A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses

Kristen W. Cohen, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Stephen C. De Rosa, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
William J. Fulp, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Allan C. deCamp, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Andrew Fiore-Gartland, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Celia R. Mahoney, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Sarah Furth, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Josh Donahue, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Rachael E. Whaley, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Lamar Ballweber-Fleming, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Aaron Seese, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Katharine Schwedhelm, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Daniel Geraghty, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Greg Finak, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Sergey Menis, IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92307, USA.
David J. Leggat, Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
Farhad Rahaman, IAVI, 125 Broad Street, 9th Floor, New York, NY 10004, USA.
Angela Lombardo, IAVI, 125 Broad Street, 9th Floor, New York, NY 10004, USA.
Bhavesh R. Borate, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Vincent Philiponis, IAVI, 125 Broad Street, 9th Floor, New York, NY 10004, USA.
Janine Maenza, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
David Diemert, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, George Washington University, Washington DC, 20052, USA.
Orpheus Kolokythas, Department of Radiology, University of Washington, Seattle, WA 98195, USA.
Nadia Khati, Department of Radiology, School of Medicine and Health Sciences, George Washington University, Washington DC 20052, USA.
Jeffrey Bethony, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, George Washington University, Washington DC, 20052, USA.
Ollivier Hyrien, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.
Dagna S. Laufer, IAVI, 125 Broad Street, 9th Floor, New York, NY 10004, USA.
Richard A. Koup, Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
Adrian B. McDermott, Vaccine Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
William R. Schief, IAVI Neutralizing Antibody Center, Scripps Research Institute, La Jolla, CA 92307, USA.
M Juliana McElrath, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA.

Document Type

Journal Article

Publication Date

5-24-2023

Journal

Science translational medicine

Volume

15

Issue

697

DOI

10.1126/scitranslmed.adf3309

Abstract

The engineered outer domain germline targeting version 8 (eOD-GT8) 60-mer nanoparticle was designed to prime VRC01-class HIV-specific B cells that would need to be matured, through additional heterologous immunizations, into B cells that are able to produce broadly neutralizing antibodies. CD4 T cell help will be critical for the development of such high-affinity neutralizing antibody responses. Thus, we assessed the induction and epitope specificities of the vaccine-specific T cells from the IAVI G001 phase 1 clinical trial that tested immunization with eOD-GT8 60-mer adjuvanted with AS01. Robust polyfunctional CD4 T cells specific for eOD-GT8 and the lumazine synthase (LumSyn) component of eOD-GT8 60-mer were induced after two vaccinations with either the 20- or 100-microgram dose. Antigen-specific CD4 T helper responses to eOD-GT8 and LumSyn were observed in 84 and 93% of vaccine recipients, respectively. CD4 helper T cell epitope "hotspots" preferentially targeted across participants were identified within both the eOD-GT8 and LumSyn proteins. CD4 T cell responses specific to one of these three LumSyn epitope hotspots were observed in 85% of vaccine recipients. Last, we found that induction of vaccine-specific peripheral CD4 T cells correlated with expansion of eOD-GT8-specific memory B cells. Our findings demonstrate strong human CD4 T cell responses to an HIV vaccine candidate priming immunogen and identify immunodominant CD4 T cell epitopes that might improve human immune responses either to heterologous boost immunogens after this prime vaccination or to other human vaccine immunogens.

Department

Microbiology, Immunology, and Tropical Medicine

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