Nanoparticle vaccine based on the pre-fusion F glycoprotein of respiratory syncytial virus elicits robust protective immune responses

Respiratory syncytial virus (RSV) is a global public health concern. Currently, RSV vaccines are approved only for use in older adults, while preventing the disease in infants and children, as well as ensuring vaccine durability, remains a significant challenge. The pre-fusion conformation of the RSV fusion (F) glycoprotein is a primary target for vaccine development, as it elicits significantly higher neutralizing antibody titers than the post-fusion form. Here, we conjugated either the first-generation RSV pre-fusion F antigen, DS-Cav1, or the second-generation antigen, Sc9-10, to a computationally designed nanoparticle platform, NPM, via a Catcher/Tag system. Conjugating RSV pre-fusion F to NPM significantly enhanced immunogenicity, stability, and bioactivity compared to display on the I53-50 nanoparticle platform. In a cotton rat challenge model, Sc9-10-NPM vaccine candidates provided effective protection across a wide dosage range, regardless of the adjuvant used. These results support the continued development of this promising nanoparticle-based RSV vaccine candidate.IMPORTANCERespiratory syncytial virus (RSV) is a major cause of severe respiratory illness in infants and young children worldwide, yet few vaccines are approved for use in these vulnerable groups. In this study, we developed a new vaccine candidate based on a second-generation RSV pre-fusion F protein, engineered for improved stability and immune response. This protein was displayed on a specially designed nanoparticle platform to enhance its effectiveness and durability. The vaccine elicited strong immune responses and provided complete protection in preclinical models, even without the use of potent adjuvants that may cause side effects. Importantly, it did not trigger adverse vaccine-enhanced disease (VED). These findings suggest that this vaccine design could offer a safer and more effective way to protect infants and other at-risk populations from RSV. Additionally, the nanoparticle platform may be applicable to vaccines against other infectious diseases.