Induction of broadly neutralizing antibody (bnAb) responses remains a central challenge to designing efficacious HIV vaccines. Lineage design strategies, in which bnAb precursors are guided via iterative immunizations to their mature forms, depend on high levels of somatic mutation and the recall of antigen-specific B cells. Recent studies have identified spatial context as an important determinant of boosting efficacy, but the application of this to HIV vaccines and the underlying mechanisms are incompletely understood. Here, using mice harboring a V3-glycan bnAb lineage precursor knock-in combined with lineage-tracing and single-cell analyses, we show that persistent germinal centers (GCs) support continued affinity maturation of founder clones and ipsilateral boosting preferentially engages these lineages in secondary GCs. In contrast, contralateral boosting predominantly recruits naïve B cells and memory B cells not directed towards the immunizing antigen. The few memory cells recruited at this site were biased towards a plasma cell fate. Finally, we identify disfavored mutational trajectories within the V3-glycan bnAb lineage, revealing intrinsic constraints on bnAb lineage evolution.
John S. Barber, K. Tonouchi, Chen-Hao Yeh et al.· bioRxiv· 0 citations
PURPOSE OF REVIEW
Since our last review of progress in inducing HIV broadly neutralizing antibodies (bnAbs) in 2023, advances have been made in achieving bnAb induction in humans. The purpose of this review is to discuss this progress and to outline remaining tasks needed to complete a prototype HIV vaccine.
RECENT FINDINGS
Several published clinical trials have succeeded in inducing bnAb precursors of multiple types, including membrane proximal external region (MPER), CD4+-mimicking CD4+-binding site (bs) and HCDR3-dominant CD4bs. Trials are underway or nearing completion for inducing V2-apex and V3-glycan bnAb precursors.
SUMMARY
Progress is being made in developing vaccine immunogens that induce bnAb B cell lineages in humans. The next tasks are to design boosting immunogens that complete bnAb affinity maturation, and to do so for two to three different bnAb specificities to prevent transmitted-founder virus escape during HIV transmission. A final task is to utilize a vaccine platform that will induce high-tittered, durable serum bnAb activity capable of providing protection for multiple years.
Barton F. Haynes, Chen-Hao Yeh, L. Baden· Current Opinion in HIV and A...· 0 citations
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