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

• Published in: Frontiers in immunology Vol. 12; p. 772864
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 08-12-2021
• Subjects: Animals; Antigens, Viral - genetics; Antigens, Viral - immunology; Female; Immunoglobulin G - blood; Immunology; Liposomes - administration & dosage; Mice; mRNA; mRNA Vaccines - administration & dosage; Nanoparticles - administration & dosage; Nipah virus (NiV); Nipah Virus - immunology; pandemic preparedness and response; Pre-F/G; Public-Private Sector Partnerships; RNA, Messenger - administration & dosage; structure-based immunogen design; T-Lymphocytes - immunology; vaccine; Viral Envelope Proteins - genetics; Viral Envelope Proteins - immunology; Viral Fusion Proteins - genetics; Viral Fusion Proteins - immunology; Viral Vaccines - administration & dosage; vaccine; pandemic preparedness and response; Nipah virus (NiV); structure-based immunogen design; T cell responses; mRNA; Pre-F/G
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.772864

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.