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Rational design of a highly immunogenic prefusion-stabilized F glycoprotein antigen for a respiratory syncytial virus
Ye Che1, Alexey V Gribenko2, Xi Song1
1Discovery Sciences, Pfizer Inc, Groton, CT 06340, USA.
Insights
Developing a stable prefusion F antigen for respiratory syncytial virus (RSV) has led to a promising bivalent vaccine. This investigational RSV vaccine shows efficacy in infants and older adults.
Area of Science:
- Virology
- Immunology
- Vaccine Development
Background:
- Respiratory syncytial virus (RSV) is a major global cause of severe respiratory illness in infants and a significant cause of respiratory disease in older adults.
- Currently, no vaccine is available for RSV prevention.
- The prefusion conformation of the RSV fusion (F) glycoprotein is the primary target for potent neutralizing antibodies and a critical antigen for vaccine design.
Purpose of the Study:
- To design and optimize immunogens that enhance the conformational stability and immunogenicity of the RSV prefusion F glycoprotein.
- To develop a stable prefusion F antigen suitable for a potential RSV vaccine.
Main Methods:
- Employed a computational and experimental strategy to engineer and screen nearly 400 F constructs.
- Utilized in vitro and in vivo characterization studies, including serum-neutralizing assays in cotton rats.
- Introduced stabilizing mutations onto F glycoprotein backbones of dominant circulating RSV genotypes (subgroups A and B).
Main Results:
- Identified engineered F constructs with enhanced conformational stability in the prefusion state.
- Achieved approximately 10-fold higher serum-neutralizing titers in cotton rats compared to the DS-Cav1 control.
- A bivalent vaccine formulation of stabilized antigens conferred complete protection against RSV challenge in cotton rats without disease enhancement.
Conclusions:
- The developed stabilized prefusion F antigens are highly immunogenic and protective against RSV.
- A bivalent vaccine incorporating these antigens has demonstrated efficacy in pivotal Phase 3 trials for both infant and older adult populations.
- This represents a significant advancement towards a broadly protective RSV vaccine.
Abstract:
Respiratory syncytial virus (RSV) is the leading, global cause of serious respiratory disease in infants and is an important cause of respiratory illness in older adults. No RSV vaccine is currently available. The RSV fusion (F) glycoprotein is a key antigen for vaccine development, and its prefusion conformation is the target of the most potent neutralizing antibodies. Here, we describe a computational and experimental strategy for designing immunogens that enhance the conformational stability and immunogenicity of RSV prefusion F. We obtained an optimized vaccine antigen after screening nearly 400 engineered F constructs. Through in vitro and in vivo characterization studies, we identified F constructs that are more stable in the prefusion conformation and elicit ~10-fold higher serum-neutralizing titers in cotton rats than DS-Cav1. The stabilizing mutations of the lead construct (847) were introduced onto F glycoprotein backbones of strains representing the dominant circulating genotypes of the two major RSV subgroups, A and B. Immunization of cotton rats with a bivalent vaccine formulation of these antigens conferred complete protection against RSV challenge, with no evidence of disease enhancement. The resulting bivalent RSV prefusion F investigational vaccine has recently been shown to be efficacious against RSV disease in two pivotal phase 3 efficacy trials, one for passive protection of infants by immunization of pregnant women and the second for active protection of older adults by direct immunization.
