Deep mining of the human antibody repertoire identifies frequent and genetically diverse CDRH3 topologies targetable by vaccination
Abstract
Germline targeting vaccination strategies against highly variable pathogens such as HIV aim to elicit broadly neutralizing antibodies (bnAbs) with particular immunogenetic or structural features. The V2 apex of the HIV Env protein is a promising target for a class of bnAbs that contain conserved structural motifs in the heavy chain complementarity determining region 3 (CDRH3). Here, we show that these structural motifs are targetable by vaccination by characterizing V2 apex “axe-like” CDRH3s in the human repertoire and developing immunogens capable of engaging them. We determined the frequency and diversity of axe-like CDRH3s in healthy human donors using a series of structural informatics approaches, finding these precursors in nearly 90% of donors. Axe-targeting immunogens based on the HIV Env Q23.17 bound axe-like precursors in cryo-electron microscopy structures, induced V2 apex-specific antibody responses in humanized mice, and induced axe-like heterologous neutralizing antibodies in rhesus macaques infected with a germline-targeted simian-HIV. These results illustrate a structure-guided immunoinformatic vaccine design paradigm that can be employed to elicit immunogenetically diverse yet structurally conserved classes of antibodies.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (39)
Rumi Habib
Shahlo O. Solieva
Vaccine and Immunotherapy Center, The Wistar Institute
Zi Jie Lin
Vaccine and Immunotherapy Center, The Wistar Institute
Sukanya Ghosh
Vaccine and Immunotherapy Center, The Wistar Institute
Kelly Bayruns
Vaccine and Immunotherapy Center, The Wistar Institute
Maya Singh
Vaccine and Immunotherapy Center, The Wistar Institute
Colby J. Agostino
Department of Biochemistry and Biophysics, The University of Pennsylvania
Nicholas J. Tursi
Vaccine and Immunotherapy Center, The Wistar Institute
Kirsten J. Sowers
Department of Medicine, Perelman School of Medicine, University of Pennsylvania
Jinwei Huang
Vaccine and Immunotherapy Center, The Wistar Institute
Ryan S. Roark
Mansi Purwar
Vaccine and Immunotherapy Center, The Wistar Institute
Younghoon Park
Kasirajan Ayyanathan
Hui Li
John W. Carey
Amber Kim
Vaccine and Immunotherapy Center, The Wistar Institute
Joyce Park
Vaccine and Immunotherapy Center, The Wistar Institute
Madison E. McCanna
Vaccine and Immunotherapy Center, The Wistar Institute
Ashwin N. Skelly
Neethu Chokkalingam
Vaccine and Immunotherapy Center, The Wistar Institute
Sinja Kriete
Vaccine and Immunotherapy Center, The Wistar Institute
Nicholas Shupin
Vaccine and Immunotherapy Center, The Wistar Institute
Alana Huynh
Vaccine and Immunotherapy Center, The Wistar Institute
Susanne Walker
Vaccine and Immunotherapy Center, The Wistar Institute
Roopak Sadeesh
Vaccine and Immunotherapy Center, The Wistar Institute
Niklas Laenger
Vaccine and Immunotherapy Center, The Wistar Institute
Jianqiu Du
Vaccine and Immunotherapy Center, The Wistar Institute
Jiayan Cui
Vaccine and Immunotherapy Center, The Wistar Institute
Ami Patel
Amelia Escolano
Vaccine and Immunotherapy Center, The Wistar Institute
Peter D. Kwong
Lawrence Shapiro
Gregory R. Bowman
Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania
Beatrice H. Hahn
George M. Shaw
David B. Weiner
Vaccine and Immunotherapy Center, The Wistar Institute
Jesper Pallesen
Department of Biochemistry and Biophysics, The University of Pennsylvania
Daniel W. Kulp
Department of Biochemistry and Biophysics, The University of Pennsylvania