News (Updated November 2, 2009)

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Beyond Thailand : Making Sense of a Qualified AIDS Vaccine "Success"

Jon Cohen

When researchers announced on 24 September that an AIDS vaccine trial had positive results for the first time in history, many wondered whether they were real. Some prominent skeptics remain, but that debate has largely given way to intense discussions about how to build on this surprising finding. "The results are conceptually a game changer," says AIDS vaccine researcher Gary Nabel, who heads the Vaccine Research Center at the U.S. National Institute of Allergy and Infectious Diseases (NIAID), the main funder of the $105 million study.

Already, researchers have begun discussing the staggering challenge of probing blood samples from the more than 16,000 people in Thailand who participated in the trial to figure out which immune responses led to the modest protection reported. "The scientific community is going to throw everything it can at this," says Nabel. "We can't afford to not pursue every clue we have here."

The key question is whether the study will help reveal the long-sought immune responses that correlate with protection. "There are no guarantees, and it's not going to be easy," Nabel says. Peggy Johnston, who heads HIV/AIDS vaccine research at NIAID, says it's a long shot: "I think it's more likely that we'll be able to eliminate a correlate."

But even if these so-called correlates of protection remain elusive, the study is leading researchers to reassess the fundamental differences between preventing and controlling an infection, related findings from recent monkey studies, and the possibility that even a mediocre vaccine can help under some conditions.

The 6-year Thai study, run by the U.S. Military HIV Research Program in collaboration with the Thai Ministry of Public Health, combined two vaccines that each had performed poorly in earlier trials (Science, 2 October, p. 26). The study's lead investigators revealed in press conferences in the United States and Thailand last month that HIV infected 51 of nearly 8200 people who received the vaccines versus 74 people of a similar number who received a placebo. Most were heterosexuals who had no high-risk behavior. This translated to 31.2% fewer infections in the vaccinated group, and it just barely met the arbitrary cutoff of statistical significance (see graph). The vaccine unexpectedly had no impact on virus levels in vaccinated people who became infected.

Other analyses not initially described to the press but revealed 20 October at an AIDS vaccine meeting in Paris and in a New England Journal of Medicine report had slightly lower levels of vaccine efficacy that did not reach statistical significance. "It's definitely not an AIDS vaccine that we would use," says immunologist Bruce Walker of Massachusetts General Hospital in Boston . Still, Walker says the positive "signal" from the trial reveals something about protection. "I think we need to take it seriously," he says.

The U.S. military has enlisted four teams of scientists, including some not affiliated with the study, to decide how best to make sense of this weak signal with the limited plasma and cells collected from individual trial participants. The groups will examine antibody and cellular immunity, whether genetic differences between participants contributed to the protection, and the potential for future animal experiments to shed light on the results.

Sorting out cause and effect will be difficult in part because most people in the study may not have been exposed to HIV. Ideally, researchers would like to compare immune responses in people exposed to the virus during the study who received the vaccine or the placebo. But this trial had a low rate of new infections, 0.19% per year, as most participants reported little or no high-risk behavior such as injecting drugs or commercial sex work. In a subset analysis of HIV-infected people in the highest risk group—which had too few numbers to reach statistical significance—the vaccine did not show any benefit.

The immunologic results reported so far mirror data from earlier studies of these two vaccines that left many researchers unimpressed. The trial designers hoped that the one-two punch of the vaccines used in the Thai study would combine the power of antibodies to prevent infection with what's known as cell-mediated immunity to clear cells that the virus manages to infiltrate. But vaccinated people in the Thai study apparently made only "binding" antibodies, poor cousins to the dreamed-of "broadly neutralizing antibodies" that can stop many strains of the virus in test-tube experiments. Now researchers are wondering whether binding antibodies offer partial protection. "At least for some populations, it may not be necessary to have broadly neutralizing antibodies," says NIAID's Johnston .

As for cell-mediated immunity, Thai vaccine recipients showed only hints that the vaccines turn on this arm of the immune system—and it could not have been that robust, because the vaccine had no impact on viral levels in people who did become infected.

In addition to comparing infected and uninfected people in the study, researchers will attempt to find correlates of protection by analyzing the viruses that managed to "break through" the vaccine protection. This may reveal immune responses that worked and others that didn't—but may need to be turned up. "That's probably going to be the most informative analysis," says Nabel.

Louis Picker, who does monkey studies of AIDS vaccines at Oregon Health & Science University in Portland , doubts that more will be learned from trial participants' blood samples. "The nonhuman primate model is probably the only way we're going to be able to dissect the Thai results," he says. To Picker and many colleagues, the Thai results suggest that the vaccines protected people against the low doses of virus typically transmitted during sex, and that protection decreased over time because of repeated exposures and waning immunity. His group and others have developed a monkey model that may tease out the mechanism.

Traditionally, researchers vaccinate monkeys and then "challenge" them with high doses of SIV, the simian AIDS virus, given intravenously. Picker, in contrast, challenges vaccinated monkeys with repeated, low doses of SIV given rectally to mimic human sexual transmission across a mucosal surface. "The Thai trial has said that using the low-dose model is probably a good thing to do," says Picker, whose own SIV studies with this approach have linked oft-ignored immune responses to protection.

Another possibility the monkey model can explore is the impact of the canarypox virus, the backbone of one of the vaccines in the Thai study. Koen Van Rompay and Marta Marthas of the University of California , Davis , published a study in 2005 that used an empty canarypox virus as a control in a low-dose challenge experiment with monkeys. The virus itself appears to have protected some animals from SIV, possibly by ramping up the more primitive innate immune system.

The Thai study, for ethical and practical reasons, did not use an empty canarypox virus in the control group. If the canarypox virus by itself did lead to the protection seen in Thailand , van Rompay says, "I don't think they'd be able to figure that out."

Aside from intensifying the hunt for correlates of protection, the Thai results also promise to affect the design of future trials. "Should we be doing efficacy trials in such low-incidence communities that have so few events?" asks Seth Berkley, head of the International AIDS Vaccine Initiative (IAVI). Indeed, some investigators contend that the only way to clarify why the Thai trial had a positive signal is to redo the study in a high-incidence heterosexual population.

Robert Grant, an HIV/AIDS researcher at the University of California , San Francisco , says the Thai study resembles trials of microbicides and behavioral interventions that have had hints of working. "We're going to have to learn to interpret results from prevention trials that show modest effects," says Grant, who is leading a large study of anti-HIV drugs as preventatives. And maybe, he says, researchers will start combining the marginally effective strategies—just as they have done with treatment—to come up with one that has enough power to make a real dent against the spread of HIV.

IAVI's Berkley stresses that the Thai study does at least bring closure to the once thorny question of whether these two vaccines hold promise. They do not. "At the end of the day, the field is going to continue to move forward other products," he says.

Argentinean researchers claimed HIV 'can be transmitted by sperm' – not agreed by others though

(UKPA) HIV can be passed on by sperm and not just semen, researchers have claimed.

Scientists at the University of Buenos Aires found that traces of the virus had attached to sperm, suggesting it could cause the infection.

But Dr Stephen Taylor, a leading HIV specialist based at Birmingham Heartlands Hospital , criticised the scope of the research, claiming it was unlikely to apply to "real life".

"The argument over whether sperm is a major factor is a long-standing debate which was very much put to bed, probably about 10 years ago," he said.

"The majority of the evidence suggests that healthy motile spermatozoa themselves do not transmit HIV.

"It is very important to realise that this is an in-vitro model system - a test tube study - which may not relate to what happens in real life at all.

"It may raise some interesting scientific questions but, in real life, I think that the findings aren't going to change very much."

Copyright © 2009 The Press Association. All rights reserved.

Proceeds of Saint Laurent sale to battle AIDS

by Claire Rosemberg Claire Rosemberg Wed Oct 28, 6:58 am ET

PARIS (AFP) – Proceeds from next month's second installment in the "sale of the century" auction of the YSL-Pierre Berge collection, are to go entirely to HIV research and to the fight against AIDS, Berge said.

Speaking ahead of the November 17-19 sale of the last items in one of the world's greatest private collections, YSL's onetime lover and business partner pledged 10 million euros (14.8 million dollars) over five years to France 's largest private anti-AIDS group, Sidaction, which he heads.

"I want to again prove my commitment to the battle against AIDS," Berge told a media conference. "The fight against an epidemic as serious as AIDS must be shared between us all."

The donation is the largest to the French group in 15 years.

"It is a misconception to think AIDS is like other illnesses," Berge said. "We are not at the end of the tunnel, we are travelling further down the tunnel."

Some of the pledged funds will be raised at next month's YSL-Berge sale, expected to fetch between three to four million euros, which is far less than the record-smashing 700-item February sale that raised 342.5 million euros (491.9 million dollars), the biggest private art sale in history.

Works to be auctioned in November are largely from the pair's country hideaway on the Normandy coast, a three-storey place with a sea view built in 1874 for wealthy Americans that the two had redecorated to evoke writer Marcel Proust's "In Search of Lost Time".

Commenting on the larger February sale, Berge told AFP he did not yet know how much of the benefits would go to research on the HIV virus.

He also announced the creation of a special fund to oversee his donations as well as a specialist anti-AIDS committee that includes 2008 Nobel Medicine winner Francoise Barre-Sinoussi.

"Research has gone a long way since the 1980s, but so much remains to be done," she said. "Thanks to this donation we will be able to continue the battle."

The first February chapter in the once-in-a-lifetime YSL sale smashed 25 records for artists as well as setting new ceilings in Art Deco and silver.

A business tycoon, arts patron and committed left-winger, Berge opted to sell the collection amassed over a lifetime after Saint Laurent 's death in June last year aged 71.

He pledged at the time to offer the proceeds to fight AIDS and to a foundation honouring Saint Laurent 's work.

"I am a man of conviction," he said Tuesday. "I have always tried to be faithful to what I believe in, to act in accordance with my ideas.

"I know full well you have to have money to defend values, so in the light of these values, money in itself is of little importance."

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