Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming.
Allan C deCampMartin M CorcoranWilliam J FulpJordan R WillisChristopher A CottrellDaniel L V BaderOleksandr KalyuzhniyDavid J LeggatKristen W CohenOllivier HyrienSergey MenisGreg FinakLamar B FlemingAbhinaya SrikanthJason R PlylerFarhad RahamanAngela LombardoVincent PhiliponisRachael E WhaleyAaron SeeseJoshua BrandAlexis M RuppelWesley HoylandCelia R MahoneyAlberto CagigiAlison TaylorDavid M BrownDavid R AmbrozakTroy SincombTina-Marie MullenJanine MaenzaOrpheus KolokythasNadia KhatiJeffrey BethonyMario RoedererDavid J DiemertRichard A KoupDagna S LauferJuliana M McElrathAdrian B McDermottGunilla B Karlsson HedestamWilliam R SchiefPublished in: NPJ vaccines (2024)
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.
Keyphrases
- clinical trial
- high dose
- low dose
- dna repair
- endothelial cells
- phase ii
- cancer therapy
- phase iii
- study protocol
- induced pluripotent stem cells
- genome wide
- open label
- randomized controlled trial
- stem cell transplantation
- hiv infected
- gene expression
- double blind
- multidrug resistant
- antiretroviral therapy
- mass spectrometry
- placebo controlled