Sanders: HIV Trimer Immunogens to Elicit bNAbs against Multiple Epitopes
This investment will be used to demonstrate, in pre-clinical models, the potential to elicit broadly neutralizing antibodies (bNAbs) in humans by using SOSIP trimer immunogens in a sequential germline-targeting, shaping, and polishing strategy. The guiding hypothesis is that inducing bNAb responses will require multiple, genetically-diverse SOSIP trimers that combine germline (gl)-targeting, immunofocusing, and bNAb lineage-maturing properties. Env vaccines usually do not engage the germline precursors of bNAbs (glbNAbs), but this step is generally necessary to initiate bNAb lineages. The BG505 GT1.1 trimer has an already-established ability to induce gl-bNAb lineages. These studies aim to iteratively improve this ability. For germline targeting to succeed, it will probably be critical to shift the balance away from non-productive but immunodominant Ab responses towards desirable sub-dominant ones associated with bNAb epitopes. Removing immunodominant glycan holes from the GT1.1 trimer and masking other distractive epitopes will be a key strategy. By improving the ability to create high-quality trimers from multiple genotypes (e.g. different clades), opportunities to broaden NAb responses will increase, including via the maturation of bNAb lineages initiated by existing and new germline-targeting trimers. Results from this preclinical program will inform the planned BG505 GT1.1 human clinical trial.
BG505 SOSIP.v4.1-GT1 (‘GT1’) is an engineered variant of the native-like BG505 SOSIP.664 trimer. It contains a 7-residue deletion and 17 single amino acid changes, including the loss of 5 Potential N-linked Glycosylation Sites (PNGS), that create or expose epitopes for gl-bNAbs against the CD4bs and the trimer apex. In comparison to SOSIP.664, GT1 shows higher affinity for gl-precursors of CD4bs and trimer apex bNAb lineages. As broad recognition is probably required for the consistent activation of human naïve B cells that express the B cell receptors (BCRs) for VRC01-class precursors, the GT1 trimer was further modified to expand the range of precursors engaged. Guided by the crystal structure of the GT1 trimer, two alternative single-residue changes were made to create the BG505 GT1.1 (E275K) and GT1.2 (N279D) constructs.
The four specific goals of this investment are described below.
1) Validate BG505 GT1.1 as a priming immunogen by:
2) Improve the BG505 GT1.1 priming immunogen to maximize the priming of favorable B cells (i.e. bNAb precursors) and minimize the competition from unfavorable B cells (i.e. off-target responses).
a) Testing its ability to activate bNAb precursors in more stringent knock-in mouse models (i.e. those in which precursor frequencies are much lower than the previously used KI models).
b) Testing its ability to select the appropriate cells in the naïve human B cell repertoire.
3) Establish sequential vaccination regimens to ‘shape’ and ‘polish’ bNAb responses.
4) Generate alternative or additional bNAb-priming or bNAb-inducing immunogens by improving the GT1.1 trimer and/or identifying GT trimers of other genotypes that better induce V2-apex bNAb precursors.