Im really a Debbie Downer when it comes to HIV-1 vaccines/’cures’/etc.
But I swear to gawd, I was just about to write a post on the strategy employed by the recent HIV-1 vaccine trial, without knowing this vaccine trial was even going on, cause I just read a really cool paper that did something very similar:
Cross-clade neutralizing antibodies against HIV-1 induced in rabbits by focusing the immune response on a neutralizing epitope
The basic idea of this paper, and the basic idea of this recent vaccine trial is the same.
1. Broad Prime – DNA
First, you ‘prime’ the immune response with something really general via DNA. So, you either use a gene gun (paper) or canarypox (vaccine trial) to deliver the DNA for say, the gp120 portion of envelope. When this DNA is in your cells, it will make gp120 just like if HIV-1 had actually infected those cells. This means that the way the protein folds, how many/what kinds of sugars are added, is exactly what HIV-1 would normally do.
What you get out the end is a really generic antibody response to a specific kind of HIV-1 gp120 (whatever kind of DNA you used). These antibodies wont necessarily neutralize the virus. They just see it as non-self. But your immune system is already primed.
This by itself isnt particularly helpful as a vaccine, as the antibodies you make wont necessarily recognize anything but a match to what you were immunized with (there are tons of different subtypes of HIV-1, all with envelops with different structures), and wont necessarily neutralize the virus if you do get exposed to a near perfect match.
2. Narrow Boost – Protein
Using lab-made envelope proteins as vaccines hasnt worked out at all. You have to make modifications to the genes to make envelope soluble instead of membrane bound, more modifications to keep them as trimers instead of monomers, the bacteria you use to make the modified proteins doesnt fold right, or doesnt add sugar right… It just hasnt worked real well on its own for generating protective HIV-1 vaccines.
But! If you use these proteins as a booster-shot– to take the broad immune response you got in #1, and use the normal B-cell somatic hypermutation/evolution process to hone that broad response into numerous specific neutralizing responses, that might work!
What they did in this paper is generate a broad immune response with HIV-1 Subtype C gp120 DNA, then gave rabbits booster-shots with peptides specific for the Variable-3 region of different subtypes of HIV-1 envelopes. The Variable-3 region is a great target for neutralizing antibodies, as this region must interact with your cells co-receptors to initiate infection. Know how I always say you cant force a person to create a specific antibody short of gene therapy? These folks got rabbits to at least make antibodies to the right region, thus increased the odds that the antibodies made would be neutralizing. Some of the rabbits made antibodies that could neutralize viruses they had never seen before! They didnt make a whole lot of antibody, and not all of the rabbits had the same kinds of responses, but this paper gave me hope that we might be able to figure out a ‘good enough for now to help some people’ strategy!
Turns out this vaccine trial was on the same page, kinda. For their boost, they used another failed vaccine, AIDSVAX, with was composed of gp120 proteins. These groups independently did the same thing– DNA prime, protein boost, good news.
The problem with this vaccine is, it might just work in specific parts of the world. What DNA you chose, what proteins you chose, all depends on which subtypes of HIV-1 were the most prevalent in that region. This is highlighted by the fact that not everyone who got the vaccine was protected… only people who made the right response and were exposed to the right virus were helped (30% reduction in risk).
BUT! Its a GREAT start. This plan, this is doable. And now we can work on figuring out the best mix that can help the most people!