The next HIV vaccine trial will focus exclusively on gay men in the U.S. This represents a dramatic restructuring of what initially was planned as a far more ambitious trial. Community representatives expressed reservations about the changes.
The news came during animated discussions at a regular meeting of the AIDS Vaccine Research Subcommittee ( AVRS ) on May 30 in Bethesda, Maryland. The group is an advisory body to the National Institutes of Health ( NIH ) .
The trial is known as PAVE 100 and is based on a series of vaccinations developed by the NIH Vaccine Research Center. Initial plans were for an ambitious trial of about 8500 participants on three continents, but the latest version cuts that back to only 2400 gay men in the US.
PAVE was supposed to start last September but was put on hold when an earlier trial, the STEP trial of a Merck vaccine, was stopped because it appeared that the vaccine actually made people more vulnerable to infection with HIV.
Subsequent analysis found that persons in the STEP trial were at greater risk for infection if they were uncircumcised and if they had higher levels of antibodies to Adenovirus 5 ( Ad5 ) . Ad5 is a common respiratory virus that has been modified to deliver the HIV vaccine in both the STEP and PAVE trials.
Whether or not the two vaccines are sufficiently different to produce different outcomes has been an ongoing debate. The latest data, presented at the AVRS meeting, suggested that while there are differences, they probably are not sufficient to provide protection from infection or slow the course disease progression in those who become infected.
Glimmer of hope
There was one 'glimmer of hope' among the new data. The University of Washington's Julie McElrath said a few vaccinated individual in the STEP trial appeared to have an association between a higher response to the gag portion of the vaccine and a lower viral set point.
Other research has shown that a lower viral set point results in slow disease progression. It suggests that the immune system is better able to control the HIV infection.
Jerald C. Sadoff was ecstatic about the news. 'It is the only positive finding of vaccine-induced protection in the entire field of HIV vaccine research. There is not another example in humans of such a finding, whether it is valid or not.'
He has been involved with successfully developing fifteen vaccines. He said the vaccine for malaria began with identifying protection in a single individual. Researchers built upon that one piece of information to create stronger ways to stimulate immune protection in broader numbers of people through a series of trials.
Sadoff said, 'There is no way to make [ the initial discovery ] valid except to repeat it.' In that sense, he was worried that the two vaccines might not be similar enough to generate the same response.
PAVE revamped
The PAVE trial is getting an extreme makeover. In addition to cutting back the numbers of participants and limiting the trial to only gay men in the US, safety concerns will restrict participants to only those who are circumcised, and persons with no detectable antibodies to the Ad5 virus.
The purpose of the trial has changed as well. The pretense that this type of vaccine might offer protection from infection has pretty much been dropped, though the question will still be asked.
The primary focus has become whether the vaccine can lower the viral set point and slow disease progression. A variety of measures have been added to help gain a better understanding of the basic science of early infection and immune response, and develop better tools to measure those responses.
The changes prompted Scripps Research Institute immunologist Dennis Burton to comment that it has become not so much a trial as 'a human experiment.' He said that would not be allowed in the lab, much less in humans, unless there was much more rigor in terms of 'thinking about what it is that we want to know from this experiment, and making sure that we have everything in place to do that.'
But there was broad consensus within the AVRS to move forward with the trial. Larry Corey, the head of the HIV Vaccine Trials Network, encapsulated that feeling when he argued that the PAVE trail was necessary to establish whether the STEP trial was the failure of an individual vaccine or of the concept of a T cell-based vaccine. He said the field needs 'the reality test' of trials to move forward.
Susan Buchbinder, with the San Francisco Department of Health, said the gay men in the STEP trial became infected with HIV at a rate of 4.6% a year. This population is in great need of additional prevention options. The PAVE trial is one of the few that would directly address their needs.
Tony Fauci, director of the National Institute of Allergy and Infectious Diseases, will make the ultimate decision on whether or not the PAVE trial will move forward. He seemed inclined to do so.
But he also stressed the need to better involve the affected community in all aspects of planning and implementing the trial. There is great need for education so that volunteers know they are participating in basic research, with virtually no hope that the vaccine they receive will provide any protection from infection with HIV.
Community reluctance
Martin Delaney with Project Inform was not convinced of the wisdom of the trial moving forward. Speaking before the AVRS he called the data 'singularly unconvincing.' After hearing the comparative analysis presented for the first time, he concluded, 'There was really no pattern of superiority, only patterns of differences. That is a word of caution as to whether these vaccines are really different.'
He warned, 'We are asking so little in this trial. It is not going to protect people, it very likely is not going to affect viral load. And if it fails to meet even those endpoints, it is going to have a very hard time with the media and in Congress three years from now.'
The Treatment Action Group ( TAG ) said in a submitted statement, 'Based on the information that is currently available to us, we feel that the uncertainties argue against spending human and fiscal resources on PAVE 100 and instead suggest focusing on improving T cell-based immunogens so they can be studied in a broader population with a greater chance of success.'
'The trial faces potentially serious obstacles to acceptability and achievability at both the community and the individual levels,' said Julie Davids in a statement to the AVRS. The executive director of the national HIV prevention group CHAMP said it is important that the community be educated to what the trial hopes to accomplish, so that volunteers make truly informed consent to participate in it.
