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bioRxiv · 10.1101/2025.02.16.638571

Neutralizing antibodies elicited by Nipah virus G-head nanoparticle target diverse sites and inhibit receptor binding and fusion

Zhou, D.·Wang, Y.·Yao, Y.·Kuang, W.·Cheng, R.·Zhang, G.·Liu, H.·Li, X.·Chiu, S.·Deng, Z.·Zhao, H.
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Abstract

Nipah virus (NiV) and Hendra virus (HeV), two highly pathogenic Henipaviruses (HNVs), pose a significant public health threat. The attachment glycoprotein (G) plays a crucial role in viral attachment and entry, making it an attractive target for vaccine and therapeutic antibody development. However, the antigenic landscape and neutralization sensitivity of the G protein remain poorly defined. Here, we systematically characterize 27 monoclonal antibodies (mAbs) elicited by NiV G head (GH) nanoparticle-immunized mice. Among these, 25 mAbs exhibit neutralizing activity against two major NiV strains, NiV-Malaysia and NiV-Bangladesh, with five mAbs also cross-inhibiting HeV infection. Although all mAbs target GH, they inhibit viral infection through distinct mechanisms, either by blocking receptor ephrin-B2 engagement with the G protein or by preventing viral membrane fusion. Notably, mAbs from two distinct groups conferred complete protection to hamsters against lethal NiV-Malaysia infection. Structural analysis of NiV GH in complex with four representative Fabs reveals four non-overlapping epitopes, including two novel antigenic sites and one shared protective epitope identified across species. Our study provides a comprehensive map of the antigenic determinants of NiV GH, elucidates the relationship between epitopes, neutralization mechanisms, and protection, and offers new insights and opportunities for antibody-based therapies and vaccine development. HighlightsMost mAbs induced in G head nanoparticle-immunized mice are potent neutralizers MAbs recognizing the G head block receptor binding or viral fusion Structural analysis shows mAbs target four distinct epitopes on G head protein Receptor competition site on G head is a shared protective antigenic site in human and multiple animals

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Zhou, D., Wang, Y., Yao, Y., Kuang, W., Cheng, R., Zhang, G., Liu, H., Li, X., Chiu, S., Deng, Z., Zhao, H.. 2025-02-19. Neutralizing antibodies elicited by Nipah virus G-head nanoparticle target diverse sites and inhibit receptor binding and fusion. https://doi.org/10.1101/2025.02.16.638571

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