Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice
Christopher A. Cottrell, Xiaozhen Hu, Jeong Hyun Lee, Patrick Skog, Sai Luo, Claudia T. Flynn, Katherine McKenney, Jonathan Hurtado, Oleksandr Kalyuzhniy, Alessia Liguori, Jordan R. Willis, Elise Landais, Sebastian Raemisch, Xuejun Chen, Sabyasachi Baboo, Sunny Himansu, Jolene K. Diedrich, Hongying Duan, Cheng Cheng, Torben Schiffner, Daniel Bader, Daniel W. Kulp, Ryan Tingle, Erik Georgeson, Saman Eskandarzadeh, Nushin Alavi, Danny Lu, Troy Sincomb, Michael Kubitz, Tina-Marie Mullen, John R. Yates, James C. Paulson, John R. Mascola, Frederick W. Alt, Bryan Briney, Devin Sok, William R. Schief
Abstract
was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.