1644. A Potent Broadly Neutralizing Antibody Isolated From Human Memory B-cells Binding to Conserved Site IV on the RSV F Protein. (26th November 2018) - Vora, Kalpit
Abstract: Background: Respiratory syncytial virus (RSV) infection is a major public health burden for infants and the elderly worldwide. Currently, there are no approved vaccines and only one moderately effective marketed antibody (Synagis®) for the prevention of RSV infection in high-risk infants. Sampling the human antibody repertoire has led to the realization that the RSV fusion (F) protein in its prefusion conformation is the preferred target for potent neutralizing antibodies and thus makes the protein an attractive candidate for vaccine developers. Methods: We report the isolation of a potent and broad RSV neutralizing monoclonal antibody (mAb), which was discovered through molecular cloning of cultured RSV postfusion F protein-baited single-sorted human memory B cells. The epitope for the mAb was mapped to RSV F protein using various methods; including X-ray crystallography, alanine scan, and RSV escape mutant generation Results: The mAb binds to both RSV pre- and postfusion F proteins at site IV and can neutralize RSV A and B laboratory strains with subnanomolar potency, superior to that of Palivizumab. Antigenic site IV is conserved between pre- and postfusion F proteins in both RSV A and B subgroups, and sequence alignment showed that the mAb-binding site was conserved in >1, 000 RSV A and B clinical isolates. In vivo cotton rat studies demonstrated protection of both the upper and lower respiratory tract of antibody-infused animals challenged with either RSV A or RSV B. Conclusion: Overall, the fully human mAb we have isolated has great potential to be developed for passive immune-prophylaxis in infants. A prevalent view of the RSV scientific community is that RSV neutralizing mAbs in human sera primarily target the prefusion F protein and predominantly bind antigenic site Ø. In contrast, our finding demonstrates that very broad and potent RSV neutralizing mAb can also recognize sites common to pre- and postfusion F proteins. Furthermore, the RSV F antigenic site IV presents a neutralizing epitope which is highly conserved. Therefore, it is worthwhile to consider site IV, in addition to site Ø, in the design of RSV subunit vaccines. Disclosures: K. Vora, Merck: Employee, Salary. Z. Chen, Merck: Employee, Salary. H. P. Su, Merck: Employee, Salary. A. Tang, Merck: Employee, Salary. K. Cox, merck: Employee, Salary. C. Callahan, Merck: Employee, Salary. L. Zhang, Merck: Employee, Salary. S. Patel, Merck: Employee, Salary. D. Nahas, merck: Employee, Salary. M. Citron, merck: Employee, Salary. P. Cejas, merck: Employee, Salary. R. Swoyer, Merck: Employee, Salary. B. Luo, merck: Employee, Salary. M. Eddins, Merck: Employee, Salary. J. Reid, Merck: Employee, Salary. A. Fridman, Merck: Employee, Salary. J. Galli, Merck: Employee, Salary. S. Cosmi, Merck: Independent Contractor, Salary. G. Dhanasekeran, Merck: Employee, Salary. Z. Wen, Merck: Employee, Salary. X. He, Merck: Employee, Salary. D. Wang, Merck: Employee, Salary. G. Heidecker, Merck: Employee, Salary. J. Flynn, Merck: Employee, Salary. J. Cook, merck: Employee, Salary. S. Soisson, Merck: Employee, Salary. D. Casimiro, Merck: Employee, Salary. A. Bett, Merck: Employee, Salary. W. Blair, Merck: Employee, Salary. D. Distefano, Merck: Employee, Salary. C. Haines, Merck: Employee, Salary.