Author:
deCamp Allan C.,Corcoran Martin M.,Fulp William J.,Willis Jordan R.,Cottrell Christopher A.,Bader Daniel L.V.,Kalyuzhniy Oleksandr,Leggat David J.,Cohen Kristen W.,Hyrien Ollivier,Menis Sergey,Finak Greg,Ballweber-Fleming Lamar,Srikanth Abhinaya,Plyler Jason R.,Rahaman Farhad,Lombardo Angela,Philiponis Vincent,Whaley Rachael E.,Seese Aaron,Brand Joshua,Ruppel Alexis M.,Hoyland Wesley,Mahoney Celia R.,Cagigi Alberto,Taylor Alison,Brown David M.,Ambrozak David R.,Sincomb Troy,Mullen Tina-Marie,Maenza Janine,Kolokythas Orpheus,Khati Nadia,Bethony Jeffrey,Roederer Mario,Diemert David,Koup Richard A.,Laufer Dagna S.,McElrath Juliana M.,McDermott Adrian B.,Hedestam Gunilla B. Karlsson,Schief William R.
Abstract
AbstractVaccine 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.One-Sentence SummaryHuman genetic variation can modulate the strength of vaccine-induced broadly neutralizing antibody precursor B cell responses.
Publisher
Cold Spring Harbor Laboratory