Immunity Project – HIV Vaccine Development Program [pdf]

Immunity Project – HIV Vaccine Development Program [pdf]
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This vaccine relies on inducing immunity to an HIV peptide* (i.e. a ~9 amino acid cleavage product of an HIV protein) that is predicted to bind to HLA molecules. At first blush, this sounds like a great idea--let's immunize people to the very thing that the immune system is supposed to recognize as bad! Unfortunately, this has been tried lots of times and usually doesn't work very well, if at all. It's been tried in cancer, it's been tried in HIV, it's been tried in practically any system you can imagine. I'm not saying that peptide vaccines don't ever work (hell, my lab has worked on one)--I'm just saying that they have had lots of promise and limited successes. In fact, animals and patients have been immunized to many cleavage products of many cancer associated antigens to little, if any, effect—or effects in animals but not in humans. We can hem and haw all day about what the specific studies show, but suffice it to say that peptide vaccines are an old idea. Perhaps Immunity will get lucky here, but I'd be surprised if there isn't a lab somewhere that has tried immunizing animals to every single breakdown product of HIV proteins already.

Immunity's white paper says that their putatively immunogenic human peptide cannot be tested in animal models because it will only bind to human HLA. So they are planning to use a mouse-analog of the human peptide to do their animal testing (or have already done this?). That is, they are planning to use (or maybe have already used?) a completely different peptide (probably 1-3 amino acids different from the human version) in animal studies than what they would use in patients. This may be a significant difference... or it might not be. There's no way to tell a priori. A more classical and IMO better approach would be to identify T cell receptor clones from patients with HIV (or without HIV) that bind to these peptides (using tetramer staining, phage display or some other high-throughput technology), demonstrate that humans are capable of creating T cells that recognize their putatively immunogenic peptide followed by T cell killing assays on cells presenting their peptide of interest. There are other approaches, but that is a commonly used one in the field.

* in some places the white paper says "peptides" and in other it says "peptide" so it's not clear if we are talking about 1 peptide or multiple. I think they are mostly talking about multiple peptides, because they want to immunize people no matter their HLA type. Different HLA types bind to different peptides. So if you have HLA A02 you will bind different peptides than if you have HLA A24... and so on for all the different HLA types.

You first need to make humanize mice (i.e. mice with human immune systems). Luckily we can make those by taking NOD/SCID mice (an [expensive] immunodeficient mouse line) and then colonize them with human hematopoietic stem cells from a human donor to reconstitue the immune system. Then you have to do a lot of experiments to make sure your humanized mice can mount immune responses. Then, you can test your peptide and see if your humanized mice will make CD8 T cells to your peptide... Finally, you can infect your mice with HIV (now that you have a humanized immune system) and see how your vaccinated vs. unvaccinated mice fare.

I have no idea what the downsides of this approach are because I don't work on HIV or with humanized mice--but mice ain't people. So after all that work you'd have shed limited light on what would happen in real people.

I would argue that a better approach is to see whether HIV patients have actually made CD8 T cells against these antigens. This can be done more inexpensively and would give you pretty good evidence that your peptide is immunogenic in real people.

"A vaccine is a biological preparation that improves immunity to a particular disease."