A Broadly Neutralizing Human Monoclonal Antibody Exhibits In Vivo Efficacy Against Both Human Metapneumovirus and Respiratory Syncytial Virus

Human metapneumovirus (HMPV), a paramyxovirus identified in 2001, is a leading cause of acute respiratory disease worldwide [1, 2]. In high-risk populations, HMPV causes significant morbidity and mortality [3, 4]. No vaccines or therapeutics specifically target HMPV, and nonspecific therapies such as ribavirin and intravenous immunoglobulin have limited efficacy [5]. HMPV has 4 subgroups, which vary in prevalence but cause similar disease [6, 7]. Although the subgroups are relatively conserved, recurrent infection occurs throughout life [8]. Reinfection likely occurs because of limited cross-protective antibodies [9] and T-cell exhaustion causing a poor memory response [10]. All paramyxoviruses have class I viral fusion (F) proteins, which exist in a pre- and postfusion state and are required for entry [11]. HMPV vaccine studies have focused on the F protein, which is immunogenic and protective in animal models [12, 13]. The F protein is highly conserved among HMPV subgroups, with >95% amino acid similarity between A and B groups and >97% similarity within a single group, suggesting that a broadly neutralizing antibody response could be evoked if a shared epitope were targeted [14]. Monoclonal antibodies (mAbs) are effective at preventing infectious diseases in high-risk populations [15]. However, the use of humanized or chimeric mAbs, both partly murine, is associated with the development of host antibodies to foreign antigens and adverse events [16, 17]. Fully human mAbs are less immunogenic [18]. Researchers have described mAbs effective at neutralizing all 4 subgroups of HMPV in vitro [19, 20], but these had limited therapeutic efficacy in rodents [21]. We hypothesized that a human mAb directed at HMPV F protein could be used to abate infection. Here, we describe a fully human mAb, 54G10, which potently neutralized all 4 subgroups of HMPV in vitro and exhibited subnanomolar affinity for the F protein. To test in vivo efficacy, we established a new mouse model permissive for all 4 HMPV subgroups in the upper and lower airways. 54G10 decreased peak HMPV titer below the limit of detection (LOD) in both prophylactic and therapeutic experiments. Sequencing of mAb-resistant mutants (MARMs) identified that 54G10's epitope is a conserved region among paramyxoviruses [22]. Confirming this, 54G10 neutralized respiratory syncytial virus (RSV), another leading cause of respiratory infections. Thus, 54G10 is a highly effective human mAb, which recognizes a similar epitope on HMPV and RSV.