Virus glycoprotein nanodisc platform for vaccine design

Kimmo I. Rantalainen; Alessia Liguori; Gabriel Ozorowski; Claudia Flynn; Jon M. Steichen; Olivia M. Swanson; Patrick J. Madden; Sabyasachi Baboo; Swastik Phulera; Anant Gharpure; Danny Lu; Oleksandr Kalyuzhniy; Patrick D. Skog; Sierra Terada; Monolina Shil; Jolene K. Diedrich; Erik Georgeson; Ryan D. Tingle; Saman Eskandarzadeh; Wen-Hsin Lee; Nushin B. Alavi; Diana Goodwin; Michael Kubitz; Sonya Amirzehni; Sunny Himansu; Devin Sok; Jeong Hyun Lee; John R. Yates; James C. Paulson; Shane Crotty

doi:10.1101/2025.05.02.651272

ImmunologybioRxivMay 2, 2025

Preprint

Virus glycoprotein nanodisc platform for vaccine design

Kimmo I. Rantalainen iD, Alessia Liguori iD, Gabriel Ozorowski iD, Claudia Flynn iD, Jon M. Steichen iD, Olivia M. Swanson iD, Patrick J. Madden iD, Sabyasachi Baboo iD, Swastik Phulera iD, Anant Gharpure iD, Danny Lu iD, Oleksandr Kalyuzhniy iD, Patrick D. Skog iD, Sierra Terada, Monolina Shil, Jolene K. Diedrich iD, Erik Georgeson iD, Ryan D. Tingle iD, Saman Eskandarzadeh iD, Wen-Hsin Lee iD, Nushin B. Alavi iD, Diana Goodwin, Michael Kubitz iD, Sonya Amirzehni, Sunny Himansu iD, , William R. Schief iD

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.

PDF DOI