Virus glycoprotein nanodisc platform for vaccine design

Rantalainen, K.; Liguori, A.; Ozorowski, G.; Flynn, C.; Steichen, J. M.; Swanson, O.; Madden, P. J.; Baboo, S.; Phulera, S.; Gharpure, A.; Lu, D.; Kalyuzhniy, O.; Skog, P.; Terada, S.; Shil, M.; Diedrich, J. K.; Georgeson, E.; Tingle, R.; Eskandarzadeh, S.; Lee, W.-H.; Goodwin, D.; Alavi, N.; Kubitz, M.; Amirzehni, S.; Himansu, S.; Sok, D.; Lee, J. H.; Yates, J. R.; Paulson, J. C.; Crotty, S.; Schiffner, T.; Ward, A. B.; Schief, W. R.

doi:10.1101/2025.05.02.651272

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bioRxiv · 10.1101/2025.05.02.651272

Virus glycoprotein nanodisc platform for vaccine design

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Abstract

Transmembrane glycoproteins of enveloped viruses are the targets of neutralizing antibodies and essential vaccine antigens. mRNA-LNP technology allows in situ production of transmembrane glycoproteins upon immunization, but biophysical characterization of transmembrane antigens and in vitro analysis of post-immunization antibody responses typically rely on soluble proteins. Here, we present a methodological platform for assembling transmembrane glycoprotein vaccine candidates into lipid nanodiscs. We demonstrate the utility of the nanodiscs in HIV membrane proximal external region (MPER)-targeting vaccine development by binding assays using surface plasmon resonance (SPR), ex vivo B cell sorting with fluorescence-activated cell sorting (FACS), and by determining the structure of a prototypical HIV MPER-targeting immunogen nanodisc in complex with three broadly neutralizing antibodies (bnAbs), including the MPER bnAb 10E8, to 3.5 [A] by cryogenic electron microscopy (cryo-EM), providing a template for structure-based immunogen design for MPER. Overall, the platform offers a tool for accelerating the development of next-generation viral vaccines.

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Rantalainen, K., Liguori, A., Ozorowski, G., Flynn, C., Steichen, J. M., Swanson, O., Madden, P. J., Baboo, S., Phulera, S., Gharpure, A., Lu, D., Kalyuzhniy, O., Skog, P., Terada, S., Shil, M., Diedrich, J. K., Georgeson, E., Tingle, R., Eskandarzadeh, S., Lee, W.-H., Goodwin, D., Alavi, N., Kubitz, M., Amirzehni, S., Himansu, S., Sok, D., Lee, J. H., Yates, J. R., Paulson, J. C., Crotty, S., Schiffner, T., Ward, A. B., Schief, W. R.. 2025-05-04. Virus glycoprotein nanodisc platform for vaccine design. https://doi.org/10.1101/2025.05.02.651272

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