A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism
By A. Krarup, D. Truan, Polina Furmanova-Hollenstein, L. Bogaert, P. Bouchier, Ilona J. M. Bisschop, M. Widjojoatmodjo, R. Zahn, H. Schuitemaker, J. McLellan and 1 more. 2015
353 citations recorded by the source corpus.
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain. Respiratory syncytial virus (RSV) is a highly contagious childhood pathogen of the respiratory tract for which no vaccine is currently available. Here the authors present a strategy to stabilize the RSV F protein in a prefusion conformation that can elicit a strong protective immune response in animal models.
Subfields: Epidemiology, Infectious Diseases
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Citations in the corpus
- Induction of Potent Neutralizing Antibody Responses by a Designed Protein Nanoparticle Vaccine for Respiratory Syncytial Virus (2019, methodology): “Additional engineered prefusion RSV F antigens have shown similar improvements in eliciting neutralizing antibody responses and in some cases, exhibit improved physical and antigenic stability relative to DS-Cav1 (Joyce et al., 2016; Krarup et al., 2015; Palomo et al., 2016).”
- Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses (2016, background): “Recently, soluble forms of hRSV F stabilized in the prefusion conformation were shown to induce higher levels of neutralizing antibodies in mice (30, 32), cotton rats (32), and nonhuman primates (30) (rhesus macaques) than those induced by soluble postfusion F; however, postfusion soluble F, which h”
- Uncleaved prefusion-optimized gp140 trimers derived from analysis of HIV-1 envelope metastability (2016, neutral): “Finally, given the presence of an HR1-like region in most enveloped viruses using the type 1 fusion mechanism 48–50 , the generic HR1 redesign is potentially a universal strategy to stabilize soluble envelope trimers for vaccine development.”
- Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen (2017, background): “The S1/S2 furin site (RSVR), which remains uncleaved in our construct due to mutagenesis (ASVG), is located on an accessible solvent-exposed loop that is disordered in our structures (Fig.”
- New Vaccine Design and Delivery Technologies (2019, background): “Additional prefusion-stabilized RSV F antigens have been generated by introducing proline mutations in between discontinuous helices that form a continuous helix upon transition to the postfusion structure [34] , and this approach has also been used to stabilize other viral glycoproteins such as the”
- Rapid profiling of RSV antibody repertoires from the memory B cells of naturally infected adult donors (2016, neutral): “Recently, stabilization of preF has been achieved by protein engineering (14, 15), and stabilized preF has been shown to induce higher titers of neutralizing antibodies than postF in animal models (14, 15).”