Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation
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 angstrom by -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.
Dartmouth Digital Commons Citation
Mas, Vicente; Rodriguez, Laura; Olmedillas, Eduardo; Cano, Olga; Palomo, Concepcion; Terron, Maria C.; Luque, Daniel; Melero, Jose A.; and McLellan, Jason S., "Engineering, Structure and Immunogenicity of the Human Metapneumovirus F Protein in the Postfusion Conformation" (2016). Dartmouth Scholarship. 290.