Structural basis for respiratory syncytial virus and human metapneumovirus neutralization

Abstract

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) continue to be a global burden to infants, the elderly, and immunocompromised individuals. In the past ten years, there has been substantial progress in the development of new vaccine candidates and therapies against these viruses. These advancements were guided by the structural elucidation of the major surface glycoproteins for these viruses, the fusion (F) protein and attachment (G) protein. The identification of immunodominant epitopes on the RSV F and hMPV F proteins has expanded current knowledge on antibody-mediated immune responses, which has led to new approaches for vaccine and therapeutic development through the stabilization of pre-fusion constructs of the F protein and pre-fusion-specific monoclonal antibodies with high potency and efficacy. In this review, we describe structural characteristics of known antigenic sites on the RSV and hMPV proteins, their influence on the immune response, and current progress in vaccine and therapeutic development.

Figure 1:

RSV F (left) and hMPV F (right) prefusion (globular) and postfusion (elongated) conformations. RSV preF PDB: 5C6B; RSV postF PDB: 3RRR; hMPV preF PDB: 8CW9; hMPV postF PDB: 5L1X. Antigenic sites are colored according to the text labels for each structure.

Figure 2:

The RSV G central conserved domain (CCD) in complex with mAbs CD002.5 in orange (PDB 6BLI), CD107.5 in light green (PDB 6BLH), and 131-2G in light blue (PDB 6UVO). Site γ1 covers residues 173-186 and is colored in blue. Site γ2 covers residues 177-188 and is colored in red. An unnamed site where mAb 131-2G binds covers residues 167-176 and is colored in green.