Oral Presentation 14th Lorne Infection and Immunity 2024

Towards broad-spectrum henipavirus vaccines & therapeutics: rational design of prefusion F glycoproteins (#57)

Ariel Isaacs 1 , Yu Shang Low 1 , Kyle L Macauslane 1 , Joy Seitanidou 1 , Cassandra L Pegg 1 , Jun J Hen 1 , Stacey TM Cheung 1 , Benjamin Liang 1 , Connor AP Scott 1 , Michael J Landsberg 1 2 , Ben L Schulz 1 , Keith J Chappell 1 2 3 , Naphak Modhiran 1 , Daniel Watterson 1 2
  1. School of Chemistry & Molecular Biosciences, University of Queensland, St Lucia, Queensland, Australia
  2. Australian Infectious Disease Research Centre, Brisbane, QLD, Australia
  3. The Australian Institute for Biotechnology and Nanotechnology, University of Queensland, St Lucia, Queensland, Australia

In August 2022, a novel henipavirus (HNV) named Langya virus (LayV) was isolated from patients with severe pneumonic disease in China. This virus is closely related to Mòjiāng virus (MojV), and both are divergent from the deadly bat-borne HNV members, Nipah (NiV) and Hendra (HeV) viruses. The spillover of LayV is the first instance of a HNV zoonosis to humans outside of NiV and HeV, highlighting the continuing threat this genus poses to global human health. In this work, we make use of the molecular clamp2 technology to stabilize the prefusion form of the LayV and MojV F glycoproteins. We couple this with cryogenic electron microcopy to solve the first high resolution structure of these antigens and perform a glycoproteomic analysis to characterize the glycan profiles. We determined the prefusion structures of MojV and LayV F proteins to 2.66 and 3.37 Å, respectively. We show that despite sequence divergence from NiV, the F proteins adopt an overall similar structure but are antigenically distinct as they do not react to known antibodies or sera. Glycoproteomic analysis revealed that while LayV F is less glycosylated than NiV F, it contains a glycan that shields a site of vulnerability previously identified for NiV. We leveraged this information to design a trivalent prefusion F HNV vaccine, and demonstrated broad-reactivity against several emerging HNVs. Concurrently, we isolated novel human-derived antibodies that target LayV F and G proteins and offer cross-reactivity to MojV. Our findings shed light on the structures and antigenic profiles of major vaccine targets of LayV and MojV. Our results carry implications for broad-spectrum HNV vaccines and therapeutic development, and we demonstrate that a multivalent HNV approach is likely required to combat emerging viruses.