HIV-1 Fusion Peptide-directed Vaccine Design Using Virus-like Particles

PROJECT SUMMARY There is an unmet need in the HIV vaccine field for immunogens that consistently elicit potent serum antibodies that neutralize a broad spectrum of HIV-1 variants in circulation worldwide. Recently, we identified a novel target for human neutralizing antibodies (NAbs): the eight N-terminal amino acids of the fusion peptide (FP) on prefusion HIV-1 envelope (Env) trimer (Science 2016). We then created a novel immunization strategy: priming with FP conjugated to the carrier protein keyhole limpet hemocyanin (FP-KLH) and boosting with HIV-1 Env trimer. This strategy has reproducibly elicited FP-directed cross-reactive NAbs in multiple studies involving mice, guinea pigs and non-human primates (NHPs), although not in every animal (Nat Med 2018, Cell 2019). The best monoclonal antibody (mAb) from an immunized NHP neutralized 98% of 58 wild-type HIV-1 strains with FP sequence matching the immunogen, and 59% of 208 strains that represent viruses worldwide and contain diverse FP sequences. Therefore, FP prime/Env boost is a promising strategy for eliciting NAb responses. To further improve FP-directed vaccine design, two main limitations need to be addressed. First, the neutralization breadth of the polyclonal sera from immunized animal is still limited. Second, the cross-neutralizing activities were only observed in a small subset of immunized animals and were generally low-titer. To address these limitations, in this proposal, we will develop novel FP immunogens and immunization strategies to improve the breadth (Aim 1), magnitude (Aim 2) and quality (Aim 3) of the FP-directed responses in guinea pigs and non- human primates.