Bay Area Reporter - March 27, 2008
Bob Roehr

"Despite hundreds and hundreds of millions of dollars, the reality in 2008 is that an HIV vaccine clearly remains beyond our grasp," said Warner Greene at the March 25 forum.

Greene, co-chair of the HIV Vaccine Summit, is a researcher at the University of California, San Francisco.

Dr. Anthony Fauci, with the National Institutes of Health, said, "We asked the question: Do we need to make an adjustment in the balance between discovery and development" in HIV vaccine research. By the end of the meeting he concluded, "The answer to that is an overwhelming yes."

The reevaluation process comes after the failure last fall of a second vaccine candidate. While few expected the vaccine to protect against infection, they hoped that it would help train the immune system to better fight HIV and result in slower progression to disease for those who became infected.

The shock was that those who received the vaccine appeared to be slightly more likely to become infected with the virus than those who received a placebo. The trial was stopped and researchers are still conducting analysis to try to understand the results.

Research priorities

A consistent theme of the meeting was the need for innovation and new ideas. Many speakers urged increased spending on basic research and a broad definition of what might contribute to vaccine research. That includes a better understanding of the steps the virus takes in establishing infection; how elite and slow progressors are better able to control the virus; and better use of the monkey model to guide vaccine development.

Continuation along the current path toward a "vaccine product" is not productive, said University of Alabama, Birmingham researcher Beatrice Hahn. "New discovery cannot always be two steps removed from a final product."

"Vaccine concepts that test only one arm of the immune system are doomed to failure," said Rafi Ahmed, from the Emory University Vaccine Center. "T cells cannot control infection on their own," he argued, a vaccine must also stimulate broadly cross-reactive neutralizing antibodies produced by B cells.

T cells take hours or days to respond to an infection, while the innate immune response of B cells is present in the mucosal tissue where the virus first enters the body through sexual contact. The vaccines that have gone into clinical trials have only tried to stimulate T cell protection.

Vaccine clinical trials are by their nature large and expensive and a tempting area to cut. But they also require long term planning and commitments. It is unclear how long and how much it would cost to make changes in developing trial sites.

Seth Berkley said there are crucial differences between trials that are designed to answer scientific questions and those designed to gain FDA approval. The latter trials generally are larger. Berkley, president of the International AIDS Vaccine Initiative, said a shift away from developing a vaccine for immediate use will mean a change in design and perhaps a reduction in cost of those trials.

Meeting participants were careful to affirm the dynamic interplay of clinical trials and basic research, with key discoveries made through both processes that have helped to shape further research in both areas.

Scripps Research Institute immunologist Dennis Burton concluded, "We need to change our mindset. We need to move from product development to scientific investigation ... I think there is a growing consensus that one needs to move funds from development to discovery."

Follow the money

Fauci controls an annual AIDS research budget of about $1.5 billion, about a third of which is devoted to vaccines. However, NIH has received little or no increase in funding over the past five years and that has resulted in a 12.3 percent decline in purchasing power.

He made the case for increased funding but also acknowledged the political reality is that it was not likely to occur. That means shifting resources within existing programs.

Later in the day, Project Inform's Martin Delaney noted that all of the discussion had been about the "easy" questions of what areas need increased funding. He urged those in attendance to take up the more difficult task of where "the less money" is going to come from. No one took up his challenge.

Fauci repeated several times throughout the day that "everything is on the table" in terms of shifting resources. When pressed as to whether some of that might come from treatment trials conducted in the United States, he danced around the issue.

"It is entirely reasonable to believe that over time, there will be the need for different emphasis on different things," he said.

NIH is concerned with research, not the provision of care. Nonetheless, a substantial number of people living with HIV get access to treatment through NIH-supported clinical trials and cohort studies. It is not clear whether the affected community will play a role in deciding how these funds are reallocated.

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