Focusing antibody responses to the fusion peptide in rhesus macaques.

• Type of Material: Article
• Authors: Christopher A Cottrell, Scripps Research Institute, La Jolla; Payal P Pratap, Scripps Research Institute, La Jolla; Kimberly M Cirelli, La Jolla Institute for Immunology; Diane G Carnathan, Emory University; Chiamaka A Enemuo, Emory University; Aleksandar Antanasijevic, Scripps Research Institute, La Jolla; Gabriel Ozorowski, Scripps Research Institute, La Jolla; Leigh M Sewall, Scripps Research Institute, La Jolla; Hongmei Gao, Duke University; Kelli M Greene, Duke University; Joel D Allen, University of Southampton; Julia T Ngo, Emory University; Yury Choe, Emory University; Bartek Nogal, Scripps Research Institute, La Jolla; Murillo Silva, Massachusetts Institute of Technology, Cambridge; Jinal Bhiman, National Health Laboratory Service, Johannesburg; Matthias Pauthner, Ragon Institute of MGH, MIT and Harvard; Darrell J Irvine, Massachusetts Institute of Technology, Cambridge; David Montefiori, Duke University; Max Crispin, University of Southampton; Dennis R Burton, Scripps Research Institute, La Jolla; Guido Silvestri, Emory University; Shane Crotty, University of California, San Diego; Andrew B Ward, Scripps Research Institute, La Jolla
• Language: English
• Date: 2023-06-27
• Publisher: Chan Zuckerberg Initiative
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1101/2023.06.26.545779
• Title of Journal or Parent Work: bioRxiv
• Keywords: antibodies; Immunodominance; HIV broadly neutralizing antibodies; somatic hypermutation; fusion peptide epitope targeting immunogen
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology; Biology, Microbiology; Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

Immunodominance of antibodies targeting non-neutralizing epitopes and the high level of somatic hypermutation within germinal centers (GCs) required for most HIV broadly neutralizing antibodies (bnAbs) are major impediments to the development of an effective HIV vaccine. Rational protein vaccine design and non-conventional immunization strategies are potential avenues to overcome these hurdles. Here, we report using implantable osmotic pumps to continuously deliver a series of epitope-targeted immunogens to rhesus macaques over the course of six months to elicit immune responses against the conserved fusion peptide. Antibody specificities and GC responses were tracked longitudinally using electron microscopy polyclonal epitope mapping (EMPEM) and lymph node fine-needle aspirates, respectively. Application of cryoEMPEM delineated key residues for on-target and off-target responses that can drive the next round of structure-based vaccine design.