From one shot for the few to one shot for all: Respiratory syncytial virus (RSV) prevention is finally catching up to the science

Review written by: Roshni Kadam

Respiratory syncytial virus (RSV) is a major global health concern and the leading cause of respiratory tract infections (LRTI) in children, particularly those under the age of six. It is estimated to cause around 33 million LRTI cases, 3.6 million hospitalizations, and more than 100,000 deaths in children under five each year. Efforts to develop a vaccine largely failed, shifting focus toward passive prophylaxis instead. The first RSV prophylaxis approved was palivizumab, a monoclonal antibody that has been in use for over a decade. Its major limitation, though, is that it is restricted to high-risk infants and offers only a limited duration of protection. Advances in structural and antibody engineering led to the discovery of newly designed antibodies nirsevimab and clesrovimab, which have performed better, enabling RSV prevention to every infant. Both nirsevimab and clesrovimab work by binding the RSV fusion (F) protein and locking it in its pre-fusion conformation, acting through two mechanisms: direct neutralization, which blocks viral entry, and Fc-mediated immune function, which recruits the infant's own immune cells to clear the infection. Nirsevimab binds site Ø, while clesrovimab targets site IV of the viral antigen.

Figure. Evolution of RSV Immunoprophylaxis: From the Palivizumab Era to Next-Generation Monoclonal Antibodies

In Merck's CLEVER phase 2b–3 clinical trial, clesrovimab reduced severe RSV infection by 92% and RSV hospitalization by 91%. Even so, some infants still develop RSV LRTI in their first months of life, and the mechanism behind these breakthrough infections isn't yet fully understood, thus the requirement for better technology to address RSV LTRI. Two factors are thought to drive breakthrough infections: viral antigenic escape, where mutations arise in the antibody's target site, and host-dependent factors where the pharmacokinetic properties of mAbs differ between infants and adults. In addition, the host immune system recognizes mAbs as foreign proteins and mounts an immune response by producing anti-drug antibodies (ADAs). These ADAs form immune complex that accelerates Ab clearance, reducing therapeutic efficacy. Recent studies in oncology and HIV research offer a promising path forward for RSV prevention, primarily through two emerging strategies beyond nirsevimab and clesrovimab: bispecific antibodies and nanobodies. The field's next step is to consolidate nirsevimab's success while building on these strategies, with the goal of reducing RSV infections in early childhood globally.