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

Ariel Isaacs,Andrew Young,Dalan Bailey,Stacey T M Cheung,Paul R Young,Daniel Watterson,Naphak Modhiran,Noushin Jaberolansar,Nazia Thakur,Simon P Graham,Keith J Chappell

doi:10.3390/v13101942

Ariel Isaacs, Andrew Young + Show 9 more

Open Access

https://doi.org/10.3390/v13101942

Copy DOI

Journal: Viruses	Publication Date: Sep 28, 2021
Citations: 11	License type: CC BY 4.0

Affiliation: University of Queensland, The Pirbright Institute

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.

Highlights

Structure-based antigen design allows for the development of vaccine approaches that elicit targeted immune responses and has been applied for glycoproteins from viruses such as HIV, Ebola, influenza, respiratory syncytial virus (RSV), SARS-CoV-2, Nipah virus (NiV) and Hendra virus (HeV) [1,2,3,4,5,6,7,8]
A molecular clamp trimerization domain was incorporated at the C-terminus of NiV F (NiV F clamp) and RSV F (RSV F clamp) glycoprotein ectodomains to stabilise them in the prefusion conformation (Figure 1A,B)
The extracellular domain of RSV G was linked to a C-terminal Fc-tag for purification means, which was cleaved after affinity purification by making use of a human rhinovirus 3C (HRV3C) protease site (Figure 1B), yielding soluble RSV G

Summary

Introduction

Structure-based antigen design allows for the development of vaccine approaches that elicit targeted immune responses and has been applied for glycoproteins from viruses such as HIV, Ebola, influenza, respiratory syncytial virus (RSV), SARS-CoV-2, Nipah virus (NiV) and Hendra virus (HeV) [1,2,3,4,5,6,7,8]. Several neutralising and protective epitopes have been mapped to the central conserved domain (CCD) of RSV G [29,30,31,32], which has been implicated in binding to the fractalkine CX3C-chemokine receptor 1 (CX3CR1) [33,34,35,36] After cellular attachment, both henipaviruses and orthopneumoviruses make use of a trimeric class I fusion protein (F) to merge viral and cellular membranes [10]. Several efforts have been made to stabilise henipavirus and RSV F proteins in the prefusion conformation through structure-based design and addition of a foldon or GCN4 trimerization domain [2,5,41]

Objectives

Methods

Results

Discussion

Conclusion