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

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

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.

Keywords: Nipah virus (NiV); Pre-F/G; T cell responses; mRNA; pandemic preparedness and response; structure-based immunogen design; vaccine.

Conflict of interest statement

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.

Figures

Figure 1
Figure 1
mRNA Dose-Response Study. (A, B) Serum samples were assessed for NiV pre-F specific IgG (A) or monomeric G-specific IgG (B) by enzyme-linked immunosorbent assay (ELISA). Line represents mean of all animals in each group +/- standard deviation. (C) VSVΔG-luciferase pseudovirus neutralization assays were performed on individual mouse sera collected at week 6. The log10 reciprocal IC80 neutralization titers for each sample was calculated by curve fitting and non-linear regression using GraphPad Prism. Line represents mean of log10 reciprocal IC80 dilution +/- standard deviation. P values were calculated using two-way ANOVA with Tukey’s multiple comparisons test (*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001). Dotted lines represent assay limits of detection.
Figure 2
Figure 2
Immunogenicity of mRNA Immunogen-Specific Design Elements. (A, C) Serum samples 6 weeks post-boost were assessed for NiV pre-F specific IgG (A) or monomeric G-specific IgG (C) by ELISA. Line represents mean of all animals in each group +/- standard deviation. (B, D) VSVΔG-luciferase pseudovirus neutralization assays were performed on individual mouse sera collected 6 weeks post-boost. The log10 reciprocal IC80 neutralization titer for each sample was calculated by curve fitting and non-linear regression using GraphPad Prism. Line represents mean of log10 reciprocal IC80 dilution +/- standard deviation. P values were calculated using one-way ANOVA with Tukey’s multiple comparisons test (**p < 0.01). Dotted lines represent assay limits of detection.
Figure 3
Figure 3
Immunogenicity of mRNA Pre-F/G Chimeric Design Elements. (A, B) Serum samples 6 weeks post-boost were assessed for NiV pre-F specific IgG (A) or monomeric G-specific IgG (B) ELISA. Line represents mean of all animals in each group +/- standard deviation. (C) VSVΔG-luciferase pseudovirus neutralization assays were performed on individual mouse sera collected 6 weeks post-boost. The log10 reciprocal IC80 neutralization titer for each sample was calculated by curve fitting and non-linear regression using GraphPad Prism. Line represents mean of log10 reciprocal IC80 dilution +/- standard deviation. P values were calculated using two-way ANOVA with Tukey’s multiple comparisons test (*p < 0.5, ***p < 0.001, ****p < 0.0001). Dotted lines represent assay limits of detection. All mRNA immunogens were codon-modified using Moderna’s proprietary codon algorithms designed to improve protein expression and mRNA manufacturability. In this figure, we specifically evaluated mRNA preparations that had used two different codon algorithms, referred to as “old” and “new”.
Figure 4
Figure 4
Biophysical Properties of Pre-F/G Chimeric Proteins with Different Trimerization Domains. (A) Negative-stain EM analysis of NiV pre-F/G chimeric proteins. (B, C) Thermodynamic and colloidal stability assessment of pre-F/G chimeric trimerization domains assessed by (B) differential scanning calorimetry (DSC) and (C) dynamic light scattering (DLS). (D) Summary of DSC and DLS data.
Figure 5
Figure 5
Immunogenicity of Pre-F/G Chimeric mRNA Trimerization Domain Designs. (A, B) Serum samples 3 weeks post-boost (week 6) were assessed for NiV pre-F specific IgG (A) or monomeric G-specific IgG (B) by ELISA. Line represents mean of all mice/group +/- standard deviation. (C) VSVΔG-luciferase pseudovirus neutralization assays were performed on individual mouse sera collected at week 6. The log10 reciprocal IC80 titer for each sample was calculated by curve fitting and non-linear regression using GraphPad Prism. Line represents mean of log10 reciprocal IC80 dilution +/- standard deviation. P values were calculated using two-way ANOVA with Tukey’s multiple comparisons test (*p < 0.05, ***p < 0.001, ****p < 0.0001). Dotted lines represent assay limits of detection.
Figure 6
Figure 6
Cellular Immune Responses to F and G. (A) Antigen-experienced (CD44+) CD4+(B) Tfh (CXCR5+ PD-1+), and (C) CD8+ T cell responses determined by AIM assay (CD40L and CD69 upregulation). N = x/gr and error bars reflect SEM. 10 mice/group were analyzed. P values were calculated using two-way ANOVA with Tukey’s multiple comparisons test (*p < 0.05, ***p < 0.001, ****p < 0.0001), comparing F peptide pool only % AIM+ cells.

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