Targeting broadly neutralizing antibody precursors: a naïve approach to vaccine design

It is believed that broadly neutralizing antibodies (bNAbs) will be an important component of an effective HIV-1 vaccine. Several immunogens have been designed that can target specific precursor B cells as a first step in a vaccine strategy to elicit bNAbs.

Germline-targeting immunogens have been developed that specifically engage precursors of reproducible classes of anti-HIV antibodies, such as VRC01-class and apex-directed bNAbs. However, these precursors represent only a small portion of the immune repertoire and any antigen will inherently present off-target epitopes to the immune system that may confound bNAb development. Novel animal models are being utilized to understand the competitive fitness of bNAb precursors in the context of immunization with germline-targeting immunogens. In parallel, immunogen design efforts are being pursued to favor the development of bNAb responses over off-target responses following immunization. New studies of bNAb precursor interactions with glycosylated Env variants can inform prime-boost regimens geared towards accelerating bNAb development.

Germline-targeting immunogens hold promise as a first step in eliciting a bNAb response through vaccination. A better understating of how efficiently germline-targeting immunogens can specifically target rare bNAb precursors is emerging. In addition, a more comprehensive structure-based understanding of critical barriers to bNAb elicitation, as well as commonalities between bNAb classes can further inform vaccine design.