Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope

Priming VRC01-precursor B cells with non-envelope immunogens disfavors boosting with HIV-1 envelope

Abstract VRC01-class antibodies are a genetically restricted class of antibodies capable of potently neutralizing diverse strains of HIV-1. Unmutated VRC01 precursors fail to recognize recombinant HIV-1 Envelope (Env) proteins, which necessitated the development of germline targeting vaccine immunog...

Full description

Saved in:
Bibliographic Details
Main Authors: Andrew Wilcox-King, Yu-Hsin Wan, Samuel C. Scharffenberger, Crystal B. Chhan, Amelia R. Davis, Leah J. Homad, Emilie Seydoux, Kellie J. MacPhee, Latha Kallur Siddaramaiah, Mariane Melo, Pia Dosenovic, Darrell J. Irvine, Ollivier Hyrien, Leonidas Stamatatos, Andrew T. McGuire
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:npj Vaccines
Online Access:https://doi.org/10.1038/s41541-025-01235-5
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract VRC01-class antibodies are a genetically restricted class of antibodies capable of potently neutralizing diverse strains of HIV-1. Unmutated VRC01 precursors fail to recognize recombinant HIV-1 Envelope (Env) proteins, which necessitated the development of germline targeting vaccine immunogens capable of initiating VRC01-class B cell response. Among these, we developed an anti-idiotypic monoclonal antibody (ai-mAb)-derived VRC01 class targeting immunogen. Because it is distinct from Env, we speculated that the ai-mAb will selectively engage naive VRC01 class B cells while limiting B cell responses directed at off-target epitopes on Env during prime-boost regimens. Here, we evaluated the serum and B cell responses to ai-mAb prime/Env boost, and Env-prime/Env boost regimens in a murine adoptive transfer model where VRC01 precursor B cells are present at physiological levels. We found that the Env-Env regimen led to the greatest expansion of on-target VRC01 B cells, drove larger VRC01-class GC responses, and elicited higher titers of circulating antibodies despite also eliciting substantial off-target Env-specific responses. Single-cell sorting experiments revealed that the ai-mAb was driving off-track somatic mutations. IgG transfer experiments demonstrated that circulating off-target antibodies provide a positive feedback mechanism that potentiates on-target B cell responses. Collectively, the results suggest that non-Env immunogens are not ideal for priming VRC01-class B cells, where sequential boosting with Env will be required to drive maturation of neutralizing breadth.
ISSN:2059-0105

Similar Items