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PAVE 100 HIV vaccine trial too risky in current state

Date Added: September 23, 2008 10:07:47 PM
Author: Anonymous
Category: Health & Fitness
In the fall of 2007, research in the field of HIV vaccination was moving confidently towards larger trials involving a broader sweep of individuals. Two vaccines in particular stood at the forefront - the Merck STEP vaccine and the PAVE 100 - and the scientific community was generally optimistic about their potential. Both bore similarities in that they relied on an adenovirus type 5 (AD-5) as a delivery method, though at different points, and were believed to generate considerable immune responses. Then in October 2007, Merck announced the shocking news 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 ascientificallyscientifically 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 no
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