Discovery medicine - the HVTN's iterative approach to developing an HIV-1 broadly neutralizing vaccine

Abstract

Purpose of review: In the past two decades, there has been an explosion in the discovery of HIV-1 broadly neutralizing antibodies (bnAbs) and associated vaccine strategies to induce them. This abundance of approaches necessitates a system that accurately and expeditiously identifies the most promising regimens. We herein briefly review the background science of bnAbs, provide a description of the first round of phase 1 discovery medicine studies, and suggest an approach to integrate these into a comprehensive HIV-1-neutralizing vaccine.

Recent findings: With recent preclinical success including induction of early stage bnAbs in mouse knockin models and rhesus macaques, successful priming of VRC01-class bnAbs with eOD-GT8 in a recent study in humans, and proof-of-concept that intravenous infusion of VRC01 prevents sexual transmission of virus in humans, the stage is set for a broad and comprehensive bnAb vaccine program. Leveraging significant advances in protein nanoparticle science, mRNA technology, adjuvant development, and B-cell and antibody analyses, the HVTN has reconfigured its HIV-1 vaccine strategy by developing the Discovery Medicine Program to test promising vaccine candidates targeting six key epitopes.

Summary: The HVTN Discovery Medicine program is testing multiple HIV-1-neutralizing vaccine candidates.

Box 1

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FIGURE 1

HVTN Discovery Medicine Program. There are 22 trials in the HVTN pipeline targeting five epitopes using several platforms and adjuvants (top). Key innovations include the use of chimeric trimers, escalating dose priming, and comparisons between protein, protein nanoparticle, and mRNA immunogen platforms. Immunogen design is supported by rigorous preclinical data including use of KI mouse and NHP models (bottom). Adapted in part from [1].

FIGURE 2

Laboratory analyses. The B cell analysis workflow outlined here includes FACS single cell sorting, BCR sequencing, and mAb cloning. These allow assessment of VH and VL allele usage, development of key mutations, and evaluation of binding affinity (top). Serological assays, which can be run in parallel, provide complementary and more rapid assessments of antibody development, including epitope-specific BAMA, epitope-specific neutralizing assay, and EMPEM (bottom). ⁺⁺ = cell sorting using two different flourochrome labeled antigens.

FIGURE 3

Hypothetical combination HIV-1 three-epitope vaccine. The table (top) illustrates a three-epitope combination featuring a two-dose prime targeting the CD4bs, V3 glycan, and MPER regions, then two different shaping boosts, followed by a polishing boost, all distributed over 12 months. A final durability boost is hypothesized at 24 months and periodically thereafter to maintain adequate bnAb levels. Two-model platform delivery options include a combination mRNA encoded CD4bs (red), V3 glycan (blue), and MPER (purple) single VLP (bottom left) or multimeric triple epitope nanoparticle (bottom right).