmon resonance. Antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular cytotoxicity (ADCC) were assessed through and serological analyses. A cotton rat challenge study was performed with MEDI8897* and MEDI8897*-TM to explore whether Fc effector functions contribute to protection from RSV.
RESULTS
Nirsevimab and MEDI8897* exhibited binding to a range of FcγRs, with expected reductions in FcγR binding affinities observed for MEDI8897*-TM. Nirsevimab exhibited ADNP, ADCP, ADCD, and ADCC activity above background levels, and similar ADNP, ADCP, and ADCD activity to palivizumab. Nirsevimab administration increased ADNP, ADCP, and ADCD activity in participant serum from the MELODY study (NCT03979313). However, ADCC levels remained similar between nirsevimab and placebo. MEDI8897* and MEDI8897*-TM exhibited similar dose-dependent reduction in lung and nasal turbinate RSV titers in the cotton rat model.
CONCLUSION
Nirsevimab possesses Fc effector activity comparable with the current standard of care, palivizumab. However, despite possessing the capacity for Fc effector activity, data from RSV challenge experiments illustrate that nirsevimab-mediated protection is primarily dependent on direct virus neutralization.
Topics: Infant; Humans; Animals; Palivizumab; Antibodies, Viral; Respiratory Syncytial Virus, Human; Respiratory Syncytial Virus Infections; Complement System Proteins; Sigmodontinae
PubMed: 37901217
DOI: 10.3389/fimmu.2023.1283120 -
Infectious Diseases and Therapy Mar 2018The REGAL (RSV Evidence - A Geographical Archive of the Literature) series has provided a comprehensive review of the published evidence in the field of respiratory... (Review)
Review
INTRODUCTION
The REGAL (RSV Evidence - A Geographical Archive of the Literature) series has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This seventh and final publication covers the past, present and future approaches to the prevention and treatment of RSV infection among infants and children.
METHODS
A systematic review was undertaken of publications between January 1, 1995 and December 31, 2017 across PubMed, Embase and The Cochrane Library. Studies reporting data on the effectiveness and tolerability of prophylactic and therapeutic agents for RSV infection were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. A further nonsystematic search of the published literature and Clinicaltrials.gov on antiviral therapies and RSV vaccines currently in development was also undertaken.
RESULTS
The systematic review identified 1441 studies of which 161 were included. Management of RSV remains centered around prophylaxis with the monoclonal antibody palivizumab, which has proven effective in reducing RSV hospitalization (RSVH) in preterm infants < 36 weeks' gestational age (72% reduction), children with bronchopulmonary dysplasia (65% reduction), and infants with hemodynamically significant congenital heart disease (53% reduction) (high SOE). Palivizumab has also shown to be effective in reducing recurrent wheezing following RSVH (high SOE). Treatment of RSV with ribavirin has conflicting success (moderate SOE). Antibodies with increased potency and extended half-life are currently entering phase 3 trials. There are approximately 15 RSV vaccines in clinical development targeting the infant directly or indirectly via the mother.
CONCLUSION
Palivizumab remains the only product licensed for RSV prophylaxis, and only available for high-risk infants. For the general population, there are several promising vaccines and monoclonal antibodies in various stages of clinical development, with the aim to significantly reduce the global healthcare impact of this common viral infection.
FUNDING
AbbVie.
PubMed: 29470837
DOI: 10.1007/s40121-018-0188-z -
Frontiers in Pediatrics 2021To define the impact of associated abnormalities on the efficacy of the novel subtropical guidelines for palivizumab prophylaxis on respiratory syncytial virus...
To define the impact of associated abnormalities on the efficacy of the novel subtropical guidelines for palivizumab prophylaxis on respiratory syncytial virus (RSV)-related hospitalizations in patients with hemodynamically significant congenital heart disease (hsCHD). This prospective study enrolled every patient seen at a tertiary care center for hsCHD, who was born between 2014 and 2018 and received at least 1 dose of palivizumab, according to the subtropical guidelines. The patients were followed until the age of 2 years. A total of 772 patients (49% male) were enrolled. Cyanotic CHD was seen in 46% of patients, of whom 23% had associated abnormalities. Lung/airway abnormalities (14%) were the most common followed by the genetic syndromes associated with CHD (7.3%). Among the 772 patients, RSV-related hospitalizations occurred in 3.2 and 2.2% children aged ≤ 12 and 13-24 months, respectively. Most of the RSV infections occurred in patients no longer satisfying the criteria for palivizumab prophylaxis. The patients with associated abnormalities but not the type of CHD, patient age, and patient sex were risk factors for RSV-related hospitalizations. The rates of RSV-related hospitalizations, admission to the intensive care unit, and endotracheal intubation were higher for patients with associated anomalies than for other patients before 24 months of age (10.2 vs. 4.0%, 67 vs. 33%, and 39 vs. 4.2%, = 0.004, 0.06, 0.013, respectively). Children with abnormalities, especially genetic syndromes and lung/airway problems associated with CHD, are at high risk for RSV-related hospitalization. Our current subtropical guidelines for palivizumab prophylaxis in patients with hsCHD, should be revised to include the results of this study.
PubMed: 35071127
DOI: 10.3389/fped.2021.756787 -
Drugs in Context 2015The peak season of respiratory syncytial virus (RSV) infections in warmer climates may extend beyond the typical five-month RSV season of temperate regions. Additional...
BACKGROUND
The peak season of respiratory syncytial virus (RSV) infections in warmer climates may extend beyond the typical five-month RSV season of temperate regions. Additional monthly doses of palivizumab may be necessary in warmer regions to protect children at high risk for serious infection by the RSV.
METHODS
In a Phase II, single-arm, single-center, non-comparative, open-label, prospective study conducted in Saudi Arabia, children at high risk for RSV infection received up to seven monthly injections of palivizumab (15 mg/kg) during the 2000-2001 RSV season. Key enrollment criteria were no previous exposure to palivizumab and gestational age ≤35 weeks, ≤6 months of age at enrollment, or chronic lung disease and ≤24 months of age at enrollment. We wished to assess the safety, immunogenicity, and pharmacokinetics of palivizumab as an extended seven-dose regimen.
RESULTS
Of 18 enrolled patients, 17 patients received seven palivizumab injections. Seven adverse events (AEs) occurred in five patients. Bronchiolitis was the most commonly reported AE. Six serious AEs occurred in four patients. No AEs were considered related to palivizumab. Trough levels of palivizumab in serum were >40 μg/mL in most patients after the first injection and in 16/18 and 14/17 patients after the fourth and sixth injections, respectively. Except for one patient at one visit, the anti-palivizumab titer was <1:10 at all visits.
CONCLUSION
These data suggest that an extended palivizumab regimen of up to seven monthly doses during the RSV season exhibited an acceptable safety profile in children at high risk for RSV infection in Saudi Arabia.
PubMed: 25767550
DOI: 10.7573/dic.212270 -
Frontiers in Medicine 2021Following the SARS-CoV-2 pandemic, several clinical trials have been approved for the investigation of the possible use of mAbs, supporting the potential of this... (Review)
Review
Following the SARS-CoV-2 pandemic, several clinical trials have been approved for the investigation of the possible use of mAbs, supporting the potential of this technology as a therapeutic approach for infectious diseases. The first monoclonal antibody (mAb), Muromonab CD3, was introduced for the prevention of kidney transplant rejection more than 30 years ago; since then more than 100 mAbs have been approved for therapeutic purposes. Nonetheless, only four mAbs are currently employed for infectious diseases: Palivizumab, for the prevention of respiratory syncytial virus (RSV) infections, Raxibacumab and Obiltoxaximab, for the prophylaxis and treatment against anthrax toxin and Bezlotoxumab, for the prevention of recurrence. Protozoan infections are often neglected diseases for which effective and safe chemotherapies are generally missing. In this context, drug resistance and drug toxicity are two crucial problems. The recent advances in bioinformatics, parasite genomics, and biochemistry methodologies are contributing to better understand parasite biology, which is essential to guide the development of new therapies. In this review, we present the efforts that are being made in the evaluation of mAbs for the prevention or treatment of leishmaniasis, Chagas disease, malaria, and toxoplasmosis. Particular emphasis will be placed on the potential strengths and weaknesses of biological treatments in the control of these protozoan diseases that are still affecting hundreds of thousands of people worldwide.
PubMed: 34712683
DOI: 10.3389/fmed.2021.745665 -
Antiviral Chemistry & Chemotherapy 2018Respiratory syncytial virus is the leading cause of pneumonia and bronchiolitis in infants and is a serious health risk for elderly and immunocompromised individuals. No... (Review)
Review
Respiratory syncytial virus is the leading cause of pneumonia and bronchiolitis in infants and is a serious health risk for elderly and immunocompromised individuals. No vaccine has yet been approved to prevent respiratory syncytial virus infection and the only available treatment is immunoprophylaxis of severe respiratory syncytial virus disease in high-risk infants with Palivizumab (Synagis). The development of respiratory syncytial virus vaccine has been hampered by the phenomenon of enhanced respiratory syncytial virus disease observed during trials of a formalin-inactivated respiratory syncytial virus in 1960s. A search for effective respiratory syncytial virus therapeutics has been complicated by the fact that some of the most advanced respiratory syncytial virus antivirals, while highly effective in a prophylactic setting, had not demonstrated clinical efficacy when given after infection. A number of respiratory syncytial virus vaccines and antivirals are currently under development, including several vaccines proposed for maternal immunization. The cotton rat Sigmodon hispidus is an animal model of respiratory syncytial virus infection with demonstrated translational value. Special cohort scenarios, such as infection under conditions of immunosuppression and maternal immunization have been modeled in the cotton rat and are summarized here. In this review, we focus on the recent use of the cotton rat model for testing respiratory syncytial virus vaccine and therapeutic candidates in preclinical setting, including the use of special cohort models. An overview of published studies spanning the period of the last three years is provided. The emphasis, where possible, is made on candidates in the latest stages of preclinical development or currently in clinical trials.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Microbial Sensitivity Tests; Molecular Structure; Rats; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory Syncytial Viruses; Sigmodontinae
PubMed: 29768937
DOI: 10.1177/2040206618770518