Cross-neutralization of four paramyxoviruses by a human monoclonal antibody

Abstract

Broadly neutralizing antibodies reactive against most and even all variants of the same viral species have been described for influenza and HIV-1 (ref. 1). However, whether a neutralizing antibody could have the breadth of range to target different viral species was unknown. Human respiratory syncytial virus (HRSV) and human metapneumovirus (HMPV) are common pathogens that cause severe disease in premature newborns, hospitalized children and immune-compromised patients, and play a role in asthma exacerbations. Although antisera generated against either HRSV or HMPV are not cross-neutralizing, we speculated that, because of the repeated exposure to these viruses, cross-neutralizing antibodies may be selected in some individuals. Here we describe a human monoclonal antibody (MPE8) that potently cross-neutralizes HRSV and HMPV as well as two animal paramyxoviruses: bovine RSV (BRSV) and pneumonia virus of mice (PVM). In its germline configuration, MPE8 is HRSV-specific and its breadth is achieved by somatic mutations in the light chain variable region. MPE8 did not result in the selection of viral escape mutants that evaded antibody targeting and showed potent prophylactic efficacy in animal models of HRSV and HMPV infection, as well as prophylactic and therapeutic efficacy in the more relevant model of lethal PVM infection. The core epitope of MPE8 was mapped on two highly conserved anti-parallel β-strands on the pre-fusion viral F protein, which are rearranged in the post-fusion F protein conformation. Twenty-six out of the thirty HRSV-specific neutralizing antibodies isolated were also found to be specific for the pre-fusion F protein. Taken together, these results indicate that MPE8 might be used for the prophylaxis and therapy of severe HRSV and HMPV infections and identify the pre-fusion F protein as a candidate HRSV vaccine.

Broadly Reactive Anti-Respiratory Syncytial Virus G Antibodies from Exposed Individuals Effectively Inhibit Infection of Primary Airway Epithelial Cells

“…All antibodies showed high levels of somatic hypermutation in the variable heavy chain (VH) and variable light chain (VL) regions (average, 15.1 and 7.6 mutations, respectively), indicative of antigen selection (Table 2). Regarding VH usage, it has been described that for infectious disease targets, such as the influenza virus hemagglutinin stem region (17), RSV (18), and hepatitis C virus (HCV) (19), the VH1-69 family is predominantly used. In this study, however, we did not observe this, since only one of the seven selected clones used VH1-69 (Table 2).…”

Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein

“…Three antibodies (5C4, AM22, and D25) were shown to bind the prefusion-specific antigenic site Ø, located at the apex of the prefusion trimer (14). Recently, two novel prefusion-specific antibodies, MPE8 and AM14, were characterized and shown to bind antigenic sites III and V, respectively (10,15,17). The epitope for MPE8 is located near the binding site of palivizumab in the groove between the helix-turn-helix and the ridge of antigenic site IV on the adjacent protomer.…”

“…Initially, the RSV F protein assembles into a homotrimeric, metastable prefusion conformation that rearranges to a highly stable postfusion conformation during fusion of the viral and target cell membrane or spontaneously (12). Six major antigenic sites are currently identified that are located on the prefusion and/or postfusion trimer conformation of the RSV F protein (10,(13)(14)(15). Palivizumab, directed to antigenic site II, is the only approved immunoprophylaxis and provided a 55% reduction in RSV-associated hospitalizations in a phase III trial (16).…”

Immobilization of the N-terminal helix stabilizes prefusion paramyxovirus fusion proteins

“…As the target of a broadly neutralizing antibody in RSV and hMPV (MPE8 epitope highlighted by the cyan surface and Palivizumab epitode highlighted by orange surface in Fig. 3B) (10,48), and a region that experiences a dramatic reduction in conformational flexibility during PIV5 F-protein refolding (29), this β-strap appears to be a critical structural motif in the proper function of the F protein.…”