Then in October 2007, Merck announced that it was suspending the STEP vaccine trials. According to recent analysis of its trial data, the vaccine failed to protect individuals from HIV. Moreover, because of the way the vaccine relied on an AD-5 vector, there was actually an increase in infection among uncircumcised men who had pre-existing neutralizing antibodies to adenovirus type 5. The vaccine did not detrimentally affect men who were circumcised and who lacked pre-existing neutralizing antibodies to Ad5. Still, the combination of suspending the trial and the fact that a promising vaccine design actually increased infection sent shock waves through the research community. One of the first to make adjustments in light of the suspended STEP trials was the PAVE 100.
Because the PAVE 100 vaccine also relied on an AD-5 vector boost, the designers of the trial were forced to revise their plans. The trial was redesigned and reduced somewhat in its proposed scope, although it remained a scientifically and logistically complex study. The redesigned PAVE 100 study would have involved testing the VRC vaccine in 2,400 U.S.-based, circumcised men who have sex with men and who lack preexisting neutralizing antibodies to Ad5. The redesigned study would have tested the vaccine's effect on viral load, provided additional safety information about the product, and examined in detail immune responses to the vaccine and their impact on viral load. They presented their revised design to the National Institute of Allergy and Infectious Diseases's AIDS Research Advisory Committee for approval but were turned down. They did, however, leave the door open, stating that they would "entertain a smaller, more focused clinical trial."
Scientist Live spoke with Dr. Anthony Fauci, the man responsible for the PAVE 100 decision at NIAID, about the trial, his decision, and future trial possibilities.
What is the Pave 100 vaccine and how does it work?
Pave 100 vaccine is a recombinant DNA product. It is DNA given three times and contains the genes of various components of the HIV virus - gag, pol, and nef. It also contains a portion of the envelope gene that would express the corresponding protein. The vaccine is given in three separate immunizations followed by a booster with an adenovirus vector that also contains the genes of HIV. It is a bit different from the Merck trial that had a disappointing result. That vaccine was fundamentally an adenovirus prime-boost-boost. The Pave 100 is different in two major senses. It is predominantly a DNA vaccine, although there is an adenovirus vector boost. However, it also contains the envelope which the Merck study did not. The Pave 100 trial was meant to determine whether you could induce cell mediated or T-cell immunity, not so much to protect against infection but more to decrease the level of the viral set point should a person become infected.
So the goal was to control infection as opposed to preventing it?
We certainly would like to prevent infection; however, this is unlikely with a vaccine that elicits only T cell immunity without neutralizing antibody.
How long has Pave 100 trial been in making and how far had it progressed before you suspended it?
There are several stages to a trial. The Pave 100 had a Phase I a couple of years ago done in a small amount of people. It looked at safety and some immunogenicity. Then it had a Phase II in a few hundred individuals mostly looking at extended safety but also more at immunological responses. The study that was scheduled to go ahead with 8500 individuals was what is called a Phase IIb trial. It is a bit bigger than a Phase IIa but not quite an efficacy trial like a Phase III. It is the latest type of design that is a bit more compact than a phase III.
So when the Step Merck trial failed, particularly with some safety issues with the adenovirus, it was clear to me that the original Pave 100 IIb trial could not go ahead as originally planned, because of the size of it and because we had to restrict it to people who were adenovirus antibody negative and circumcised. The designers of the trial presented a trial to me that was smaller than 8500 people but big enough to get immunological correlates. That was a trial designed to a size of 2400 people. That was the trial that I ultimately decided not to go ahead with. The reason I decided not to go ahead with it was because I did not think, given the fact that we know so little about correlative immunity, that it was prudent to make a trial large enough to be able to determine correlative immunity even if the vaccine might not really work in terms of giving you a lower viral load.
So I went back to the investigators and told them that I reject the Pave 100 but I would entertain the possibility of a smaller trial with fewer people that would ask and answer one question: Does the vaccine give you a lower viral set point for people who get infected? If it did not, I would not want to pursue any immunological correlates. If it did, then we could expand the trial to get the necessary immunological correlates. I did not want to accept a larger trial until I was sure that the vaccine gave a positive signal.
In terms of the new version of the trial you indicated you would be open to, is that still with the aim of searching for a potential vaccine or are you more studying the effects, essentially limiting your goals.
Well actually, I am being more precise in my goal. I am asking for a design that is much more precise. Does it or does it not lower the viral set point? If it does, then we will expand it and try and find out the intricacies of what the possibilities of the correlative immunity are. If it does not, then the trial is over.
Critics have suggested that your decision to suspend the trial was more based on financial, rather than scientific reasons.
It was not a fiscal decision, though those issues are always involved. Fiscal considerations go into everything you do in research because there are a limited number of resources. It was fundamentally a scientific decision. It did not make sense to vaccinate people, to put more people at risk, to collect more samples, and to involve more people than absolutely necessary in order to answer my question.
(Reporting by Marc Landas)
