HIV bnAb Lineage Guide: Germline-Targeting Vaccine Simulator

Vaccine Cascade

Stage 1 of 3

Stage 1: Germline Priming 0-6 SHM

Targets rare naive VH1-2 precursors (frequency ~1:30,000) by removing steric glycan at Asn276.

Stage 2: Core Intermediate Boost 6-14 SHM

Selects for CDRH2 5-amino-acid insertions and initial Glycan 276 accommodation.

Stage 3: Native Trimer Polish 14-24 SHM

Forces lineage maturation to overcome N276/N463 glycan barriers for pan-clade neutralization.

Naive Precursor Pool Freq 1 in 33,000

Somatic Hypermutation Cycles 18 Cycles

Adjuvant & T-FH Help Strength Strong (TLR-7/8)

Neutralization Breadth 89.4% +76% vs baseline

Mean CDRH2 Mutations 14.2 aa Arg71, Asn58 acquired

Target Affinity (KD) 1.8 nM High-affinity CD4bs

Decoy Diversion Rate 4.2% Steric escape avoided

B-Cell Somatic Lineage Phylogeny (VH1-2*02)

Target bnAb Branch Off-Target Decoy Apoptotic Deletion

Epitope Affinity Landscape & Steric Barrier Trajectory Free Energy ($\Delta G$) vs Steric Glycan Accommodation

IC50: 0.12 µg/mL

VRC01-Class

Clone #VRC-18.4 KD: 1.8 nM

Heavy Chain: IGHV1-2*02 / CDRH3: 14 aa

Light Chain: IGKV1-33 (5 aa CDRL3 deletion)

Steric Clashes Avoided: Asn276, Asn463 glycan shield

Essential Acquired Somatic Mutations:

Trp50Arg (CD4 mimic) Asn58Asp (Charge lock) Arg71Ser (Loop flex) Thr28Ile Ser30Arg

[00:00] Initialized naive B-cell repertoire. Precursors: ~30/million.

[00:01] Loaded IAVI G001 Sequential Cascade preset.