Strategies for a multi-stage neutralizing antibody-based HIV vaccine

Abstract

A critical property of a prophylactic HIV vaccine is likely to be its ability to elicit broadly neutralizing antibodies (bnAbs). BnAbs typically have multiple unusual features and are generated in a fraction of HIV-infected individuals through complex pathways. Current vaccine design approaches seek to trigger rare B cell precursors and then steer affinity maturation toward bnAbs in a multi-stage multi-component immunization approach. These vaccine design strategies have been facilitated by molecular descriptions of bnAb interactions with stabilized HIV trimers, the use of an array of sophisticated approaches for immunogen design, the development of novel animal models for immunogen evaluation and advanced technologies to interrogate antibody responses. In this review, we will discuss leading HIV bnAb vaccine immunogens, immunization strategies and future improvements.

Figure 1. Immunogens that can form components of a neutralizing antibody-based HIV vaccine

(a) Schematic showing native envelope trimer immunogens (SOSIP.664, native flexibly-linked (NFL) and uncleaved prefusion optimized (UFO) platforms), which form the basis of both priming and boosting immunization steps are shown. Trimers from multiple clades can be generated. (b) CD4 binding site (CD4bs) germline-targeting immunogens, including the engineered outer domain germline-targeting version 8 (eOD-GT8) immunogen (generated by computational approaches and refined through yeast-display and multimerized on nanoparticles), the 426c gp120 core, (which incorporates multiple glycan deletions around the CD4bs) and BG505 SOSIP-GT1 (SOSIP.664 modified to have enhanced binding of CD4bs germline-reverted antibodies) are illustrated. (c) Immunogens designed to select for antibodies with a long heavy chain complementarity determining region 3 (CDRH3), including the BG505 10MUT MD39 trimer to elicit PGT121-class V3-N332 bnAbs and trimers possessing “glycan holes” close to the trimer apex to generate V2 apex bnAbs. (d) Lineage-based immunogens, derived from virus-antibody co-evolution studies in donors CH505 and CAP256, are in development for the elicitation of CD4bs and V2 apex bnAbs. (e) Minimal epitope immunogens, including the N-terminal region of the fusion peptide (FP) fused to keyhole limpet hemocyanin (KLH) and V3-glycopeptides coupled to a T-helper epitope.

Figure 2. Animal models for immunogen evaluation and analysis of antibody responses

(a) Five animal models (non-human primates, cows, guinea pigs, rabbits and mice) have been used to evaluate the immunogenicity of several current vaccine candidates. Within the mouse model, wild-type, immunoglobulin (Ig) gene knock-in mice (containing the rearranged Ig genes for the inferred unmutated common ancestor (UCA) versions of HIV broadly neutralizing antibodies), and mice transgenic for the human Ig locus have been used. The particular immunogen design platforms tested within each animal model system are shown. (b) Schematic depicting three critical technologies that have been used to evaluate vaccine-elicited antibody responses. Monoclonal antibodies, isolated by antigen-specific single B cell sorting and deep sequencing of B cell transcripts can then be used to identify many members of the corresponding B cell lineages. Finally, electron microscopy can be used to identify the epitopes of the vaccine-elicited antibodies. Information derived from the technologies can be fed back to support iterative immunogen design.