Day 47: Thoughs on “Will there ever be an HIV vaccine?”

Robert Steinbrook presents an interesting commentary on the prospect of an HIV vaccine in this week’s New England Journal of Medicine. The article focuses on the Merck vaccine failure and what it means for the future of HIV vaccines. The most sobering part of the article comes not from Dr. Steinbrook, though, but Anthony Fauci, who says “To be brutally honest with ourselves, we have to leave open the possibility . . . that we might not ever get a vaccine for HIV. People are afraid to say that because they think it would then indicate that maybe we are giving up. We are not giving up. We are going to push this agenda as aggressively and energetically as we always have. But there is a possibility—a clear finite possibility—that that’s the case.”

In my interactions with HIV basic scientists and immunologists, I get the impression that most researchers are not too favorable on the prospect of a workable vaccine anytime in the near future. While I hate to be pessimistic and I think all options must be considered, I tend to agree. There are only two approaches to a preventative vaccine that I think are really worth merit and, unfortunately, most of the vaccine candidates are not looking at these options (more below). Currently, most vaccine candidates are relatively traditional, focusing on generating an immune response against viral proteins. HIV reverse transcriptase is so error prone, though, that I think the virus will be able to squeak out of any response targeted against the viral proteins. Everyone knows this and yet all of the vaccines I see still target the viral proteins. Other methods have looked at creating antibodies that target the CD4-gp120 complex—when conserved aspects of the viral spike are no longer shielded by sugars and are exposed. While I think that these antibodies might block infection, I wonder about the concentrations needed to provide protection. These epitopes are exposed for extremely brief periods of time, meaning that you need an antibody with a very fast on-rate at very high concentrations. It doesn’t seem reasonable to me. Then again, as I like to frequently point out, I am often wrong.

One of the roads that I do find promising that some are looking at is the composition of the virus at infection. When HIV infection is established, there are certain aspects of the virus that are conserved. Once infection is established, the virus quickly mutates and evolves to be better suited to the environment. Thus, the viral particles that establish infection are different from the majority of viral particles during infection. It may be that there are certain characteristics of HIV that are important for establishing infection that can be targeted by a vaccine. If we can tease out the aspects of the virus that are important for the initial establishment of infection, we could design vaccines against these features. It’s a tricky prospect, though, because you have to get viral samples very soon after initial infection. I know that at least a couple of groups are working on this, including Julie Overbaugh at the University of Washington.

The other road that I think is at least worth considering is looking at host factors on the virus. I have mentioned this a couple of times in the blog, but HIV is highly enriched in host proteins in the envelope including MHC molecules. Unlike viral proteins, host proteins won’t mutate and evade a vaccine. Plus, MHC molecules are some of the most immunogenic molecules out there. An allovaccine would be easy to create and might have activity against HIV and other retroviruses. There are, of course, serious considerations with this type of vaccine, though, not the least of which is its effect on fertility. It’s still worth looking at, although I fear that almost no one is considering this option.

 

M. Linde