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

Abstract

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.

Assessment of the immunogenicity and protection of a Nipah virus soluble G vaccine candidate in mice and pigs

“…G glycoprotein is considered an important antigen for NiV vaccine development. Many vaccines that use Nipah virus G protein or G protein + F protein as antigens are under development ( Guillaume et al, 2004 ; Prescott et al, 2015 ; Singh et al, 2019 ; Isaacs et al, 2021 ). The results showed that most neutralizing antibodies were induced by G protein ( Weingartl et al, 2006 ).…”

A platform technology for generating subunit vaccines against diverse viral pathogens

“…Pseudovirus neutralisation assays were conducted using lentivirus-based pseudotypes as previously described ( 51 – 53 ). Briefly, HEK293T cells were transfected with p8.91 (encoding for HIV-1 gag-pol), CSFLW (lentivirus backbone expressing a firefly luciferase reporter gene) and viral glycoprotein (NiV F + G or LASV GPC) using PEI transfection reagent.…”

Structure and antigenicity of divergent Henipavirus fusion glycoproteins

“…A similar approach to that undertaken with RSV was recently shown to stabilize the NiV and HeV F glycoproteins in the prefusion conformation 26 . In parallel, we have previously shown that prefusion NiV F can be stabilized by a novel molecular clamp trimerization domain in the absence of heterologous mutations 25 , 28 . Here, we use a similar approach to determine the structures of LayV and MojV F glycoproteins in the prefusion conformation via cryogenic electron microscopy (cryo-EM) and to characterize their glycosylation profiles with mass spectrometry glycoproteomics, in order to inform future vaccine design and therapy against these emerging viruses.…”

“…This outlines a rational basis for neutralizing antibody discovery and structure-based vaccine design against prefusion F. Indeed, several antibodies targeting the prefusion conformation of F have been isolated and shown to be neutralizing and protective 21 – 24 . Moreover, vaccine studies with prefusion-stabilized NiV F have been shown to elicit potent neutralizing responses 25 – 28 . While these studies yielded vital information into HNV vaccine design, it is unknown whether this immunity extends to other divergent HNVs such as MojV and LayV.…”