Development of a VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies

Seydoux, Emilie; Wan, Yu-Hsin; Feng, Junli; Wall, Abigail; Aljedani, Safia; Homad, Leah J.; MacCamy, Anna J.; Weidle, Connor; Gray, Matthew D.; Brumage, Lauren; Taylor, Justin J.; Pancera, Marie; Stamatatos, Leonidas; McGuire, Andrew T.

An effective HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs). Broad and potent VRC01-class bNAbs have been isolated from multiple infected individuals, suggesting that they could be reproducibly elicited by vaccination. Several HIV-1 envelope-derived germline-targeting immunogens have been designed to engage naive VRC01-class precursor B cells. However, they also present off-target epitopes that could hinder development of VRC01-class bNAbs. We characterize a panel of anti-idiotypic monoclonal antibodies (ai-mAbs) raised against inferred-germline (iGL) VRC01-class antibodies. By leveraging binding, structural, and B cell sorting data, we engineered a bispecific molecule derived from two aimAbs; one specific for VRC01-class heavy chains and one specific for VRC01-class light chains. The bispecific molecule preferentially activates iGL-VRC01 B cells in vitro and induces specific antibody responses in a murine adoptive transfer model with a diverse polyclonal B cell repertoire. This molecule represents an alternative non-envelope-derived germline-targeting immunogen that can selectively activate VRC01-class precursors in vivo.