Respiratory Syncytial Virus Entry and Interventions

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease in young children and elderly people. RSV is a filamentous enveloped, negative-sense, single-stranded RNA virus that belongs to the Ortho-pneumovirus genus of the pneumoviridae family in the order mononegavirales, which is usually transmitted through close contact After a short period of replication in the epithelial lining of the nasopharynx and upper respiratory tract, an RSV infection may spread to the small bronchioles or alveoli of the lower respiratory tract. Host immune responses to RSV infection increase mucus production and inflammation, leading to a narrowing of the airway that results in bronchiolitis in young children and acute respiratory illness in older adults or those with underlying chronic conditions. Currently, the only licensed intervention for RSV is passive immunoprophylaxis of high-risk infants with a humanized monoclonal antibody.

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Fig 1. Respiratory syncytial virus virion.
(Source: Microbiology, February 2019.)

Clinical Interventions

Preclinical and clinical development of RSV interventions primarily falls into three categories: monoclonal antibodies, small molecules and vaccines.

RSV Monoclonal Antibodies. High levels of RSV-neutralizing-antibody titres correlate with protection in children and adults, including elderly individuals. In the late 1990s and early 2000s, an RSV intravenous immune globulin infusion preparation, RespiGam, was used prophylactically to prevent severe RSV associated lower respiratory tract disease in young children with bronchopulmonary dysplasia or premature birth. In 2003, palivizumab (Synagis), a humanized murine monoclonal antibody that binds the F glycoprotein was used. During the past 10 years, hundreds of human-derived antibodies directed against the RSV F and RSV G proteins have been isolated and characterized, and cocktails of antibodies against F and G, or against two different antigenic sites on F, are also being considered.

Small-molecule fusion inhibitors. On the basis of crosslinking studies with RSV virions138 and biochemical and structural studies with peptides comprising the heptad repeats of the RSV F1 subunit, it was thought that the small molecules bound to a fusion intermediate of F and prevented the postfusion conformation from completely forming.

Vaccines. Attributed to the study of the structure and function of the viral proteins, the morphology and architecture of the virion, the immune responses to natural infection and the causes of vaccine-enhanced disease. These advances have created a complex vaccine landscape with over 30 candidates in clinical or preclinical development. Vaccine development of candidates containing the F protein has focused on structure-based engineering approaches to stabilize F in the prefusion conformation. For particle-based and subunit-based vaccines intended for elderly individuals or maternal immunization, the challenge will be to induce an antibody response of sufficient titer and duration to protect elderly people and newborns from severe disease during the RSV season. Live-attenuated and chimeric virus vaccines are primarily intended for the paediatric population, vaccines based on viral vectors and DNA or RNA are also thought to be safe for infants.

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