Background:
An effective antibody-based HIV-1 vaccine will require the consistent induction of potent cross-reactive HIV-1-neutralizing responses. Epitope-focusing approaches have elicited consistent, but low titer, cross-clade neutralizing responses against multiple sites of vulnerability. However, consistent, broad, and potent neutralizing responses against HIV-1 have not been achieved by vaccination.
Methods:
To demonstrate feasibility towards the consistent, broad, and potent neutralizing responses, we combined vaccination targeting the fusion peptide-site of vulnerability with infection by simian-human immunodeficiency virus (SHIV).
Results:
In four macaques with vaccine-induced neutralizing responses, SHIV infection boosted plasma neutralization to 45-77% breadth on a cross-clade panel of 208 strains with geometric mean ID50 titers of ~100, a level of potency recently shown to protect against mucosal SHIV challenge from fusion peptide-directed antibodies. Neutralization fingerprinting identified epitope-specific signatures in plasma and observed higher estimates for fusion peptide-directed specificity versus other known specificities. By longitudinally plasma viral RNA sequencing, we observed evidence of strong viral selection by post-SHIV week 16 at the N terminus of the fusion peptide and at the structural adjacent regions, including residues nearby glycan 88. Molecular dissection of these responses into component antibody specificities by antibody isolation and cryo-EM structure determination revealed 15 of 16 isolated antibodies with cross-clade neutralization breadth to be directed towards the fusion peptide-site of vulnerability. In each macaque, isolated monoclonal antibodies recapitulated the plasma-neutralizing response (r =0.71-0.97), with fusion peptide-binding antibodies reaching breadths of 40-60% (IC50 <50 μg/ml) on a 208 strains panel. Longitudinal phylogenetic analysis revealed each of the top macaques to have only 1-2 broadly neutralizing fusion peptide-binding lineages, each induced before SHIV infection.
Conclusions:
These results provide explicit in-vivo molecular examples for one or few B-cell lineages affording potent cross-reactive plasma-neutralizing responses. While increased titers in the current study resulted from SHIV-infection boosting, it will be interesting to test fusion peptide-Env trimer immunogens not only with altered boosting regimens, but also with altered priming regimens, such as with the escalating prime, extended-boost regimen.