Variability in HIV Vaccine Design

Considering HIV diversity from the perspective of designing vaccines.

HIV is an incredibly diverse virus, and for a vaccine to be effective it must elicit immune responses that can recognize the vast array of circulating variants. I’ll cover three different strategies that we are currently using to attempt to design a useful HIV vaccines. In the first, we use phylogenetically-corrected methods to identify signature site mutational patterns that are associated with an immunologically relevant feature. We first validated the method by using it to define signature patterns associated with susceptibility to a very well characterized neutralizing antibody, IgG1b12. We went on to apply it to identifying signatures associated with viruses that elicited potent immune responses in natural infections, and are currently testing a virus with this signatures as an immunogen. Second, we have developed a strategy called mosaic vaccines, a strategy that uses a genetic algorithm to attempt to maximize global coverage of epitopes recognized by T lymphocytes (epitopes are the small sections of a pathogen that form targets for the immune response). This method has proven to be very promising in animal studies, and I will provide an update regarding mosaic inserts being tested in Phase 1 human clinical trials. Third, we are in the process of adapting the methods we used for T cell mosaic design, to optimizing the coverage of B cell (antibody) epitopes, which are generally discontinuous and structure- dependent, and we have made some progress on the design aspects of B- cell mosaic vaccines; this work is ongoing. Finally, I will discuss a re-evaluation of data from a large HIV efficacy trial that raises both eyebrows and new hypotheses regarding the potential importance of neutralizing antibodies for prevention of infection.