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Protocol for Recombinant RBD-based SARS Vaccines: Protein Preparation, Animal Vaccination and Neutralization Detection
Published on: May 2, 2011
Structure-based design of a fusion glycoprotein vaccine for respiratory syncytial virus
Jason S McLellan1, Man Chen, M Gordon Joyce
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Insights
Researchers engineered a stabilized respiratory syncytial virus (RSV) fusion (F) glycoprotein targeting a key vulnerable site. This stabilized antigen elicited significantly higher neutralizing antibody levels in animal models, offering potential for improved RSV vaccines.
Area of Science:
- Virology
- Structural Biology
- Immunology
Background:
- Respiratory syncytial virus (RSV) is a major cause of pediatric hospitalization.
- Current vaccines have limitations in providing comprehensive protection.
- The prefusion form of the RSV fusion (F) glycoprotein contains critical antigenic sites, including site Ø, targeted by potent neutralizing antibodies.
Purpose of the Study:
- To engineer a stabilized RSV fusion (F) glycoprotein antigen.
- To enhance the stability of antigenic site Ø on the F glycoprotein.
- To develop a potentially more effective antigen for RSV vaccines.
Main Methods:
- Structure-based design was employed to stabilize the RSV F glycoprotein.
- Cysteine residues were introduced, and hydrophobic cavities were filled to enhance stability.
- X-ray crystallography was used to determine the structures of stabilized F variants.
- Immunization studies were conducted in mouse and macaque models.
Main Results:
- Stabilized RSV F variants maintained antigenic site Ø integrity under various stress conditions (pH, osmolality, temperature).
- Six crystal structures revealed how modifications improved F glycoprotein stability.
- Immunization with stabilized F variants induced high levels of RSV-specific neutralizing antibodies in animal models, exceeding protective thresholds.
Conclusions:
- Stabilized RSV F glycoproteins targeting antigenic site Ø represent a promising platform for next-generation RSV vaccines.
- The engineered antigen elicits potent neutralizing antibody responses.
- This approach may lead to more effective prophylactic strategies against RSV infection.
Abstract:
Respiratory syncytial virus (RSV) is the leading cause of hospitalization for children under 5 years of age. We sought to engineer a viral antigen that provides greater protection than currently available vaccines and focused on antigenic site Ø, a metastable site specific to the prefusion state of the RSV fusion (F) glycoprotein, as this site is targeted by extremely potent RSV-neutralizing antibodies. Structure-based design yielded stabilized versions of RSV F that maintained antigenic site Ø when exposed to extremes of pH, osmolality, and temperature. Six RSV F crystal structures provided atomic-level data on how introduced cysteine residues and filled hydrophobic cavities improved stability. Immunization with site Ø-stabilized variants of RSV F in mice and macaques elicited levels of RSV-specific neutralizing activity many times the protective threshold.
