A foldon-free prefusion F trimer vaccine for respiratory syncytial virus to reduce off-target immune responses

Area of Science:

• Virology
• Vaccinology
• Structural Biology

Background:

• Respiratory syncytial virus (RSV) causes significant respiratory illness in infants and the elderly.
• Current RSV vaccines utilize prefusion F (preF) trimers with foldon domains, which can elicit undesirable anti-foldon antibodies.
• These antibodies may impact vaccine efficacy and safety.

Purpose of the Study:

• To design a novel, foldon-free RSV preF trimer immunogen.
• To overcome the limitations of existing RSV vaccines related to anti-foldon antibody responses.
• To develop a potentially more effective and safer next-generation RSV vaccine candidate.

Main Methods:

• Molecular dynamics simulations to understand preF destabilization.
• Introduction of amino acid substitutions to stabilize the preF trimer.
• Antigenic analysis and cryo-electron microscopy to validate the prefusion conformation.
• Immunogenicity and protective efficacy studies in mouse models and non-human primates.

Main Results:

• A stable, foldon-free RSV preF trimer was successfully designed.
• The new design elicits strong immunogenicity and protective responses in naive and pre-exposed animal models.
• Neutralizing antibody titers were comparable to approved RSV vaccines.
• Absence of undesirable anti-foldon antibody responses was confirmed.

Conclusions:

• The foldon-free RSV preF trimer represents a promising immunogen for next-generation vaccines.
• This design overcomes the issue of anti-foldon antibodies seen with current vaccines.
• Further development could lead to improved RSV vaccines with enhanced safety and efficacy profiles.