STEP project leaders ended the trial prematurely in 2007 because it seemed like people who got the vaccine were more susceptible to being infected with HIV. Because the vaccine used a vector engineered from adenovirus serotype 5 (Ad5), which is similar to a virus that causes the common cold, the leading hypothesis was that the vaccine caused a heightened immune response in people who had previously been exposed to the cold virus. This would make those people more vulnerable to infection because HIV attacks active immune cells, particularly if those immune cells migrate to mucosal tissues like the gut.
Yesterday’s PNAS paper found that, indeed, the vector boosted immune cells specific to Ad5 and made them express proteins that targeted them to gut, especially if there were relatively high levels of adenovirus antibody floating around. Sounds like a guilty verdict for the vector — except that this hypothesis had already been tested by two independent groups (O’Brien et al, Hutnick et al, in Nature Medicine) and the experiments turned up negative. So who’s right?
There are some important differences between how the studies were conducted that may explain the conflicting results. The PNAS study was performed in vitro: The authors bombarded immune cells taken from healthy volunteers with Ad5 vector. The groups publishing in Nature Medicine, on the other hand, analyzed immune cells from frozen blood samples taken from people who received the vaccine in the phase I safety trials that preceded STEP.
These are two very different beasts: a petri dish and a pipette full of vector versus a human body and STEP levels of the actual STEP vector. There’s certainly a time and a place for in vitro systems, but when assessing a specific outcome like the failure of the HIV vaccine, the most relevant data (e.g. from humans involved in the vaccine’s clinical trial) is going to be the most meaningful.
That said, negative results can be difficult to interpret, and the lead author of the PNAS paper says the “easiest explanation” for why the groups publishing in Nature Medicine didn’t find the activated immune cells was “because [the cells] migrated out of the blood to the mucosal tissues.” (The Scientist)
Image: HIV on an immune cell (CDC.gov)