Development of broadly neutralizing human monoclonal antibodies against henipaviruses

PROJECT SUMMARY Henipaviruses (HNVs), including Hendra (HeV) and Nipah (NiV) viruses, are highly pathogenic agents causing severe respiratory and neurological diseases in humans and animals. With case fatality rates ranging from 40% to >75%, and classification as biosafety level 4 (BSL-4) pathogens, these viruses pose a significant public health concern. Current vaccine and monoclonal antibody (mAb) candidates are targeted against closely related NiV and HeV. While promising, these narrowly focused approaches are insufficiently broad in their effectiveness, rendering them inadequate against increasingly diverse HNV clades. This project aims to overcome this critical gap by developing human broadly neutralizing antibodies (bnAbs) against HNV fusion (F) and receptor-binding glycoproteins (RBP/G). Our primary objective is to overcome current limitations by developing bnAbs effective against a wide range of HNVs, with a secondary objective of assessing the utility of the eliciting immunogens in future vaccine development. Our approach accounts for the existing diversity among HNVs, targeting not only NiV and HeV but also Ghana virus (GhV) and Cedar virus (CedV) as representatives of the extant diversity amongst bona fide henipaviruses. Informed by structure-function data, we will design novel immunogens to elicit broadly neutralizing antibodies (bnAbs) to HNV F and G proteins. By immunizing Harbour H2L2 mice transgenic for human immunoglobulin VH-VK genes, we overcome limitations posed by the rarity of convalescent patient samples, which has commonly been used to derived human mAbs against infectious agents. Our initial characterization of potent bnAbs derived from immunized Harbour H2L2 mice provide a strong premise for this project. Our driving hypothesis is that rationally designed immunogens can induce bn Abs, and that these bnAbs can be developed as prophylactic or therapeutic agents against a broad spectrum of HNVs. We will (1) comprehensively characterize extant bnAbs already generated from Harbour H2L2 mice, (2) design and engineer immunogens expected to enhance the immunogenicity of conserved epitopes on F and G proteins, (3) assess the protective efficacy of developed bnAb candidates in animal models, and (4) develop optimized mAb cocktails for broad- spectrum HNV therapy. This project is poised to make significant advancements in the development of bnAbs as countermeasures against the wide array of HNVs. It offers a developmental pipeline that could greatly enhance our approach to managing these highly pathogenic viruses. The outcomes will not only contribute to the immediate need for effective therapies but will also have broader implications for the field of antiviral countermeasures.