Abstract
Abstract Induction of long-lived plasma cells producing protective HIV-1 Envelope (Env)-specific antibody (Ab) is a primary goal of HIV vaccine strategies. However, vaccine-induced Env-specific human plasma cells have not yet been identified. In an effort to do so, samples were obtained from HVTN 105, a phase I trial in which participants were immunized with the same bivalent gp120 protein, AIDSVAX B/E, as used in RV144, although combined with a DNA immunogen (instead of ALVAC-HIV) in various prime/boost strategies. Participants who received a boosting regimen that included AIDSVAX B/E had robust peripheral blood plasmablast responses as measured by Env-specific ELISpot (n=21) and flow cytometry (n=20). The Env-specific immunoglobulin repertoire of the plasmablasts, assessed by monoclonal Ab generation (>110 mAbs total from 15 participants), was dominated by VH1 gene usage (~60%, VH1-2>VH1-46>VH1-24), and had modest mutation from germline (~5%). Ongoing epitope mapping has indicated V3 is a dominant target; however other regions including V1/V2 and C1/C5 were also targeted. The majority of the mAbs are high avidity, and a subset can mediate Ab-dependent cellular phagocytosis; additional functional analysis is ongoing. Bone marrow was evaluated ~7 months after immunization (n=3), and although ELISpot of CD138+ plasma cells could readily detect influenza specific IgG Ab secreting cells (ASCs), Env-specific IgG ASCs were not convincingly detected by ELISpot. However, when using VH deep sequencing of the bone marrow (n=4), multiple members of plasmablast-derived mAb clonal lineages were detected. Our results indicate that HIV-1 Env-specific B cells are present in human bone marrow after vaccination, but may persist at very low frequency.
Published Version
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