Respiratory syncytial Virus (RSV)

What is Respiratory syncytial Virus (RSV)?

Respiratory syncytial virus (RSV) is an RNA virus in the family Paramyxoviridae with a genome of negative-stranded single-stranded RNA. It was first isolated in 1956 by scientist Morris from the nasopharyngeal secretions of chimpanzees, an experimental animal with cold symptoms. In 1957, Chanock also isolated the virus from throat swab specimens from two children with pneumonia and wheezing. Because it causes adjacent cells to fuse during cell culture, the cell lesion forms a structure similar to syncytia, which is vividly called the respiratory syncytial virus. It is highly contagious, one is transmitted through droplets, that is, through coughing or sneezing, the droplets produced are transmitted from person to person, or pollute the surface of environmental objects. The second is through contact transmission, which is mainly transmitted through hand contact with the environment and surfaces contaminated by the virus or the face of a person, and then through contact with one's own mouth, nose and face.

Respiratory syncytial Virus pathophysiology

RSV is mainly transmitted through airborne droplets or contact with contaminated objects. Once the virus enters the body, it first infects the epithelial cells of the nasopharynx and then rapidly spreads to the lower respiratory tract. During infection, the F protein of RSV induces syncytial action in respiratory epithelial cells to form multinucleated giant cells, which is the origin of the name RSV.

Pathological responses elicited by RSV infection include infiltration of inflammatory cells, increased airway secretions, and airway obstruction. These reactions may cause dyspnea, especially in young children and patients with underlying lung disease. Viral infection can also cause the shedding of bronchial epithelial cells, leading to narrowing of the airways and airflow limitation. In severe cases, RSV infection may lead to alveolar inflammation and edema, further worsening respiratory function.

The genome of RSV is a linear single-stranded RNA surrounded by a helical nucleocapsid, which in turn is surrounded by a lipoprotein envelope, giving it a spherical or filamentous appearance. The RSV genome is approximately 15.2 kb in length and contains 10 open reading frames (ORFs) encoding 11 proteins, 9 of which are structural proteins and 2 are non-structural proteins, which are essential for pathogenicity and immune evasion. The 9 structural proteins included 4 envelope proteins: adhesion protein G, fusion protein F, matrix protein M, and small hydrophobic protein SH. and 5 ribosomal proteins: nucleoprotein N, phosphoprotein P, polymerase subunit protein L, M2-1, M2-2. The nonstructural proteins NS-1 and NS-2 play an important role in inhibiting innate immune induction, interferon-stimulated gene (ISG) expression, and dendritic cell maturation.

Fig.1 Structure diagram of RSV virion. (Azzari Chiara, et al., 2021)

RSV infectious disease

RSV is a highly contagious pathogen with a significant increase in infection rates, especially during the winter and early spring epidemic seasons. RSV can be transmitted by droplets or by touching contaminated surfaces. RSV transmission is very common in infants and young children, and almost all children under the age of two will experience at least one RSV infection. The virus can also cause severe respiratory illness in the elderly and immunocompromised people.

The clinical manifestations of RSV infection are varied, and mild cases only present with cold-like symptoms, such as nasal congestion, cough, fever, etc. In severe cases, it can lead to acute bronchitis, bronchiolitis or pneumonia, and even respiratory failure. RSV infection in older adults or people with chronic cardiopulmonary disease is usually more severe and at higher risk of hospitalization and death.

Treatments for Respiratory syncytial Virus

To date, there is no effective treatment for respiratory syncytial virus (RSV) infection worldwide. Current treatment is focused on symptomatic management and broad-spectrum antiviral therapy. In recent years, many researchers have explored a lot of drugs for the prevention and treatment of RSV, and some drugs such as monoclonal antibodies, fusion inhibitors and immunoglobulins have entered the phase III clinical research stage, which brings new hope for the prevention and treatment of RSV.

Vaccine treatment

In terms of immunoglobulin, RSV intravenous immunoglobulin (RSV-IVIG) is a polyclonal antibody preparation composed of IgG with strong specificity. Immunoglobulin R-001 has completed a number of clinical studies and has shown good antiviral and anti-infective effects.

Although there is no RSV prophylactic vaccine on the market in the world, with the in-depth study of the structure of RSV F protein, RSV vaccine candidates have made significant progress. As of September 2021, there are 33 RSV vaccines in development, of which 20 are in clinical trials, including mRNA vaccines, recombinant vector vaccines, subunit vaccines, virus-like particle vaccines, live attenuated vaccines, and chimeric vaccines. These studies offer new hope for RSV prevention.

Medicine therapy

Antivirals: Ribavirin is a drug with broad antiviral activity that was approved by the United States Food and Drug Administration (FDA) in 1985 for the treatment of severe respiratory syncytial virus (RSV) lower respiratory tract infections. Zirixorvir (AK0529, RO-0529) is a potent and selective oral bioavailable inhibitor of respiratory syncytial virus (RSV) fusion (F) protein. It has significant anti-RSV activity with an EC50 value of 3 nM and exhibits a favorable animal pharmacokinetic profile. Similarly, Presatovir is a viral fusion protein inhibitor with an EC50 of 0.43 nM. Presatovir can inhibit a variety of respiratory syncytial virus clinical isolates by blocking the virus-cell fusion process, and can interfere with the conformational changes of RSV fusion proteins before and after fusion. Currently, a phase II clinical trial for the treatment of respiratory syncytial virus infection is ongoing.

Interferon (IFN): Another drug widely used in antiviral therapy. In particular, recombinant human α interferon has shown some potential in antiviral therapy, which can be used in combination with conventional supportive care to help reduce the symptoms of RSV infection and speed up the recovery process of patients.

Monoclonal antibody: Palivizumab is currently the only biologic approved by the FDA for the prevention of RSV infection in high-risk children. Palivizumab specifically recognizes and binds to epitope II of the RSV F protein, thereby effectively preventing the virus from entering the host cell and exerting its preventive effect. In 2014, the United States Academy of Pediatrics specifically recommended the drug for preterm infants (less than 32 weeks' gestational age) with severe hemodynamic abnormalities, heart disease, or chronic lung disease to reduce the risk of RSV infection. In addition, Nirsevimab, jointly developed by AstraZeneca and Sanofi, is a novel recombinant human immunoglobulin monoclonal antibody that exhibits a stronger neutralizing effect than Palivizumab by preventing RSV from fusing with cell membranes.

The study also found that the inflammatory response plays an important role in the development of severe RSV disease, suggesting that combining antiviral drugs with anti-inflammatory therapy may be an effective strategy for the treatment of RSV infection. In addition, experimental studies have also suggested that the anti-influenza drug Enzaplatovir may play a certain role in the treatment of RSV infection, although this finding needs to be further validated, but it provides new possibilities for the treatment of RSV infection.

Reference

• Azzari, Chiara, et al., Epidemiology and prevention of respiratory syncytial virus infections in children in Italy. Italian Journal of Pediatrics 47 (2021): 1-12.

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