Ian from the Immunity Project team here.

Thanks for the follow up!

No evidence yet that human analogs are immunogenic. Doing new experiment to find out.

Yes! Using human version of the peptide for the new experiment. The NOG mouse model we are using will not infect with HIV - hence the in-vitro arm - I realize that humanized mice do exist that we could infect - we may try that later. Looking to take CD8/CD4 cells from vaccinated mice. Infect the (isolated) CD4 cells, combine and follow p24.

That's an interesting approach.

Re not knowing if the human analogs are immunogenic yet: An alternative way to to answer your question would be to identify a T cell receptor (TCR) clone that recognizes your peptides of interest. There are several ways of identifying TCR clones that match your peptide of interest. Probably the best way is via phage display. The advantages here are manifold:

1. By identifying a human TCR you immediately prove that your peptide is recognized by the human immune system (immunogenic)--you still need to do a bit more work to show that the immune system will produce this antibody in response to your peptide--but that's a pretty good start.

2. You could perform phage display separately on TCRs from elite controllers and more susceptible patients. The differences in these TCRs would likely make for a very interesting academic publication.

3. You could make a TCR-like antibody based on this TCR. If your vaccination strategy failed, hey at least now you have an antibody you can take into trials!

Thanks for this thread. I really enjoyed seeing the science discussed. I've been interested in computational vaccine design and HIV evolutionary dynamics for a long time. I kind of see the whole thing as a dynamical system and a hidden Markov model. Essentially since the copy mechanism is leaky and produces multiple variants, and the immune system produces a selective response, how do you know that the single epitope you vaccinate against will be sufficient? I would expect their to be multiple stable populations and hence a need multiple vaccine epitopes (including populations that are stable under specific drug regimes).

This is what makes rgejman's phage display comments so interesting. We already know two major populations (Hiv-1 and Hiv-2 exist).

Great comments! We expect the beneficial targets to be HLA restricted. We need to do more work to understand if any one individual needs to hit two targets - we think right now that a "master vaccine" would need to contain multiple peptides to cover multiple HLA type individuals yielding at least one "valid" target per individual.

This sounds really interesting! Let me talk to my team. I would love to discuss this with you further. Please email me at [email protected]