Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infections in infants, the elderly, and immunocompromised individuals. RSV possesses a single-stranded, negative-sense RNA genome encoding 11 viral proteins. Strategies to combat RSV infection primarily focus on prevention, including vaccination and passive immunization. The F protein, highly conserved across different strains, is a primary target for RSV vaccine development.
RSV's structure and function
The RSV viral genome is 15.2 kilobase pairs long and contains 10 genes arranged in the sequence 3'-NS1-NS2-NPM-SH-GF-(M2-1/M2-2)-L-5', encoding 11 proteins. Non-structural proteins (NS1) and (NS2) help evade the innate immune response. They inhibit apoptosis and interferon (IFN) activation signaling pathways, thereby promoting viral replication. Small hydrophobic proteins (SH), adhesion proteins (G), and fusion proteins (F) are transmembrane glycoproteins. Among them, F and G proteins are crucial for viral invasion of host cells. The F protein usually exists in a trimer form, transitioning from a pre-F conformation to a post-F conformation during viral-host cell membrane fusion. The F protein is highly conserved among different strains and is a major target for RSV vaccine development. Small hydrophobic proteins (SH) act as viral channel proteins, enhancing membrane permeability and regulating host cell apoptosis. Nucleoproteins (N) encapsulate the viral genome, preventing its degradation and serving as templates for transcription and replication. The large polymerase protein (L), nucleoprotein (N), and phosphoprotein (P) form an RNA-dependent RNA polymerase (RdRp) complex, essential for viral transcription and replication. Four nucleocapsid proteins (N, P, L, and M2-1) interact with the viral genome RNA assembly to form a helical ribonucleoprotein (RNP) complex. The M2 gene has two overlapping open reading frames encoding two proteins, M2-1 and M2-2. M2-1 links the M protein to the RNP, while M2-2 is involved in transcription and replication. The matrix protein (M), located within the viral envelope, is necessary for viral particle assembly and release.
(Data source: Huang X) et al. Microorganisms. 2026)
Pathological mechanisms of RSV
RSV initially invades the upper respiratory tract and gradually spreads to the lower respiratory tract. The virus primarily targets ciliated epithelial cells, leading to cell damage and extensive shedding. Simultaneously, host pattern recognition receptors (TLRs and RIG-I) activate the immune response upon viral recognition, inducing the release of IL-33 and TSLP. These factors subsequently trigger the activation of ILC2 and Th2 cells, resulting in excessive secretion of type 2 cytokines. This excessive inflammatory response promotes the recruitment of immune cells and characteristic pathological changes, leading to obstructive bronchial pathology. Upon alveolar invasion, RSV inhibits the production and secretion of surfactant by type II alveolar epithelial cells, impairs alveolar fluid clearance, and induces inflammatory vascular leakage. These pathological changes collectively lead to alveolar collapse, pulmonary edema, and impaired gas exchange, ultimately manifesting as severe pneumonia.
(Data source: Liang X, et al. MedComm (2020). 2025)
Targeted therapy for RSV
Vaccines for the elderly and pregnant women have been approved for marketing, providing effective active immunization protection for high-risk groups. To date, the U.S. Food and Drug Administration (FDA) has approved two preventive antibodies (Palivizumab and Nirsevimab ) and three RSV vaccines (Arexvy, Abrysvo, and mRESVIA). However, no vaccines have yet been approved for infants and young children. Therefore, in this vulnerable population, passive immunization with antibodies is the only prevention/treatment option against RSV.
(Data source: Liang X, et al. MedComm (2020). 2025)
Palivizumab is a human-mouse chimeric monoclonal antibody targeting the pre-F protein antigen site II , currently approved for the prevention of respiratory syncytial virus (RSV) infection in preterm infants and infants with congenital heart disease or respiratory distress syndrome (BPD). In high-risk infants, palizumab has been shown to reduce morbidity but not mortality. Furthermore, due to its limited cost-effectiveness, the American Academy of Pediatrics revised its eligibility criteria for palizumab treatment in 2014 to limit its clinical use. The revision eliminated routine palizumab treatment for children born between 29 and 35 weeks of age without BPD and discontinued palizumab prophylaxis after RSV infection.
Motavizumab (MEDI-524) is a second-generation humanized recombinant IgG1 monoclonal antibody derived from the in vitro affinity maturation of the mouse complementary decision regions of the heavy and light chains of palivizumab. Like palivizumab, it targets antigenic site II of the pre-F fusion protein. Its binding affinity to the RSV F glycoprotein is 70 times that of palivizumab, and its in vitro RSV neutralization capacity is approximately 20 times that of palivizumab. This increased neutralizing activity may be associated with a further reduction in RSV replication and a significant decrease in cytokine and chemokine concentrations. MEDI-524 also outperforms palivizumab in terms of long-term pulmonary abnormalities. MEDI-524 significantly reduces RSV viral load in the lungs and upper respiratory tract, shortening the duration and severity of the disease.
Suptavumab is another Palivizumab-based anti-F protein monoclonal antibody that targets antigenic site V of the pre-F fusion protein. Although preclinical studies demonstrated high efficacy of suptavumab against RSV in a cotton rat model, it failed to show clinical benefit for RSV-related hospitalized or outpatient lower respiratory tract infections in a phase III clinical trial in preterm infants. The primary reason for this failure was the discovery of two amino acid mutations (L172Q and S173L) in all circulating RSV-B strains, which prevented suptavumab from binding to its F protein. Therefore, development of suptavumab was terminated due to failure to meet clinical endpoints.
(Data source: Liang X, et al. MedComm (2020). 2025)
