Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming

Allan C. deCamp, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. adecamp@scharp.org.
Martin M. Corcoran, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
William J. Fulp, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Jordan R. Willis, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Christopher A. Cottrell, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Daniel L. Bader, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Oleksandr Kalyuzhniy, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
David J. Leggat, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Kristen W. Cohen, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Ollivier Hyrien, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Sergey Menis, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Greg Finak, 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.
Abhinaya Srikanth, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Jason R. Plyler, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 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.
Vincent Philiponis, IAVI, 125 Broad Street, 9th floor, New York, NY, 10004, USA.
Rachael E. Whaley, 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.
Joshua Brand, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Alexis M. Ruppel, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Wesley Hoyland, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Celia R. Mahoney, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Alberto Cagigi, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Alison Taylor, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
David M. Brown, The Foundation for the National Institutes of Health, North Bethesda, MD, USA.
David R. Ambrozak, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Troy Sincomb, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Tina-Marie Mullen, IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Janine Maenza, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Orpheus Kolokythas, Department of Radiology, University of Washington, Seattle, WA, 98195, USA.

Document Type

Journal Article

Publication Date

3-11-2024

Journal

NPJ vaccines

Volume

9

Issue

1

DOI

10.1038/s41541-024-00811-5

Abstract

Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.

Department

Microbiology, Immunology, and Tropical Medicine

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