This post is really frustrating to write.
Its frustrating because this paper could (should) be FANTASTICALLY COOL, but it was just really frustrating to read:
You all know there is a TON of genetic diversity in HIV-1. That has been a huge barrier for vaccine design. You put one HIV-1 variant in a vaccine, people are exposed to another, they still get sick. Our vaccines are eliciting a very narrow immune response. Our immune systems are only seeing exactly what our vaccine tells it to see.
We would like our HIV-1 vaccines to make ‘broad’ immune response– Youre vaccinated with Variant A1, but you are protected against all Variant A and B1/2/3/4 and C3/6/9, etc. We can find antibodies in AIDS patients that are ‘broadly neutralizing’ (can shut down lots of subtypes of HIV-1), but we cant force your immune system to make that antibody, short of gene therapy.
This group tried a new approach. They put different variants of HIV-1 into adenoviruses:
- Consensus M– They took every HIV-1 Group M sequence in the Los Alamos National Laboratory HIV Sequence Database and averaged them.
- Consensus B + Consensus C– They took all the Subtype B sequences and averaged them, and all the Subtype C sequences and averaged them, and put them both in one vaccine
- Optimized C– They took all the Subtype C sequences and broke them into chunks of nine amino acids. They then computationally ‘optimized’ the amino acid sequences, trying to get the most putative T-cell epitopes covered
- Optimized mosaics– They took ALLLLLLL the HIV-1 sequences in the database, broke them up into nine amino acid chunks, and did the same thing as Optimized C. Since there is not just one potential optimal sequence, they put the top two optimal ones into one vaccine. This sequence might contain one optimal Subtype A epitopes and 50 optimal B epitopes and 25 optimal C– its a mosaic! This would hopefully be better than just putting in averaged sequences, or the optimal epitopes for just one subtype.
This is a really friggen neat idea! And it might have worked okay, um, kinda?
Here is where things get frustrating: There are literally no methods in this paper. It was almost unreadable, to the point where I physically cannot judge (peer review) the science of what they did. Im basically ‘taking their word for it’, whole cloth.
I can understand this on one level, as if they think they are making THE HIV-1 vaccine, they dont want to tell everyone right now how they are generating the mosaics (its one thing to make a computer sequence, its another thing to actually generate that sequence for experimental use in the lab). But there was no, not even basic, biochemical characterization of these mosaics.
For instance, they made this entirely artificial envelope sequence, and apparently made the envelope protein well enough that they could get (minor) but see-able neutralizing antibodies. Putting together a sequence of amino acids that is going to get chopped up and presented in MHC is very different than putting together a sequence of amino acids and getting an envelope protein that is structurally sound enough to be appropriately folded, glycosylated, processed, and presented on the surface of cells infected with the vaccine (but not cleaved or fusogenic!). I can make small, minor amino acid changes within my constructs and accidentally kill the envelope… but they put these sequences together piece-meal and got a structurally normal Env?
That is just one example– the whole paper, a Nature paper, is a question mark for me. No details for anything they did, even trivial things. So why did they publish at all? Why did they publish in Nature, if they werent really going to tell anyone anything?
I wish I could tell you all more about this (maybe) cool avenue for an HIV-1 vaccine.