Published online 1 October 2009 | Nature | doi:10.1038/news.2009.969

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Future of HIV vaccine unclear

Puzzling hints of success require explanation before trials can move forward.

As the dust settles from last week's surprising announcement that an HIV vaccine combination may protect some people from the virus, scientists are talking about what else the vaccine trial might tell them.

On 24 September, leaders of a US$119-million study of 16,000 people in Thailand reported that the combination of two shots had reduced the risk of HIV infection by one-third (see 'Vaccine protects against HIV virus'). Now, the vaccine's fate will depend on whether scientists can figure out its 'correlate of protection' — in other words, what caused it to partially protect some people from HIV. The key does not seem to be anything scientists had predicted, which has led to much head-scratching — and some unease.

The vaccine contained two components, and it will be impossible to untangle which of the two triggered a partial protective effect against HIV.PUNCHSTOCK

"It's a humbling thing, because for the first time we got a positive signal and it doesn't jump out at us as being related to any classical parameters you would expect from a successful vaccine," says Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, which supported the trial. "That tells us maybe we were not measuring the right thing."

Scientists are scheduled to present more data from the study at the AIDS Vaccine 2009 meeting in Paris from 19 to 22 October. The trial's backers will also talk there about what types of experiments could be done, using blood specimens taken during the trial, to determine the vaccine's correlate of protection.

In the meantime, scientists who were sceptical about the trial have urged caution until all of the data have been released. "Nobody should draw any conclusion from what was in the press release until the peer-review process has been completed and there's been time for more sophisticated analysis of the data," says John Moore, an AIDS researcher at Weill Cornell Medical College in New York.

The history of this particular vaccine study is somewhat controversial, and the news last week unleashed a flurry of plaudits and "I told you so's". The San Francisco Chronicle rushed to assign credit for its success to a local hero, reporting that the trial's findings were "the result of decades of work by Bay Area scientist Donald Francis", who has championed the development of AIDSVAX, one of the two components used in the vaccine. And in a scathing opinion piece in the UK newspaper The Independent, one commentator singled out the group of 22 scientists, including Moore, who opposed the trial in 2004. The piece said that "thankfully", the opposition "has been proved wrong", and compared the scientists and backers involved in the trial to Nobel laureates such as James Watson, Francis Crick and Barbara McClintock.

Francis himself, however, has refrained from gloating: "I don't know if I feel vindicated," he says. "Any time you can make a vaccine for HIV that seems to work, it's a huge step forward." But figuring out the correlate of protection is "not going to be easy", he says.

That will be difficult because of the way the Thai trial was designed, which makes it impossible to tell which of the two vaccine components — AIDSVAX or the second component, ALVAC — triggered the partial protective effect seen in the trial.

Same data, different interpretations

And even groups that have supported the HIV vaccine quest for years have been measured in their response to the latest news, perhaps wary of major disappointment should the trial's results not hold up, as has happened in the past with other HIV vaccines.

For instance, Francis's former company, VaxGen, based in South San Francisco, California, angered many scientists and HIV activists in 2003 when it used thin statistical evidence to claim that some ethnic subgroups may have been protected in large clinical trials of AIDSVAX — even though those trials found AIDSVAX ineffective overall, and there was little scientific reason to suggest that people of different races would respond differently to the vaccine.

More recently, in 2007 researchers halted a separate trial, known as the STEP trial, after the vaccine it tested seemed to increase the risk of HIV infection. Since then, however, that interpretation has changed with time and after further analysis (see 'Mystery of HIV vaccine failure deepens').

"When people are saying we've just made history, those are some pretty grand statements, and it would be horrible if these results unravelled based on further statistical analyses," says Richard Jefferys, a vaccine-project coordinator at the non-profit Treatment Action Group in New York.

Many scientists have also noted that, out of 16,000 participants, the difference between the number infected in the placebo and vaccine groups was only a handful of individuals.

Francis, however, predicts that such concerns will dissipate as more of the data are released. "I'm sure there's some defensive stance, but people haven't seen all the data yet, and it's pretty clear — it's not a subtle finding," he says. "People will say 'Yes, indeed, there's protection', and then they'll start to ask why."

In fact, Francis is already anticipating the need to manufacture more doses of vaccine for further clinical trials. ALVAC is made by Sanofi-Pasteur of Lyon, France — a company with a long history of vaccine manufacturing. The commercial history of AIDSVAX, by contrast, is more complex.

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Francis and other scientists began developing AIDSVAX in the 1980s at biotech firm Genentech, based in South San Francisco, California, and formed VaxGen as a spin-off from Genentech in 1995. Francis then created Global Solutions for Infectious Disease, a non-profit organization also based in South San Francisco, to carry AIDSVAX forward after VaxGen's large clinical trials of it failed in 2003.

As a result, Global Solutions now owns the rights to the vaccine in developing nations, whereas VaxGen and Genentech both have options to sell the vaccine in developed countries. Yet VaxGen barely still exists as a company; it has been running out of money since the US government cancelled an anthrax vaccine contract with the firm in 2006. And Genentech is now owned by the Swiss drug-maker Roche, which does not make vaccines. "The question is who would take on the rights to the vaccine in the industrialized world?" Francis asks.

Fauci says that new doses of the vaccines will probably be necessary for follow-up studies to find out the scientific basis for the vaccines' success, and so that more effective ones can be developed. "I don't think that there necessarily has to be major production from a company" for the follow-up studies, he says.

And whether there will be any need for the vaccine beyond those studies is still unclear. 

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