able to confirm that the vaccine candidate was safe and well-tolerated in all populations tested in the trial. Overall, the vaccine candidate produced an immune response in 16 per cent of trial volunteers. This information served precisely the purpose that immunogenicity data in a Phase I trial is meant to serve: it gave researchers clues about what might be the appropriate dose of the candidate, in this case informing them that they needed to try a higher dose of vaccine in the next round of testing. Researchers had good reason to believe a higher dose would improve immune responses, since they had seen such a result in animal experiments with tgAAC09.



Thus, in the next trial of tgAAC09, conducted in three countries in Africa, a higher dose of the vaccine candidate was tested in some volunteers. The clinical development strategy for tgAAC09 had always been to test the vaccine in Europe, India and Africa, but the preliminary results from the trial in Europe and India, which suggested a higher dose was needed, influenced the design of the Africa trial.

The trial in Africa was called a Phase II trial because of a local practice of using Phase I to refer to the first test of a candidate in humans; because of its small size (91 volunteers), it could otherwise have been called a Phase I trial. One media account questioned why the higher dose of tgAAC09 was tested in a Phase II trial before it was tested in a Phase I trial in the same population. A given dose of a vaccine candidate is always first tested in a small group of volunteers to ensure the safety and tolerability of the dose before it is considered for testing in a larger group of volunteers. This safety precaution can be achieved in a number of ways.

In the trial of tgAAC09 in Africa, it was achieved in this way: the trial involved only 91 volunteers, compared to the 80 volunteers in the Phase I trial in Europe and India, and the observations and laboratory tests to assess safety were equally thorough. Those volunteers were divided into four groups: one received placebo, two received the medium and high doses of the vaccine candidate previously tested in the Phase I trial, and the fourth received a new, higher dose. Thus, only a small group of volunteers receivedthe previously untested highest dose, in keeping with the precaution against testing doses for the first time on large groups. This is a common clinical development strategy.

The increased dose of tgAAC09 used in the trial proved safe and well-tolerated. Unfortunately, even at the highest practical dose, the vaccine candidate, in IAVI's view, did not produce sufficiently robust immune responses to justify taking it forward in testing any further as a single

agent.

This result was disappointing but not surprising, given the nature of pharmaceutical product development, in which the vast majority of candidates never advance past Phase I and Phase II trials to efficacy testing. Of all the AIDS vaccine candidates that have been developed, only three have advanced to efficacy testing. It is a disappointment when a candidate does not perform well – to the volunteers who selflessly committed themselves to the trial, to the communities that have supported it, to the researchers and trial sponsors. But such an outcome cannot be known in advance. If it could be, there would be no need for human trials of experimental vaccines and drugs. The only way to develop new vaccines and drugs is by testing in human trials the candidates that appear, from laboratory and animal data, to be the most promising.

tgAAC09 was just such a candidate. What's more, from every properly conducted trial, whatever its result, comes new knowledge that helps to illuminate the search for more effective candidates.


IAVI is committed to that search, believing that the best hope for ending the AIDS pandemic resides in a preventive vaccine. We at IAVI believe the effort to develop an AIDS vaccine should be commensurate with the scope of the AIDS pandemic, that the world's best scientists must be engaged in the search, that researchers in the field must move speedily to identify and pursue the most promising approaches, and that they must work flexibly, moving on to different approaches when faced with those that do not merit further advancement. In science, failure is a teacher. It is not a cause for discouragement or disparagement, certainly not when the stakes are as high as they are in the effort to combat the scourge of AIDS.