Eliciting neutralizing antibodies and B cell responses using novel HIV Env immunogens in non-human primates

PROJECT SUMMARY A broadly effective HIV vaccine remains a high priority to reduce the spread of this highly pathogenic virus in the human population. Neutralizing antibodies, broadly cross-neutralizing are highly likely needed to be generated from evolving vaccine candidate immunogens, either protein-based or mRNA-based. Recently, we have elicited

cross-neutralizing serum and serum IgG responses in all macaques immunized with a series of 4 recombinant highly stable and homogeneous NFL trimers arrayed at high density on fully synthetic trimer-liposomes. Besides serum cross-neutralization we now have compelling EMPEM apex densities (Ozorowski/Ward – HIVRAD

Structural Core C) to heterologous near-native protein trimers derived from tier 2 viruses not in the immunogen series. In addition, we know have isolated monoclonal antibodies that possess long and tip-charged HCDR3s that compete with PGT145 and VRC26 for trimer-binding. These data indicate that these neutralizing antibodies

are likely apex-directed, cross-neutralizing antibodies – a very significant accomplishment for the field. To launch this study, we initially tested a set of NFL trimers available from the Wyatt lab for recognition by the germline- reverted NHP bNAb RHA1 from George Shaw (Roark et al, Science 2021). Remarkably, the Q23 NFL displayed

detectable binding that was enhanced by multi-valent array on covalent trimer-liposomes. Accordingly, we used Q23 NFL trimers and Q23 trimer-liposome (high-valency array) in SMNP adjuvant (Darrell Irvine) to elicit autologous neutralization. We followed the Q23 NFL prime with heterologous boosting of trimers that are the

most sensitive to apex-directed bNAbs (ie, ZM233, see below). Using this prime:boost strategy we elicited neutralization of multiple clinical isolates, including the well-studied CH505 transmitter/founder virus. At this juncture, our initial apex-targeting vaccine experiment in NHPs appears to be quite successful. We have elicited

both autologous Q23, ZM233 and 1428 neutralization, as well as cross-neutralization of tier 2 isolates not in the vaccine regimen. Accordingly, here, we propose to perform heterologous protection studies of the NFL- trimer vaccinated NHPs by repetitive low-dose mucosal challenge with the well-characterized, clinical isolate,

transmitter-founder-based CH505 SHIV.