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Dryad

mRNA prime–boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models

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Abstract

Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4 binding site (CD4bs) of the HIV Envelope have shown promise in clinical trials. Here, we preclinically validated the mRNA-LNP delivery of one such immunogen, eOD-GT8, as a soluble self-assembling 60mer nanoparticle in humanized mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation with no sign of exclusionary competition. Boosts drove precursor B cell participation in germinal centers, the accumulation of somatic hypermutations, including in key VRC01-class positions, and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles delivered by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversify along the bnAb pathway.