The increase in activity followed a long delay after a catastrophic vaccine failure in the s killed two infants.
Infectious Diseases in Children spoke with Ramilo and other experts about some of the historical challenges of RSV vaccine development, the vaccines in the pipeline they are most excited about and how close researchers are to bringing a vaccine to market. RSV is the leading cause of serious lower respiratory diseases in young children worldwide, according to researchers. The virus is estimated to cause up to , deaths annually across the globe, and most of these deaths occur among young children.
About 3. In the United States alone, 75, to , children aged 2 years and younger are hospitalized annually, according to the NIH. The NIH cites RSV as the single most important cause of severe lower respiratory tract infection in young children, frequently causing winter outbreaks of acute respiratory disease. The most common clinical manifestations are upper respiratory tract infections and bronchiolitis, and complications include otitis media and pneumonia.
Among those at highest risk for severe disease are premature infants, young children with congenital heart or chronic lung disease and young children with compromised immune systems, as well as adults with compromised immune systems and older adults, according to the CDC. Although RSV is considered a cold virus, it goes further into the airways in small children and those who are immunocompromised.
The RSV virus was discovered in as the chimpanzee coryza agent, and it was subsequently associated with bronchiolitis in children, according to Barney S.
In a commentary published in Current Opinion in Virology, Graham noted that RSV has multiple mechanisms of evading immunity, including anatomical evasion, conformational evasion of neutralizing antibody and direct modulation of immune function. Direct modulation of immune function includes the NS1 and NS2 proteins interfering with interferon, an innate antiviral defense mechanism, whereas the G protein can bind dendritic cells and affect their function.
The virus evades much of the systemic immune mechanisms by residing primarily outside the body. The immune response from RSV is very different from that of other common viruses, Ramilo said. For instance, if you are infected with measles, you develop immunity for life.
But if you develop RSV, you can acquire it again because there is no immune memory developed against the virus. The process of understanding how to develop protection against RSV has been very slow, Ramilo said, but he is much more optimistic than he was just a few years ago.
Graham noted that there are multiple strategies for developing RSV vaccines. Severe disease most commonly occurs in very young infants. Additionally, children with any of the following underlying conditions are considered at high risk:.
Infants and young children with RSV infection may have rhinorrhea and a decrease in appetite before any other symptoms appear. Cough usually develops one to three days later. Soon after the cough develops, sneezing, fever, and wheezing may occur. Most otherwise healthy infants and young children who are infected with RSV do not need hospitalization. Most improve with supportive care and are discharged in a few days.
Adults who get infected with RSV usually have mild or no symptoms. Symptoms are usually consistent with an upper respiratory tract infection which can include rhinorrhea, pharyngitis, cough, headache, fatigue, and fever. Disease usually lasts less than five days. Pediatrics 99 , — Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Beeler, J. Neutralization epitopes of the F-glycoprotein of respiratory syncytial virus - effect of mutation upon fusion function.
Kwakkenbos, M. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming.
This study reports the isolation and characterization of the first prefusion F-specific monoclonal antibodies, although their specificity was not known at the time. Goodwin, E. Infants infected with respiratory syncytial virus generate potent neutralizing antibodies that lack somatic hypermutation. Immunity 48 , — Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors. Collarini, E. Potent high-affinity antibodies for treatment and prophylaxis of respiratory syncytial virus derived from B cells of infected patients.
Mousa, J. A novel pre-fusion conformation-specific neutralizing epitope on the respiratory syncytial virus fusion protein. Corti, D. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Zhu, Q. A highly potent extended half-life antibody as a potential RSV vaccine surrogate for all infants. Transl Med. US National Library of Medicine.
Costello, H. Targeting RSV with vaccines and small molecule drugs. Drug Targets 12 , — Heylen, E. Drug candidates and model systems in respiratory syncytial virus antiviral drug discovery. Cianci, C. Targeting a binding pocket within the trimer-of-hairpins: small-molecule inhibition of viral fusion. Roymans, D. Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein.
Yan, D. Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors. USA , E—E Battles, M. Molecular mechanism of respiratory syncytial virus fusion inhibitors. This work describes the binding site and mechanism of action for small-molecule fusion inhibitors. Samuel, D. GS inhibits pre- to postfusion conformational changes of the respiratory syncytial virus fusion protein. Agents Chemother.
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Liang, B. Improved prefusion stability, optimized codon usage, and augmented virion packaging enhance the immunogenicity of respiratory syncytial virus fusion protein in a vectored-vaccine candidate. Stobart, C. A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation. Polypeptides of respiratory syncytial virus. Walsh, E. Monoclonal antibodies to respiratory syncytial virus proteins: identification of the fusion protein. Garcia, J. Cytoplasmic inclusions of respiratory syncytial virus-infected cells: formation of inclusion bodies in transfected cells that coexpress the nucleoprotein, the phosphoprotein, and the 22K protein.
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A stabilized headless measles virus attachment protein stalk efficiently triggers membrane fusion. Liu, Q. Unraveling a three-step spatiotemporal mechanism of triggering of receptor-induced Nipah virus fusion and cell entry. Iorio, R. Glycoprotein interactions in paramyxovirus fusion. Future Virol. Neutralizing epitopes on the respiratory syncytial virus fusion glycoprotein. Download references. Melero, a wonderful colleague and scientist who contributed much to the study of the RSV F and G proteins.
The authors thank B. Graham, J. Langedijk and members of the McLellan laboratory for helpful comments on the manuscript, and M. Gilman for assistance with the figures. Nature Reviews Microbiology thanks L. Bont and other anonymous reviewer s for their contribution to the peer review of this work. You can also search for this author in PubMed Google Scholar. Correspondence to Jason S. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Abstract Respiratory syncytial virus RSV is a leading cause of lower respiratory tract disease in young children and elderly people. The virion The RSV genome is Full size image. Glycoprotein synthesis and structure G and F are the major glycoproteins on the surface of the virion and have important roles in entry. Attachment glycoprotein The G protein is produced in infected cells as either a full-length, membrane-bound form that is responsible for viral attachment 36 or as a secreted isoform sG that mediates immune evasion 37 Fig.
Host cell entry The entry process consists of two main steps: attachment of the virion to the host cell and fusion of the viral and host cell membranes Box 1. Box 1 The life cycle of respiratory syncytial virus The infectious cycle of respiratory syncytial virus RSV begins upon attachment of the virion to the apical surface of polarized, ciliated airway epithelial cells 95 see the figure.
Box 2 Paramyxovirus entry The genomes of paramyxoviruses and pneumoviruses encode similar proteins, and until recently, both types of virus were classified in the same family — Paramyxoviridae. Clinical interventions Preclinical and clinical development of RSV interventions primarily falls into three categories: monoclonal antibodies, small molecules and vaccines.
Antibodies High levels of RSV-neutralizing-antibody titres correlate with protection in children and adults, including elderly individuals 4 , , Conclusions and outlook There has been substantial progress in our understanding of RSV entry, although the basic science continues to lag behind clinical advances.
References 1. PubMed Article Google Scholar 2. PubMed Article Google Scholar 9. PubMed Article Google Scholar Article Google Scholar Reviewer information Nature Reviews Microbiology thanks L.
McLellan Authors Michael B. Battles View author publications. View author publications. Ethics declarations Competing interests J. Glossary Nasopharynx The upper part of the pharynx that connects with the nasal cavity.
Bronchioles Small tubes in the lung through which air is delivered to the alveoli. Alveoli Small air sacs in the lung that provide rapid gas exchange with blood. Bronchiolitis Inflammation of the bronchioles that reduces air passage. Formalin An aqueous solution of formaldehyde. Neutrophil Most abundant type of white blood cell. Immune complex An antibody bound to its antigen. Passive immunoprophylaxis The administration of an exogenously produced antibody given before infection occurs.
Apoptosis Programmed cell death. Glycoproteins Proteins to which carbohydrates are covalently attached. Ectodomain The portion of a membrane protein that resides outside the cell or virion. Cystine noose A surface-accessible loop structure containing one or more disulfide bonds. Serotype A serologically distinguishable strain of a microorganism.
Protomer A structural unit of an oligomeric protein. Antigenic drift The accumulation of amino acid substitutions that reduce antibody binding. Apical surface The surface of a polarized cell that faces the lumen or external environment.
Type 1 alveolar pneumocytes Surface epithelial cells of alveoli involved in gas exchange. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents DAAs that target key steps in the viral life cycle.
A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins.
This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection. ReViral Ltd. More by G. Stuart Cockerill. More by James A. More by Neil Mathews. Cite this: J. Article Views Altmetric -. Citations Cited By. This article is cited by 19 publications. Stuart Cockerill, Richard M. Gilman, James A.
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