Focusing antibody responses to the fusion peptide in rhesus macaques

Christopher A Cottrell; Payal P Pratap; Kimberly M Cirelli; Diane G Carnathan; Chiamaka A Enemuo; Aleksandar Antanasijevic; Gabriel Ozorowski; Leigh M Sewall; Hongmei Gao; Kelli M Greene; Joel D Allen; Julia T Ngo; Yury Choe; Bartek Nogal; Murillo Silva; Jinal Bhiman; Matthias Pauthner; Darrell J Irvine; David Montefiori; Max Crispin; Dennis R Burton; Guido Silvestri; Shane Crotty; Andrew B Ward

doi:10.1101/2023.06.26.545779

Focusing antibody responses to the fusion peptide in rhesus macaques

bioRxiv [Preprint]. 2023 Jun 27:2023.06.26.545779. doi: 10.1101/2023.06.26.545779.

Authors

Christopher A Cottrell^{1

2}, Payal P Pratap^{1

2}, Kimberly M Cirelli³, Diane G Carnathan^{2

4}, Chiamaka A Enemuo⁴, Aleksandar Antanasijevic^{1

2}, Gabriel Ozorowski^{1

2}, Leigh M Sewall^{1

2}, Hongmei Gao⁵, Kelli M Greene⁵, Joel D Allen⁶, Julia T Ngo⁴, Yury Choe⁴, Bartek Nogal^{1

2}, Murillo Silva⁷, Jinal Bhiman⁸, Matthias Pauthner⁹, Darrell J Irvine^{2

7}, David Montefiori⁵, Max Crispin⁶, Dennis R Burton^{2

10

9}, Guido Silvestri^{2

4}, Shane Crotty^{2

3

11}, Andrew B Ward^{1

2}

Affiliations

¹ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
² International AIDS Vaccine Initiative Neutralizing Antibody Center, the Collaboration for AIDS Vaccine Discovery (CAVD) and Scripps Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
⁴ Division of Microbiology and Immunology, Emory National Primate Research Center, Emory University, Atlanta, GA 30329, USA.
⁵ Duke Human Vaccine Institute and Department of Surgery, Duke University Medical Center, Durham, NC, USA.
⁶ School of Biological Sciences, University of Southampton, Southampton, SO17 1BJ, UK.
⁷ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁸ Centre for HIV and STI, National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa.
⁹ Ragon Institute of MGH, MIT and Harvard, Cambridge, MA02139, USA.
¹⁰ Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA.
¹¹ Division of Infectious Disease and Global Public Health, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

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.

Publication types

Preprint

Abstract

Publication types

Grants and funding