Congrats Lynda! Amazing milestone and well-deserved!!

A huge thank you to the Ward and Wilson labs (Scripps), the Batista lab (Ragon) and our collaborators all over. This work has led to a clinical trial (https://buff.ly/4jHBMaH), which we're incredibly excited about. First results: soon! 🔜

4. We are not there yet - bnAbs are still the holy grail for HIV vaccines, and we likely need more booster immunogens that mimic the high complexity of HIV itself.

3. We can now manipulate B cell responses at an atomic level - two highly dissimilar B cell receptors can target the same residues with the same antibody orientation, as long as your immunogen is designed to favor these interactions.

2. Such a trimer may be more restrictive compared to nanoparticle approaches (at the cost of affinity), but the lineages that are elicited are (naturally) capable of recognizing trimers - which is necessary as the virion itself has Env trimers and trimers only on its surface.

Altogether, we reached some important conclusions for the field:
1. A germline-targeting trimer can kickstart broadly neutralizing antibody lineages that target multiple epitopes succesfully.

One other antibody, 12C11, targets a different CD4 binding site epitope - reminiscent of human broadly neutralizing antibody CH103. Strikingly, the person from which CH103 was isolated ALSO had another lineage of CD4 binding site neutralizing antibody that co-evolved with it.

as known human broadly neutralizing antibodies do. We did not expect to see this great deal of convergence between two B cells from different species and with such a different genetic makeup of their B cell receptor.

CD4 binding site sub-epitopes and even antibodies that target the fusion peptide - another extremely conserved region of HIV Env! One antibody, 21N13, which only shares ~40% of its sequence with known human bnAbs, targets THE EXACT SAME residues on the conserved CD4bs epitope...

Well - the approach that we took, vaccinating with a full Env trimer, led to the induction of antibodies that target all kinds of epitopes. We isolated monoclonal antibodies that target our intended site (the CD4 binding site), but also others that target different...

Also, monoclonal antibodies isolated from these animals show surprising neutralization breadth - our end goal! However, non-human primates do not have the exact precursor that our vaccine targets. What's happening, then?

...we see robust induction of germinal centers and somatic hypermutation typical of broadly neutralizing antibodies.

In non-human primates, we confirmed that there is a robust serum response to the epitope that we intended to generate antibodies against - the CD4 binding site.

We verified that indeed these Env modifications led to increased binding of bnAb precursors, and called our vaccine "germline-targeting trimer 1.1" (or: GT1.1) after its ability to target those precursors. In mice that express these precursors...

...have the ability to become broadly neutralizing antibodies (bnAbs) as they target a very conserved region: the CD4 binding site (CD4bs) - engaging them specifically with a vaccine is a MUST in HIV vaccine research.

We changed HIV Env, the only target for neutralizing antibodies on HIV, to be able to make contacts with germline precursors of known broadly neutralizing antibodies. These precursors are rare (1 in 1,000,000 B cells) but...