Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming

Allan C deCamp; Martin M Corcoran; William J Fulp; Jordan R Willis; Christopher A Cottrell; Daniel L V Bader; Oleksandr Kalyuzhniy; David J Leggat; Kristen W Cohen; Ollivier Hyrien; Sergey Menis; Greg Finak; Lamar Ballweber-Fleming; Abhinaya Srikanth; Jason R Plyler; Farhad Rahaman; Angela Lombardo; Vincent Philiponis; Rachael E Whaley; Aaron Seese; Joshua Brand; Alexis M Ruppel; Wesley Hoyland; Celia R Mahoney; Alberto Cagigi; Alison Taylor; David M Brown; David R Ambrozak; Troy Sincomb; Tina-Marie Mullen; Janine Maenza; Orpheus Kolokythas; Nadia Khati; Jeffrey Bethony; Mario Roederer; David Diemert; Richard A Koup; Dagna S Laufer; Juliana M McElrath; Adrian B McDermott; Gunilla B Karlsson Hedestam; William R Schief

doi:10.1038/s41541-024-00811-5

Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming

NPJ Vaccines. 2024 Mar 11;9(1):58. doi: 10.1038/s41541-024-00811-5.

Authors

Allan C deCamp^#¹, Martin M Corcoran^#², William J Fulp^#³, Jordan R Willis^{4

5

6}, Christopher A Cottrell^{4

5

6}, Daniel L V Bader^{4

5

6}, Oleksandr Kalyuzhniy^{4

5

6}, David J Leggat⁷, Kristen W Cohen³, Ollivier Hyrien³, Sergey Menis^{4

5

6}, Greg Finak³, Lamar Ballweber-Fleming³, Abhinaya Srikanth⁷, Jason R Plyler⁷, Farhad Rahaman⁸, Angela Lombardo⁸, Vincent Philiponis⁸, Rachael E Whaley³, Aaron Seese³, Joshua Brand⁷, Alexis M Ruppel⁷, Wesley Hoyland⁷, Celia R Mahoney³, Alberto Cagigi⁷, Alison Taylor⁷, David M Brown⁹, David R Ambrozak⁷, Troy Sincomb^{4

5

6}, Tina-Marie Mullen^{4

5

6}, Janine Maenza^{3

10}, Orpheus Kolokythas¹¹, Nadia Khati¹², Jeffrey Bethony¹³, Mario Roederer⁷, David Diemert^{13

14}, Richard A Koup⁷, Dagna S Laufer⁸, Juliana M McElrath³, Adrian B McDermott⁷, Gunilla B Karlsson Hedestam¹⁵, William R Schief^{16

17

18

19

20}

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. adecamp@scharp.org.
² Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
³ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
⁴ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁵ Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁶ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, 92037, USA.
⁷ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁸ IAVI, 125 Broad Street, 9th floor, New York, NY, 10004, USA.
⁹ The Foundation for the National Institutes of Health, North Bethesda, MD, USA.
¹⁰ Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
¹¹ Department of Radiology, University of Washington, Seattle, WA, 98195, USA.
¹² Department of Radiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
¹³ Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
¹⁴ Department of Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, DC, USA.
¹⁵ Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden. gunilla.karlsson.hedestam@ki.se.
¹⁶ IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
¹⁷ Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
¹⁸ Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, 92037, USA. schief@scripps.edu.
¹⁹ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, 02139, USA. schief@scripps.edu.
²⁰ Moderna Inc., Cambridge, MA, 02139, USA. schief@scripps.edu.

^# Contributed equally.

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.

Abstract

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