Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation

Más, Vicente; Rodriguez, Laura; Olmedillas, Eduardo; Cano, Olga; Palomo, Concepción; Terrón, María C.; Luque, Daniel; Melero, José A.; McLellan, Jason S.; Plemper, Richard K.

doi:10.1371/journal.ppat.1005859

Title: Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation

Journal Article · Fri Sep 09 00:00:00 EDT 2016 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.1005859· OSTI ID:1324810

Más, Vicente ^[1]; Rodriguez, Laura ^[2]; Olmedillas, Eduardo ^[1]; Cano, Olga ^[1]; Palomo, Concepción ^[1]; Terrón, María C. ^[1]; Luque, Daniel ^[1]; Melero, José A. ^[1]; McLellan, Jason S. ^[3]; Plemper, Richard K. ^[4]

Inst. de Salud Carlos III, Madrid (Spain)
Univ. of Rochester Medical Center, NY (United States); Inst. de Salud Carlos III, Madrid (Spain)
Geisel School of Medicine at Dartmouth, Hanover, NH (United States)
Georgia State Univ., Atlanta, GA (United States)

Human metapneumovirus (hMPV) is a paramyxovirus that is a common cause of bronchiolitis and pneumonia in children less than five years of age. The hMPV fusion (F) glycoprotein is the primary target of neutralizing antibodies and is thus a critical vaccine antigen. To facilitate structure-based vaccine design, we stabilized the ectodomain of the hMPV F protein in the postfusion conformation and determined its structure to a resolution of 3.3 Å by X-ray crystallography. The structure resembles an elongated cone and is very similar to the postfusion F protein from the related human respiratory syncytial virus (hRSV). In contrast, significant differences were apparent with the postfusion F proteins from other paramyxoviruses, such as human parainfluenza type 3 (hPIV3) and Newcastle disease virus (NDV). The high similarity of hMPV and hRSV postfusion F in two antigenic sites targeted by neutralizing antibodies prompted us to test for antibody cross-reactivity. The widely used monoclonal antibody 101F, which binds to antigenic site IV of hRSV F, was found to cross-react with hMPV postfusion F and neutralize both hRSV and hMPV. Despite the cross-reactivity of 101F and the reported cross-reactivity of two other antibodies, 54G10 and MPE8, we found no detectable cross-reactivity in the polyclonal antibody responses raised in mice against the postfusion forms of either hMPV or hRSV F. The postfusion-stabilized hMPV F protein did, however, elicit high titers of hMPV-neutralizing activity, suggesting that it could serve as an effective subunit vaccine. Structural insights from these studies should be useful for designing novel immunogens able to induce wider cross-reactive antibody responses.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Inst. of Health

Grant/Contract Number:: AC02-06CH11357; SAF2015-67033-RSAF2012-31217; BFU 2013-43149-R; P20GM113132

OSTI ID:: 1324810

Journal Information:: PLoS Pathogens, Vol. 12, Issue 9; ISSN 1553-7374

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 31 works

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Title: Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation

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