Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine.

Rebecca J Loomis,Vladimir Presnyak,Deepika Nair,Ria T Caringal,John R Mascola,Lauren A Chang,Samantha Falcone,Barney S Graham,Elisabeth Narayanan,Lisa A Kueltzo,Anthony T Dipiazza,Geoffrey B Hutchinson,Sunny Himansu,Andrea Carfi,Guillaume B E Stewart-Jones,Tracy J Ruckwardt,Kaitlyn M Morabito,Olubukola M Abiona,Yaroslav Tsybovsky

doi:10.3389/fimmu.2021.772864

Abstract

Nipah virus (NiV) represents a significant pandemic threat with zoonotic transmission from bats-to-humans with almost annual regional outbreaks characterized by documented human-to-human transmission and high fatality rates. Currently, no vaccine against NiV has been approved. Structure-based design and protein engineering principles were applied to stabilize the fusion (F) protein in its prefusion trimeric conformation (pre-F) to improve expression and increase immunogenicity. We covalently linked the stabilized pre-F through trimerization domains at the C-terminus to three attachment protein (G) monomers, forming a chimeric design. These studies detailed here focus on mRNA delivery of NiV immunogens in mice, assessment of mRNA immunogen-specific design elements and their effects on humoral and cellular immunogenicity. The pre-F/G chimera elicited a strong neutralizing antibody response and a superior NiV-specific Tfh and other effector T cell response compared to G alone across both the mRNA and protein platforms. These findings enabled final candidate selection of pre-F/G Fd for clinical development.

Highlights

Nipah virus (NiV) is an enveloped non-segmented negativestrand RNA virus in the Henipavirus genus of the Paramyxoviridae family [1]
NiV is listed as a high priority pathogen by the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC) and the Coalition of Epidemic Preparedness Innovations (CEPI) [30], and there is a need for medical countermeasures, vaccines
Mice immunized with prefusion conformation (pre-F), postfusion conformation (post-F) or pre-F/G mRNA had robust F-specific antibody responses (Figure 1A) regardless of mRNA dose, while mice immunized with hexameric G (Hex G) protein did not elicit detectable F-specific antibodies

Summary

Introduction

Nipah virus (NiV) is an enveloped non-segmented negativestrand RNA virus in the Henipavirus genus of the Paramyxoviridae family [1]. NiV infection results in primarily respiratory symptoms with potential neurological manifestations, documented human-to-human transmission and a high mortality rate (60-70%) in recent outbreaks [3, 5, 8, 21,22,23,24,25,26,27,28,29]. NiV is listed as a high priority pathogen by the World Health Organization (WHO), Centers for Disease Control and Prevention (CDC) and the Coalition of Epidemic Preparedness Innovations (CEPI) [30], and there is a need for medical countermeasures, vaccines. As part of pandemic preparedness efforts, we selected NiV as a prototype paramyxovirus pathogen to optimize antigen design, dissect the humoral and cellular immune responses to vaccination and identify mechanisms of protection. An effective and rapid vaccine response strategy for outbreaks or pandemics requires both precise antigen design and a method for rapid manufacturing and deployment

Objectives

Methods

Results

Conclusion