In the news ... 2008

Failure of flagship HIV vaccine spurs summit

by Martin Delaney
April 15, 2008

Last year’s failure of the flagship HIV vaccine to produce even a hint of effectiveness dealt a striking blow to the hopes for a vaccine, leading some to suggest that perhaps one is beyond our reach. The story of its failure has been written about extensively by Project Inform and others. Simply put, it didn’t prevent HIV infection; it didn’t reduce the viral load “set point” in those who became infected; and there was even a hint that it may have increased the risk of infection in some people.

What matters now is what to do about it because researchers, activists and others are all over the map. At one extreme are those who believe we should continue testing other (largely similar) vaccines in hopes that one might yet surprise us. At the opposite end of the spectrum are people calling for a complete overhaul of the research program and a temporary hold on any other clinical studies. “Beyond reasonable or wise” is the view promoted by a well-known AIDS organization that has argued loudly to halt all vaccine research funding and redirect it towards treatment and care.

In an attempt to move forward, the National Institute of Allergy and Infectious Diseases (NIAID) held a vaccine “summit” near Washington, DC on March 25. More than 200 researchers and interested parties — many with hotly conflicting views — met to hear the problems and opportunities defined as clearly as possible in hopes of finding common ground.

Dr. Anthony Fauci, Director of NIAID and in some ways the one in the hot seat over the failure of vaccine research, led the day off by describing how research funds are used. He made it clear he shared the view of critics who argue that it’s time to re-emphasize lab and animal research while reducing, for the time being, the amount spent on human testing of vaccines. He stopped short of suggesting that all current vaccines were doomed to fail, as some critics have argued. He also steered clear about whether or not to proceed with the next large scale study called PAVE 1000.

PAVE, which would use a vaccine largely similar to Merck/NIH’s failed vaccine, was scheduled to start in 2008 with an eventual 8,000 people. Many now feel that such a study would be a colossal waste of money and might inhibit people from participating in future studies if it fails. It’s widely believed that Dr. Fauci supports moving forward with a smaller study, with perhaps as few as 2,000. He emphasized that any decisions about that study would not be made at the summit, but rather by the group of advisory committees and oversight mechanisms currently in place.

He described the various funding mechanisms and stressed that increased funds for discovery research would have to come out of the budgets from other programs. For the next few years at least, the prospects are dim for any overall increase in net funding for NIAID and AIDS research.

With these points setting the boundaries of the summit, the remainder of the day was spent in a series of presentations and discussions over what could be done. A short list of speakers presented their views on three key subject areas: (1) vaccine-related basic research, discovery and clinical development; (2) animal model development and usage; and (3) clinical research and studies.

Most of the discussion was polite, almost to the point of making some wonder if people held back their true feelings. By the end of the day, it seemed that people certainly had their opportunity to express their views. Whether this was enough to lead to any meaningful change was less clear. No firm plans or conclusions were announced, though that was not the intention of the meeting.

Many went on to Denver the next day for the annual Keystone Conference, a scientific meeting about HIV pathogenesis and basic science. Dr. Fauci and Dr. Carl Dieffenbach, the newly appointed head of the Division of AIDS (DAIDS), encouraged those going to Denver to continue the discussion there, affirming that the summit was only a first step. Though other meetings haven’t been announced, everyone agreed that the issues warrant further time and attention.

A cynic might ask whether anything was really accomplished. It’s too early to know. At the least, people had their chance to be heard. Still, a few large gaps opened up over key issues. One critical point: if NIAID directs more money to basic science and vaccine discovery, where is it going to come from? Dr. Fauci made it clear that new money from Congress was unlikely. Everyone gingerly sidestepped this question because the answer was fairly obvious: it would likely have to come from the clinical vaccine research funds.

This was exactly what the basic (laboratory) scientists called for — less spending on human vaccine studies that they feel have little or no chance of working. Many of the basic scientists seem to believe that there should be no more large scale testing until we have a vaccine candidate that shows real hope of succeeding. Even their advocates agree that few if any of the current vaccines have much chance of actually protecting a person from HIV infection. At most, the hope has been that they might reduce the viral load “set point” after a person is infected.

Some advocates argue that whether or not the vaccines are protective, we might learn things from them through large scale testing. Critics say this is a very slim hope, one that comes at a very high price. A large vaccine study, like PAVE, can cost more than $100 million. That’s a very high price at any time, but especially so in an economic recession. Some scientists argue that this money could be better spent on vaccine discovery in hopes of coming up with better candidates that might someday truly warrant large studies.

In many ways, this is the key question faced by the field today, but one that no one seemed willing to confront at the summit. Instead, people presented their own beliefs and left it up to the audience to decide which approach made the most sense. Dr. Fauci, for his part, tried to steer the summit away from this question, insisting that the decision about PAVE or other large studies would be made by the appropriate bodies and committees.

However, some scientists most critical of NIAID’s approach to vaccine research privately argue that people who are inherently invested in seeing these studies go forward dominate those committees and advisory boards. To a degree, this is understandable since these groups naturally seek their membership from experts in the field. But the critics’ challenge is also understandable, in that those experts often come from the same institutions if the studies are approved. While some independent advocacy groups and “vaccine preparedness” organizations are also represented on these committees, critics say that such groups have almost always favored moving ahead with clinical studies. People calling for change argue that there are few if any counter-balancing forces on these boards.

To be fair, one could equally argue that the people calling for change are also ones who might benefit from such change, in the sense that more grant money might be available to them. While these feelings were often evident in side conversations throughout the summit, no one expressed them from the microphone, which was probably for the better. The “can of worms” remains unopened.
Since the summit, the debate has continued at scientific meetings, over the internet and in magazine articles. This is very much what Dr. Fauci called for. When these complex issues remain below the surface, they are never resolved. The summit served to start a dialogue and make it clear that the NIH was open to hearing from all voices and not merely locked into a plan of its own. The question is what happens next.

Dr. Fauci repeatedly stated that the summit was the start of a longer process of re-evaluation and priority setting, as well it should be. There’s too much at stake here to sweep any of this under the rug. One article in Science Magazine quoted him extensively in what many readers saw as a trial balloon asking the question, “Where will the money come from?” In it, the Science reporter quoted Fauci as suggesting that PAVE might move forward with 2,000 people. He suggested that $10 million might be saved from reducing the size of this study and other cuts in vaccine programs.

However, these figures left many scratching their heads. It implied that cutting PAVE down to one-fourth of its planned size would save less than $10 million of the $130 million budgeted for it. One scientist we spoke to asked, “Where did the rest of the money go? Do we really only save such a small amount by cutting its size that drastically?” Others still asked, “Why are we doing the study at all if we don’t really believe it will work?” Another question is where will the other cuts, implied but not specified, come from? An even more complex question is how to make the money available once it has been liberated, regardless of where it comes from.

Strange as it sounds, distributing grant money from the NIH is complex and ill-understood. For example, one obvious suggestion many scientists make is to ‘increase the payline’ for investigator grants. In a gross simplification, this is the percentage of grant applications that will be approved, after being reviewed and ranked. Simple as this sounds, in a period of flat funding, it would have a small positive effect in the first year, and would actually make things much worse in subsequent years. The proper solution lies in using and developing other creative mechanisms available to scientists.

A key question that must be negotiated between Fauci and the scientific community is whether shifting $10 million is enough to make a difference. Some argue that if no current vaccines are likely to work, why is $182 million of AIDS research money going to be spent testing these vaccines in 2009, according to the current budget? A similar question might be raised though, “Isn’t $225 million for AIDS vaccine basic science and discovery enough?” Which important studies and research proposals, if any, are being denied funding?

These are the questions that must be debated and negotiated in the coming year to get vaccine research back on track. As the dialogue continues, it’s important for all parties to remember that no one is to blame for the failure of vaccine research today. HIV has proven itself an extremely difficult challenge for vaccine researchers. We can never forget that it’s possible we won’t be able to create an AIDS vaccine. But we are far from being able to conclude that it’s impossible either.

As we raise questions about how government money should be spent, it might also be valuable to broaden the question. NIAID is not the sole source of funding, though it is the largest. Other main sources include the non-profits International AIDS Vaccine Initiative and Bill and Melinda Gates Foundation, and several pharmaceutical companies with experience in vaccine development. While these are privately funded, they overlap in many ways with the NIH program. That can be either good or bad.

Competition is often helpful, as industry has shown. But it can also be bad when it leads to duplication of effort and conflicts of interest. Currently, there’s a mix of competition and collaboration between the NIH and the private organizations. It's unclear whether this mix results in the most efficient way to search for a vaccine.

Reflecting on the NIH vaccine program might also be a good time to reflect on how these private efforts can best contribute to the overall goal. Many researchers have privately talked about the ways in which these organizations overlap each other’s efforts. None will comment “on the record” though for fear of jeopardizing their own funding possibilities. Perhaps the conversation can only occur at the levels of the leadership in these organizations.

In the earliest days of AIDS research, after HIV was discovered, many researchers believed that it would be impossible to ever develop treatment for the disease. Two years later, the first effective drug was approved. In the first few years after we realized that potent combinations of drugs could not “eradicate” HIV, many researchers argued confidently that there will never be a cure. Ten years later, there’s a growing cadre of scientists who believe that finding a way to control HIV without a lifetime of drugs is perhaps the only viable solution to the world's epidemic.

Today, in 2008, some say we will never have a vaccine. Perhaps not, but history suggests that this is not the time to give up. It is critically important that government and scientists alike follow through on the process that has begun with the vaccine summit of 2008.