Potent Henipavirus Neutralization by Antibodies Recognizing Diverse Sites on Hendra and Nipah Virus Receptor Binding Protein

Dong, Jinhui; Cross, Robert W.; Doyle, Michael P.; Kose, Nurgun; Mousa, Jarrod J.; Annand, Edward J.; Borisevich, Viktoriya; Agans, Krystle N.; Sutton, Rachel E.; Nargi, Rachel S.; Majedi, Mahsa; Fenton, Karla A.; Reichard, Walter; Bombardi, Robin; Geisbert, Thomas W.; Crowe, James E.

doi:10.1016/j.cell.2020.11.023

Cited by 37 publications

(67 citation statements)

References 74 publications

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“…Conversely, HENV-103 approaches the HeV-RBP perpendicular to the receptor binding domain at the putative interface between protomers within the RBP tetramer ( Figure S4B ). This antigenic site overlaps with previously published mAbs, including HENV-32 ( Aguilar et al, 2009 ; Dong et al, 2020 ). In summary, HENV-103 and HENV-117 map to distinct antigenic sites by nsEM, with HENV-117 mimicking ephrin-B2 binding, while HENV-103 binds at the putative dimeric interface.…”

Section: Resultssupporting

confidence: 75%

“…This mAb potently neutralizes both HeV and NiV in vitro and protects against infection and disease in experimental henipavirus challenge models using ferrets or non-human primates ( Bossart et al, 2011 ; Geisbert et al, 2014 ; Mire et al, 2016 ). More recently, two human mAbs, HENV-26 and HENV-32, were shown to neutralize HeV and NiV by distinct mechanisms and protect from NiV Bangladesh (NiV B ) strain challenge in a ferret model ( Dong et al, 2020 ). While these studies have laid a foundation for our understanding of how to target henipaviruses therapeutically, many questions remain regarding the antigenicity of the attachment glycoprotein, and whether escape mutations from these mAbs can develop in vivo .…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we isolated hmAbs from circulating B cells of an individual with occupation-related exposure to the equine HeV vaccine (Equivac HeV), the same individual from whom therapeutic mAbs HENV-26 and HENV-32 were previously isolated ( Dong et al, 2020 ; Middleton et al, 2014 ). Members of this large panel of antibodies target diverse antigenic sites, many of which are sites of vulnerability for neutralization for at least one virus.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Resultssupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…The attachment protein (G) of henipaviruses is a type II protein with a tetrameric (dimer of dimers) structure and is the primary target for vaccines and therapeutics, as it is involved in binding host cellular receptors ephrin B2/B3 [11][12][13][14]. Indeed, several protective epitopes within henipavirus G have been characterised [15][16][17][18][19] and vaccination with HeV G has yielded promising results in several animal models [20][21][22][23][24]. This lead to the licensure of an equine vaccine in Australia and the progression of this vaccine candidate into human clinical trials [25].…”

Section: Introductionmentioning

confidence: 99%

Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates

Isaacs

Cheung

Thakur

et al. 2021

Viruses

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Nipah virus (NiV) and respiratory syncytial virus (RSV) possess two surface glycoproteins involved in cellular attachment and membrane fusion, both of which are potential targets for vaccines. The majority of vaccine development is focused on the attachment (G) protein of NiV, which is the immunodominant target. In contrast, the fusion (F) protein of RSV is the main target in vaccine development. Despite this, neutralising epitopes have been described in NiV F and RSV G, making them alternate targets for vaccine design. Through rational design, we have developed a vaccine strategy applicable to phylogenetically divergent NiV and RSV that comprises both the F and G proteins (FxG). In a mouse immunization model, we found that NiV FxG elicited an improved immune response capable of neutralising pseudotyped NiV and a NiV mutant that is able to escape neutralisation by two known F-specific antibodies. RSV FxG elicited an immune response against both F and G and was able to neutralise RSV; however, this was inferior to the immune response of F alone. Despite this, RSV FxG elicited a response against a known protective epitope within G that is conserved across RSV A and B subgroups, which may provide additional protection in vivo. We conclude that inclusion of F and G antigens within a single design provides a streamlined subunit vaccine strategy against both emerging and established pathogens, with the potential for broader protection against NiV.

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“…A human monoclonal antibody (mAb) m102.4 has been administered as emergency PEP in 16 human cases and has demonstrated safety, tolerability and intended immunogenicity in phase 1 trials (13). Combinations of cross-reactive humanized antibodies against the fusion (F) protein and the RBP have also been described for clinical development as PEP (14–16), and a human vaccine using HeV-sG is now in phase 1 clinical trials (17).…”

Section: Introductionmentioning

confidence: 99%

Novel Hendra virus variant detected by sentinel surveillance of Australian horses

Annand

Horsburgh

et al. 2021

Preprint

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A novel Hendra virus (HeV) variant was identified from a horse that suffered acute fatal disease consistent with HeV infection through multidisciplinary and interagency syndromic sentinel surveillance research. Novel molecular assays for HeV detection are described in the light of routine testing failure. In silico analysis of the variant receptor-binding protein in comparison with prototypic HeV supported that the monoclonal antibody m102.4 used for post-exposure prophylaxis, as well as the equine vaccine, should be effective also against this novel variant. Similarity of this virus (99%) to a partial sequence detected from a South Australian grey-headed flying fox, along with case exposure to this species in Queensland, suggests the variant circulates at least across the range of this flying fox species. Investigation into HeV diversity, comparative kinetics and pathogenicity, reservoir-species associations, viral-host co-evolution and spillover dynamics should be prioritized. Biosecurity practices should be updated to appreciate HeV spillover risk across all regions frequented by flying foxes regardless of species.

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Potent Henipavirus Neutralization by Antibodies Recognizing Diverse Sites on Hendra and Nipah Virus Receptor Binding Protein

Cited by 37 publications

References 74 publications

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

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

Combinatorial F-G Immunogens as Nipah and Respiratory Syncytial Virus Vaccine Candidates

Novel Hendra virus variant detected by sentinel surveillance of Australian horses

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