The Experts below are selected from a list of 216 Experts worldwide ranked by ideXlab platform

Giovanni Piedimonte - One of the best experts on this subject based on the ideXlab platform.

  • respiratory syncytial virus prevention and therapy past present and future
    Pediatric Pulmonology, 2011
    Co-Authors: Melvin Wright, Giovanni Piedimonte
    Abstract:

    Respiratory syncytial virus (RSV) is the most common respiratory pathogen in infants and young children worldwide. More than 50 years after its discovery, and despite relentless attempts to identify pharmacological therapies to improve the clinical course and outcomes of this disease, the most effective therapy remains supportive care. Although the quest for a safe and effective vaccine remains unsuccessful, pediatricians practicing during the past decade have been able to protect at least the more vulnerable patients with safe and effective Passive Prophylaxis. This review summarizes the history, microbiology, epidemiology, pathophysiology, and clinical manifestations of this infection in order to provide the reader with the background information necessary to fully appreciate the many challenges presented by the clinical management of young children with bronchiolitis. The last part of this article attempts an evidence-based review of the pharmacologic strategies currently available and those being evaluated, intentionally omitting highly experimental approaches not yet tested in clinical trials and, therefore, not likely to become available in the foreseeable future.

  • Palivizumab in the Prophylaxis of respiratory syncytial virus infection
    Expert Review of Anti-infective Therapy, 2005
    Co-Authors: Silvia Cardenas, Alexander Auais, Giovanni Piedimonte
    Abstract:

    Respiratory syncytial virus infection continues to be one of the most important health problems in infancy. Active Prophylaxis against this infection (i.e., vaccination) is not available. Therefore, protection of high-risk infants is possible only by Passive Prophylaxis with specific antibodies. Palivizumab (Synagis®) and respiratory syncytial virus intravenous immune globulin are licensed by the US Food and Drug Administration for the prevention of severe lower respiratory tract infections caused by respiratory syncytial virus in infants with bronchopulmonary dysplasia, infants with a history of premature birth (≤35 weeks gestational age) and children with hemodynamically significant congenital heart disease. Palivizumab is a humanized monoclonal antibody produced by recombinant DNA technology, directed to an epitope in the A antigenic side of the F-protein of the respiratory syncytial virus. This review discusses the characteristics of this drug in detail.

  • Effect of Respiratory Syncytial Virus on Apnea in Weanling Rats
    Pediatric Research, 2005
    Co-Authors: Carlos Sabogal, Alexander Auais, Galia Napchan, Edward Mager, Bo-guang Zhou, Cleide Suguihara, Eduardo Bancalari, Giovanni Piedimonte
    Abstract:

    Apnea is a common complication of respiratory syncytial virus (RSV) infection in young infants. The purpose of this study was to determine whether this infection affects apnea triggered by sensorineural stimulation in weanling rats. We also studied which neurotransmitters are involved in this response and whether Passive Prophylaxis with a specific neutralizing antibody (palivizumab) confers protection against it. Weanling rats were inoculated intranasally with RSV, adenovirus, or virus-free medium. Changes in respiratory rate and apnea in response to nerve stimulation with increasing doses of capsaicin were measured by plethysmography. Capsaicin-induced apnea was significantly longer in RSV-infected rats at postinoculation days 2 (upper airways infection) and 5 (lower airways infection), and apnea-related mortality occurred only in the RSV-infected group. Reduction in the duration of apnea was observed after selective inhibition of central γ-aminobutyric acid (GABA) type A receptors and neurokinin type 1 receptors for substance P. Prophylactic palivizumab protected against apnea and apnea-related mortality. These results suggest that sensorineural stimulation during RSV infection is associated with the development of apnea and apnea-related death in early life, whose mechanism involves the release of GABA acting on central GABA type A receptors and substance P acting on neurokinin type 1 receptors.

  • Persistent Airway Inflammation after Resolution of Respiratory Syncytial Virus Infection in Rats
    Pediatric Research, 2004
    Co-Authors: Giovanni Piedimonte, Richard G Hegele, Alexander Auais
    Abstract:

    Neurogenic inflammation is markedly potentiated in airways that are infected with respiratory syncytial virus (RSV). Aims of this study were to determine whether this potentiation persists after the virus is cleared, investigate the mechanism of postviral potentiation, and define whether Prophylaxis with a MAb against the RSV fusion protein (palivizumab) prevents this effect. Thirty days after inoculation, no evidence of active RSV infection was found in the airway epithelium by plaque assay or immunostaining and no viral nucleic sequences were detected by PCR, yet capsaicin-induced plasma extravasation in the airways that were infected 30 d earlier with RSV was still significantly larger compared with pathogen-free controls. Substance P content in lung tissues and capsaicin-induced release of this peptide from sensory nerves were significantly increased at 30 d. The administration of palivizumab 24 h before virus inoculation prevented the development of abnormal neurogenic inflammatory responses. Our data suggest that the airways remain abnormally susceptible to the proinflammatory effects of sensory nerves after RSV infection is cleared, as a result of changes in sensory innervation, and that this abnormality can be prevented by Passive Prophylaxis against RSV.

Man Chen - One of the best experts on this subject based on the ideXlab platform.

  • Structural basis of respiratory syncytial virus subtype-dependent neutralization by an antibody targeting the fusion glycoprotein.
    Nature communications, 2017
    Co-Authors: Daiyin Tian, Man Chen, Syed M. Moin, Michael B. Battles, Kayvon Modjarrad, Azad Kumar, Masaru Kanekiyo, Kevin W. Graepel, Noor M. Taher, Anne L. Hotard
    Abstract:

    A licensed vaccine for respiratory syncytial virus (RSV) is unavailable, and Passive Prophylaxis with the antibody palivizumab is restricted to high-risk infants. Recently isolated antibodies 5C4 and D25 are substantially more potent than palivizumab, and a derivative of D25 is in clinical trials. Here we show that unlike D25, 5C4 preferentially neutralizes subtype A viruses. The crystal structure of 5C4 bound to the RSV fusion (F) protein reveals that the overall binding mode of 5C4 is similar to that of D25, but their angles of approach are substantially different. Mutagenesis and virological studies demonstrate that RSV F residue 201 is largely responsible for the subtype specificity of 5C4. These results improve our understanding of subtype-specific immunity and the neutralization breadth requirements of next-generation antibodies, and thereby contribute to the design of broadly protective RSV vaccines.

  • Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors
    Science immunology, 2016
    Co-Authors: Morgan S.a. Gilman, Carlos A. Castellanos, Man Chen, Joan O. Ngwuta, Eileen C. Goodwin, Syed M. Moin, Vicente Mas, José A. Melero, Peter F. Wright, Barney S. Graham
    Abstract:

    Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in young children and the elderly. There are currently no licensed RSV vaccines, and Passive Prophylaxis with the monoclonal antibody palivizumab is restricted to high-risk infants in part due to its modest efficacy. Although it is widely agreed that an effective RSV vaccine will require the induction of a potent neutralizing antibody response against the RSV fusion (F) glycoprotein, little is known about the specificities and functional activities of RSV F-specific antibodies induced by natural infection. Here, we have comprehensively profiled the human antibody response to RSV F by isolating and characterizing 364 RSV F-specific monoclonal antibodies from the memory B cells of three healthy adult donors. In all donors, the antibody response to RSV F is comprised of a broad diversity of clones that target several antigenic sites. Nearly half of the most potent antibodies target a previously undefined site of vulnerability near the apex of the prefusion conformation of RSV F (preF), providing strong support for the development of RSV vaccine candidates that preserve the membrane-distal hemisphere of the preF protein. Additionally, the antibodies targeting this new site display convergent sequence features, thus providing a future means to rapidly detect the presence of these antibodies in human vaccine samples. Many of the antibodies that bind preF-specific surfaces are over 100 times more potent than palivizumab, and several cross-neutralize human metapneumovirus (HMPV). Taken together, the results have implications for the design and evaluation of RSV vaccine candidates and offer new options for Passive Prophylaxis.

  • RESEARCH ARTICLE Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein
    2016
    Co-Authors: Morgan S.a. Gilman, Man Chen, Syed M. Moin, Vicente Mas, Azad Kumar, Nita K. Patel, Kari Kramer, Qing Zhu, Stephanie C. Kabeche, Concepción Palomo
    Abstract:

    Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for Passive Prophylaxis and have also aided the design of vaccine antigens that display prefusion-specific epitopes. To date, prefusion-specific antibodies have been shown to target two antigenic sites on RSV F, but both of these sites are also present on monomeric forms of F. Here we present a structural and functional characteriza-tion of human antibody AM14, which potently neutralized laboratory strains and clinical iso-lates of RSV from both A and B subtypes. The crystal structure and location of escape mutations revealed that AM14 recognizes a quaternary epitope that spans two protomers and includes a region that undergoes extensive conformational changes in the pre- to post-fusion F transition. Binding assays demonstrated that AM14 is unique in its specific recogni-tion of trimeric furin-cleaved prefusion F, which is the mature form of F on infectious virions. These results demonstrate that the prefusion F trimer contains potent neutralizing epitope

  • Characterization of a Prefusion-Specific Antibody That Recognizes a Quaternary, Cleavage-Dependent Epitope on the RSV Fusion Glycoprotein.
    PLoS pathogens, 2015
    Co-Authors: Morgan S.a. Gilman, Man Chen, Syed M. Moin, Vicente Mas, Azad Kumar, Nita K. Patel, Kari Kramer, Qing Zhu, Stephanie C. Kabeche, Concepción Palomo
    Abstract:

    Prevention efforts for respiratory syncytial virus (RSV) have been advanced due to the recent isolation and characterization of antibodies that specifically recognize the prefusion conformation of the RSV fusion (F) glycoprotein. These potently neutralizing antibodies are in clinical development for Passive Prophylaxis and have also aided the design of vaccine antigens that display prefusion-specific epitopes. To date, prefusion-specific antibodies have been shown to target two antigenic sites on RSV F, but both of these sites are also present on monomeric forms of F. Here we present a structural and functional characterization of human antibody AM14, which potently neutralized laboratory strains and clinical isolates of RSV from both A and B subtypes. The crystal structure and location of escape mutations revealed that AM14 recognizes a quaternary epitope that spans two protomers and includes a region that undergoes extensive conformational changes in the pre- to postfusion F transition. Binding assays demonstrated that AM14 is unique in its specific recognition of trimeric furin-cleaved prefusion F, which is the mature form of F on infectious virions. These results demonstrate that the prefusion F trimer contains potent neutralizing epitopes not present on monomers and that AM14 should be particularly useful for characterizing the conformational state of RSV F-based vaccine antigens.

  • Structure of a Major Antigenic Site on the Respiratory Syncytial Virus Fusion Glycoprotein in Complex with Neutralizing Antibody 101F
    Journal of virology, 2010
    Co-Authors: Jason S. Mclellan, Man Chen, Barney S. Graham, Jung-san Chang, Yongping Yang, Albert Kim, Peter D. Kwong
    Abstract:

    Respiratory syncytial virus (RSV) is a major cause of pneumonia and bronchiolitis in infants and elderly people. Currently there is no effective vaccine against RSV, but Passive Prophylaxis with neutralizing antibodies reduces hospitalizations. To investigate the mechanism of antibody-mediated RSV neutralization, we undertook structure-function studies of monoclonal antibody 101F, which binds a linear epitope in the RSV fusion glycoprotein. Crystal structures of the 101F antigen-binding fragment in complex with peptides from the fusion glycoprotein defined both the extent of the linear epitope and the interactions of residues that are mutated in antibody escape variants. The structure allowed for modeling of 101F in complex with trimers of the fusion glycoprotein, and the resulting models suggested that 101F may contact additional surfaces located outside the linear epitope. This hypothesis was supported by surface plasmon resonance experiments that demonstrated 101F bound the peptide epitope ∼16,000-fold more weakly than the fusion glycoprotein. The modeling also showed no substantial clashes between 101F and the fusion glycoprotein in either the pre- or postfusion state, and cell-based assays indicated that 101F neutralization was not associated with blocking virus attachment. Collectively, these results provide a structural basis for RSV neutralization by antibodies that target a major antigenic site on the fusion glycoprotein.

Yoh-ichi Matumoto - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of Varicella-Zoster Virus (VZV) Glycoprotein Expression by a Human Monoclonal Antibody against VZV Glycoprotein III
    The Journal of infectious diseases, 1993
    Co-Authors: Masahiro Ito, Ken-ichi Mizutani, Toshiya Kamiya, Toshiaki Ihara, Hitoshi Kamiya, Minom Sakurai, Toru Sugano, Yoh-ichi Matumoto
    Abstract:

    Effects of human monoclonal antibodies (MAbs) against varicella-zoster virus (VZV) glycoproteins (gp) on VZV glycoprotein expression were analyzed by flow cytometry. Human embryonic fibroblast (HEF) cells were inoculated with cell-free VZV and cultured in the presence of human MAbs. While human MAbs directed against gpI (V2) and -II (V1) did not affect VZV expression, a human MAb against gpIII (V3) inhibited expression of VZV gpI, -II, -III, and -IV. V3 also inhibited spread of VZV from infected to uninfected cells. Interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha were able to synergize with V3 and inhibit VZV gp expression. These results suggest that human MAb V3 may be useful for Passive Prophylaxis against VZV infection and for treatment of severe VZV infection.

Hasan S. Jafri - One of the best experts on this subject based on the ideXlab platform.

  • Treatment of respiratory syncytial virus: antiviral therapies
    Pediatric Infectious Disease Journal, 2003
    Co-Authors: Hasan S. Jafri
    Abstract:

    Treatment of respiratory syncytial virus (RSV) in infants with bronchiolitis is complicated because of the multifactorial nature of this infection. The signs and symptoms of RSV result from a combination of direct viral cytopathic effects, host inflammatory responses that lead to airway obstruction and bronchoconstriction. It is logical that therapies targeting just one of these processes might be minimally effective, at best. Thus an important goal is to identify patients at risk and intervene to prevent disease, whenever possible. Once disease has been identified, the clinician must decide whether antiviral therapy is appropriate. Familiarity with typical viral load dynamics during the course of a lower respiratory tract infection can assist in the therapeutic decision process. For example in a patient who has had airway obstruction and other respiratory symptoms for >3 days, viral load has already peaked. Clearly this pattern has important implications for antiviral therapies. Preventive strategies include educating parents and family about hand washing, cleaning environmental surfaces, isolating infants and children with infection and avoiding crowded places such as busy day-care centers. High risk patients, who meet the American Academy of Pediatrics criteria for RSV Prophylaxis, may be candidates for Passive Prophylaxis.

Gregory A Prince - One of the best experts on this subject based on the ideXlab platform.

  • Respiratory syncytial virus antiviral agents
    Expert Opinion on Therapeutic Patents, 1999
    Co-Authors: Gregory A Prince
    Abstract:

    Control of respiratory syncytial virus (RSV) disease has remained an elusive goal for over four decades. Ribavirin (Virazole®), licensed as an RSV therapeutic over a decade ago, has been viewed with decreasing enthusiasm by clinicians but no other therapeutic regimen has emerged as a preferred alternative. Passive Prophylaxis using polyclonal or monoclonal immunoglobulins has proven safe and effective, but high costs have generally limited utilisation to high-risk infants leaving the larger infant population, as well as several subpopulations of high-risk children and adults, without a widely-applicable form of Prophylaxis. Many classes of anti-RSV compounds have been identified, acting at various stages of the viral replication cycle. Most have shown antiviral activity only in vitro, but even those showing in vivo activity have failed to show a significant clinical therapeutic effect. While insufficiently potent antiviral activity might explain this phenomenon, a more likely explanation is that an effect...