Cooperativity mediated by rationally selected combinations of human monoclonal antibodies targeting the henipavirus receptor binding protein

Abstract

SUMMARY Hendra virus and Nipah virus (NiV), members of the Henipavirus (HNV) genus, are zoonotic paramyxoviruses known to cause severe disease across six mammalian orders, including humans. We isolated a panel of human monoclonal antibodies (mAbs) from the B cells of an individual with prior exposure to equine Hendra virus (HeV) vaccine, targeting distinct antigenic sites. The most potent class of cross-reactive antibodies achieves neutralization by blocking viral attachment to the host cell receptors ephrin-B2 and ephrin-B3, with a second class being enhanced by receptor binding. mAbs from both classes display synergistic activity in vitro . In a stringent hamster model of NiV Bangladesh (NiV B ) infection, antibodies from both classes reduce morbidity and mortality and achieve synergistic protection in combination. These candidate mAbs might be suitable for use in a cocktail therapeutic approach to achieve synergistic potency and reduce the risk of virus escape.

Architecture and antigenicity of the Nipah virus attachment glycoprotein

“…The nAH1.3 mAb was previously shown to potently neutralize NiV-M, NiV-B, and HeV in vitro ( 31 ). Using a green fluorescent protein (GFP)–encoding, replication-competent Cedar (henipa)virus (rCedV) chimeras in which the native glycoproteins are substituted with the NiV-B (rCedV-NiV-B-GFP) or the HeV (rCedV-HeV-GFP) F and G glycoproteins ( 35 ), we determined nAH1.3 half-maximum inhibitory concentrations (IC 50 ) of 33 and 32 ng/ml, respectively (fig. S3A).…”

“…3B). We then carried out virus neutralization assays using rCedV-NiV-B-GFP or rCedV-HeV-GFP to examine whether these mAbs had synergistic virus-neutralizing activity ( 35 ). Using a concentration matrix of each mAb, we found that combining m102.4 and nAH1.3 led to synergistic neutralization of the two rCedV chimeras (Fig.…”

“…Presenting the head antigen as an ordered array through multivalent display holds the promise of enhancing immunogenicity, as recently described for SARS-CoV-2 ( 50 , 55 , 56 ), and would allow presentation of a mosaic of HNV head domains with the goal of inducing neutralizing Ab responses with maximal breadth ( 44 , 56 – 58 ). Finally, the enhanced expression yield, stability, and homogeneity of the NiV G head domain compared with HeV sG ( 35 ) would improve scalability of the manufacturing process of such a vaccine.…”

Structural basis for antibody recognition of vulnerable epitopes on Nipah virus F protein

“…Neutralizing antibodies to NiV bind to two viral surface glycoproteins, G and F [36,38,40,41,45,46]. Recently isolated and characterized F monoclonal antibodies are prefusion specific and directed to epitopes near the apex of NiV F located within domain 3 [38][39][40].…”

Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine

“…Based on experience with related paramyxoviruses and pneumoviruses, both the NiV F and G proteins are considered relevant protective antigens and targets for vaccine-elicited neutralizing antibodies. Several recently isolated and characterized monoclonal antibodies have shown F-binding neutralizing antibodies to be pre-F specific (49)(50)(51)(52) and five major antigenic sites have been identified on HeV G that inhibit virus by multiple mechanisms and are cross-reactive with NiV G (53,54). The neutralizing humoral response primarily targets G, which has been the primary focus of vaccine development.…”