Structure-based vaccine design holds great promise for combatting viral pathogens that create substantial burdens on global health. For HIV, the soluble ectodomain of the envelope glycoprotein (Env), which is the primary target for neutralizing antibody responses, is the focal point for vaccine design. Several different platforms of stable, soluble Env trimers locked in a prefusion, antigenically optimal, conformation are now available and provide the basis for further design efforts. The investigators of this grant developed the native flexibly-linked (NFL) platform, which does not require furin cleavage. The Ward and Wilson labs (Co-PIs of the Structure Core) have shown that NFL trimers adopt native-like structures and the Wyatt lab (Project 1) that they induce neutralizing antibody responses in rabbits and guinea pigs. In fact, a small subset of monoclonal antibodies that have been isolated from these animals show some neutralization breadth, a key next step in trimer-based vaccine design. We have already mapped these antibodies by electron microscopy and showed that one antibody targets an epitope that overlaps with the CD4bs and another targets an epitope near the base of the trimer, similar to some known human broadly neutralizing antibodies. These desirable immune responses are relatively infrequent, but show the promise of these trimer-based immunogens. Based on new structural information and the desire to improve the antigenicity and immunogenicity, further NFL trimers are continually being redesigned. For example, the NFL platform has been elaborated to include the MPER as well as a glycan- depleted version that increases accessibility of the CD4bs, and has been successfully been incorporated into liposomes for multivalent presentation. Each new design was enabled by the available structural information. Hence, this core will continue to provide the necessary structural information to drive Env trimer vaccine innovation in an iterative manner, at the front-end aiding in the design of new immunogens (with Project 1), in the middle by informing boosting strategies using our EM serum profiling analysis (with Project 2), and at the back-end by evaluating the antibody responses to such immunogens at low and high resolution (with Project 2).
