Trends and Insights into RSV treatment

Role of preclinical models to develop effective therapeutics by Elizabeth Stillman , Director - PCET

Respiratory syncytial virus (RSV) is a common respiratory virus. Since people do not generate life-long immunity following an infection, a single person will have several RSV infections over their lifespan. In most cases, an RSV infection causes mild, cold-like symptoms, especially in older children and healthy adults. However, RSV infections can be more severe, especially in infants and young children as well as older adults. RSV is a significant cause of respiratory illness in children under 2 years old, and it is a leading cause of bronchiolitis (inflammation of the small airways in the lungs) and pneumonia in this age group, resulting in a high incidence of hospitalizations, especially during the winter months. In older adults, especially those with underlying health issues, RSV infections can lead to pneumonia and other serious respiratory complications.

Due to the disease and financial burden caused by RSV, therapies and vaccines are critical to combat RSV infections. Until recently, Synagis was the only approved drug (a monoclonal antibody) for the prevention of RSV disease, and its use was limited to high-risk and premature infants. Recently, new vaccines and monoclonal antibodies have been approved. From the vaccine effort, on May 3, 2023, the US Food and Drug Administration (FDA) approved the world's first RSV vaccine, Arexvy, for individuals aged 60 years and older. A second RSV vaccine, Abrysvo, was approved by the FDA on May 31, 2023, also for individuals aged 60 years and older and has since been approved as a maternal RSV vaccine, given to pregnant women to protect infants aged up to 6 months. From the prophylactic monoclonal antibody approach, the FDA recently approved AstraZeneca’s and Sanofi’s nirsevimab (Beyfortus TM) for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in neonates and infants born during or entering their first RSV season, and in children up to 2 years of age who are vulnerable to severe RSV disease. From the small-molecule antiviral approach, there are no approved therapeutics, however several are in development.

Given the recent successes for vaccines and monoclonal antibodies, what is next for RSV?? There is still a need to develop antivirals to treat disease in high-risk populations. Enanta Pharmaceuticals has had recent preclinical success with their EDP-323 antiviral that targets the RSV L polymerase protein. LINK EDP-323 along with Enanta’s RSV antiviral, EDP-938, are both in clinical stage evaluation. There will also be continued development of alternative RSV vaccines for specific age groups as well as development of vaccines that combine multiple common respiratory viral targets with RSV, such influenza, human metapneumovirus (hMPV) and paramyxoviruses. One example is Icosavax’s, IVX-A12 bivalent vaccine which targets both RSV and hMPV and is in Phase 1 clinical trials.

For pre-clinical RSV research, mice and cotton rats have been used extensively for decades.? While the mouse model has a variety of immunological tools and reagents to evaluate RSV immune responses to infection, the cotton rat is highly permissive to both the RSV A and RSV B strains. Both the mouse and cotton rat are well established models to provide a first pass in vivo analysis before moving forward with non-human primate and clinical trials for the development of RSV vaccines, antibodies, and antivirals.