Abstract
Licensed vaccines or therapeutics are rarely available for pathogens with epidemic or pandemic potential. Developing interventions for specific pathogens and defining generalizable approaches for related pathogens is a global priority and inherent to the UN Sustainable Development Goals. Nipah virus (NiV) poses a significant epidemic threat, and zoonotic transmission from bats-to-humans with high fatality rates occurs almost annually. Human-to-human transmission of NiV has been documented in recent outbreaks leading public health officials and government agencies to declare an urgent need for effective vaccines and therapeutics. Here, we evaluate NiV vaccine antigen design options including the fusion glycoprotein (F) and the major attachment glycoprotein (G). A stabilized prefusion F (pre-F), multimeric G constructs, and chimeric proteins containing both pre-F and G were developed as protein subunit candidate vaccines. The proteins were evaluated for antigenicity and structural integrity using kinetic binding assays, electron microscopy, and other biophysical properties. Immunogenicity of the vaccine antigens was evaluated in mice. The stabilized pre-F trimer and hexameric G immunogens both induced serum neutralizing activity in mice, while the post-F trimer immunogen did not elicit neutralizing activity. The pre-F trimer covalently linked to three G monomers (pre-F/G) induced potent neutralizing antibody activity, elicited responses to the greatest diversity of antigenic sites, and is the lead candidate for clinical development. The specific stabilizing mutations and immunogen designs utilized for NiV were successfully applied to other henipaviruses, supporting the concept of identifying generalizable solutions for prototype pathogens as an approach to pandemic preparedness.
Highlights
Nipah virus (NiV), an enveloped, non-segmented negativestrand RNA virus, is classified in the Henipavirus genus of the Paramyxoviridae family, along with closely related Hendra (HeV) and Cedar (CedPV) viruses, and several other uncharacterized henipaviruses isolated from Africa [1,2,3,4,5,6,7]
We found that prefusion-stabilized NiV F induced more potent neutralizing activity than postfusion F, supporting the importance of stabilizing the prefusion conformation to increase immunogenicity, as previously observed with RSV F and PIV14 F [45, 48, 50]
Solving the crystal structure of the RSV F protein in its prefusion conformation led to the discovery of highly neutralization-sensitive epitopes at the apex of preF that were absent in the rearranged postfusion-stabilized F NiV06 (post-F) structure
Summary
Nipah virus (NiV), an enveloped, non-segmented negativestrand RNA virus, is classified in the Henipavirus genus of the Paramyxoviridae family, along with closely related Hendra (HeV) and Cedar (CedPV) viruses, and several other uncharacterized henipaviruses isolated from Africa [1,2,3,4,5,6,7]. NiV was first isolated during an outbreak on the Malaysian peninsula with 265 suspected infections and 105 deaths and another 11 infections and one death in Singapore that occurred between September 1998 and June 1999. The Malaysian strain of NiV is primarily encephalitic with no documented cases of human-to-human transmission [10]. While most cases have zoonotic exposures, the Bangladesh strain of NiV can spread human-to-human by the respiratory route [12, 18,19,20,21,22], infection can be neurotropic, and patients often develop encephalitis [8, 15, 23,24,25,26]. There is limited genomic variation between the two predominant strains of NiV, sharing ∼92% nucleotide homology [14]
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