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Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: Structure, antigenic profile, immunogenicity, and protection.
Vaccine 2019; 37(41):6112-6124V

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in the very young, elderly, and immunocompromised for which there is no vaccine. The surface exposed RSV fusion (F) glycoprotein is required for membrane fusion and infection and is a desirable vaccine candidate. RSV F glycoprotein structure is dynamic and undergoes significant rearrangements during virus assembly, fusion, and infection. We have previously described an RSV fusion-inactive prefusogenic F with a mutation of one of two furin cleavage sites resulting in the p27 region on the N-terminus of F1 with a truncated fusion peptide covalently linked to F2. A processing intermediate RSV prefusogenic F has been reported in infected cells, purified F, budded virus, and elicited a strong immune response against p27 in RSV infected young children. In this report, we demonstrate that prefusogenic F, when expressed on the cell surface of Sf9 insect and human 293T cells, binds monoclonal antibodies (mAbs) that target prefusion-specific antigenic sites Ø and VIII, and mAbs targeting epitopes common to pre- and postfusion F sites II and IV. Purified prefusogenic F bound prefusion F specific mAbs to antigenic sites Ø and VIII and mAbs targeting pre- and postfusion sites II, IV, and p27. Mice immunized with prefusogenic F antigen produced significantly higher levels of anti-F IgG and RSV neutralizing antibodies than prefusion or postfusion F antigens and induced antibodies competitive with mAbs to sites Ø, VIII, II, and IV. RSV prefusogenic F neutralization antibody responses were enhanced with aluminum phosphate adjuvant and significantly higher than prefusion F. Prefusogenic F vaccine protected cotton rats against upper and lower respiratory tract infection by RSV/A. For the first time, we present the structure, antigenic profile, immunogenicity, and protective efficacy of RSV prefusogenic F nanoparticle vaccine.

Authors+Show Affiliations

Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States.Novavax, Inc., Gaithersburg, MD, United States. Electronic address: gsmith@novavax.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31416644

Citation

Patel, Nita, et al. "Respiratory Syncytial Virus Prefusogenic Fusion (F) Protein Nanoparticle Vaccine: Structure, Antigenic Profile, Immunogenicity, and Protection." Vaccine, vol. 37, no. 41, 2019, pp. 6112-6124.
Patel N, Massare MJ, Tian JH, et al. Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: Structure, antigenic profile, immunogenicity, and protection. Vaccine. 2019;37(41):6112-6124.
Patel, N., Massare, M. J., Tian, J. H., Guebre-Xabier, M., Lu, H., Zhou, H., ... Smith, G. (2019). Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: Structure, antigenic profile, immunogenicity, and protection. Vaccine, 37(41), pp. 6112-6124. doi:10.1016/j.vaccine.2019.07.089.
Patel N, et al. Respiratory Syncytial Virus Prefusogenic Fusion (F) Protein Nanoparticle Vaccine: Structure, Antigenic Profile, Immunogenicity, and Protection. Vaccine. 2019 Sep 24;37(41):6112-6124. PubMed PMID: 31416644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Respiratory syncytial virus prefusogenic fusion (F) protein nanoparticle vaccine: Structure, antigenic profile, immunogenicity, and protection. AU - Patel,Nita, AU - Massare,Mike J, AU - Tian,Jing-Hui, AU - Guebre-Xabier,Mimi, AU - Lu,Hanxin, AU - Zhou,Haixia, AU - Maynard,Ernest, AU - Scott,Daniel, AU - Ellingsworth,Larry, AU - Glenn,Gregory, AU - Smith,Gale, Y1 - 2019/08/12/ PY - 2018/12/22/received PY - 2019/07/06/revised PY - 2019/07/26/accepted PY - 2019/8/17/pubmed PY - 2019/8/17/medline PY - 2019/8/17/entrez KW - Cotton rat KW - Prefusogenic fusion glycoprotein KW - Respiratory syncytial virus KW - Vaccine SP - 6112 EP - 6124 JF - Vaccine JO - Vaccine VL - 37 IS - 41 N2 - Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in the very young, elderly, and immunocompromised for which there is no vaccine. The surface exposed RSV fusion (F) glycoprotein is required for membrane fusion and infection and is a desirable vaccine candidate. RSV F glycoprotein structure is dynamic and undergoes significant rearrangements during virus assembly, fusion, and infection. We have previously described an RSV fusion-inactive prefusogenic F with a mutation of one of two furin cleavage sites resulting in the p27 region on the N-terminus of F1 with a truncated fusion peptide covalently linked to F2. A processing intermediate RSV prefusogenic F has been reported in infected cells, purified F, budded virus, and elicited a strong immune response against p27 in RSV infected young children. In this report, we demonstrate that prefusogenic F, when expressed on the cell surface of Sf9 insect and human 293T cells, binds monoclonal antibodies (mAbs) that target prefusion-specific antigenic sites Ø and VIII, and mAbs targeting epitopes common to pre- and postfusion F sites II and IV. Purified prefusogenic F bound prefusion F specific mAbs to antigenic sites Ø and VIII and mAbs targeting pre- and postfusion sites II, IV, and p27. Mice immunized with prefusogenic F antigen produced significantly higher levels of anti-F IgG and RSV neutralizing antibodies than prefusion or postfusion F antigens and induced antibodies competitive with mAbs to sites Ø, VIII, II, and IV. RSV prefusogenic F neutralization antibody responses were enhanced with aluminum phosphate adjuvant and significantly higher than prefusion F. Prefusogenic F vaccine protected cotton rats against upper and lower respiratory tract infection by RSV/A. For the first time, we present the structure, antigenic profile, immunogenicity, and protective efficacy of RSV prefusogenic F nanoparticle vaccine. SN - 1873-2518 UR - https://www.unboundmedicine.com/medline/citation/31416644/Respiratory_syncytial_virus_prefusogenic_fusion_(F)_protein_nanoparticle_vaccine:_Structure,_antigenic_profile,_immunogenicity,_and_protection L2 - https://linkinghub.elsevier.com/retrieve/pii/S0264-410X(19)31010-2 DB - PRIME DP - Unbound Medicine ER -