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

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.
Competing Interests: Authors SF, VP, EN, SH and AC were employed by company Moderna Inc. YT is employed by Leidos Biomedical Research, Inc., supported in part with funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001. RL, GS-J, JM, and BG are inventors on patent applications involving Nipah virus vaccine designs. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Loomis, DiPiazza, Falcone, Ruckwardt, Morabito, Abiona, Chang, Caringal, Presnyak, Narayanan, Tsybovsky, Nair, Hutchinson, Stewart-Jones, Kueltzo, Himansu, Mascola, Carfi and Graham.)