AUTHOR=Loomis Rebecca J. , DiPiazza Anthony T. , Falcone Samantha , Ruckwardt Tracy J. , Morabito Kaitlyn M. , Abiona Olubukola M. , Chang Lauren A. , Caringal Ria T. , Presnyak Vladimir , Narayanan Elisabeth , Tsybovsky Yaroslav , Nair Deepika , Hutchinson Geoffrey B. , Stewart-Jones Guillaume B. E. , Kueltzo Lisa A. , Himansu Sunny , Mascola John R. , Carfi Andrea , Graham Barney S. TITLE=Chimeric Fusion (F) and Attachment (G) Glycoprotein Antigen Delivery by mRNA as a Candidate Nipah Vaccine JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.772864 DOI=10.3389/fimmu.2021.772864 ISSN=1664-3224 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.