AFTER more than a decade of false starts, the day is finally approaching when we will have a vaccine to fight AIDS. But already debate is raging over how – or even if – it should be used.
The trouble is that the first vaccines to be approved almost certainly won’t work very well. They are likely to prevent fewer than half of the people who receive them becoming infected, and this protection might only last a few years. And that creates a dilemma. Should we dish out these vaccines anyway, so that at least some people will be protected? Or could they make HIV spread faster by giving vaccinated people a false, and potentially fatal, sense of security?
żěè¶ĚĘÓƵs and policy makers face a very difficult decision. If they get it wrong, they’ll not only fail to curb the most destructive plague in modern history, they might actually make it worse. Yet there’s still no clear consensus on whether and how the first vaccines should be used.
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“We really need to be discussing this now. Not looking back after the event and saying what we should have done,” says Frances Gotch of Imperial College London, who is coordinating vaccine trials for the International AIDS Vaccine Initiative.
The big crunch will come at the end of next year when Californian biotech firm VaxGen gets the results of its phase III trials (żěè¶ĚĘÓƵ, 20 July, p 16). But most vaccine researchers think VaxGen’s AIDSVAX is unlikely to protect more than a third of people – if it works at all.
“If it’s only 30 per cent efficacious, will that be enough?” asks Gotch. “The problem is it could instill a false sense of security. It is going to encourage rash behaviour.”
“When people take vaccinations they think they offer solid protection,” she says. “In this case it won’t. That’s the danger. And we shouldn’t underestimate the difficulty in dispelling this notion.”
Jim Key, director of communications for VaxGen, agrees that if AIDSVAX does turn out to be less than 50 per cent effective, it would be given only to high-risk populations – and then only if accompanied by hard-hitting health education programmes. “Reinforcing the prevention message would be absolutely critical,” he says.
But given how difficult it has sometimes been to encourage condom use, it’s questionable how effective such advice will be. “It’s not possible to start giving vaccines without considering the local cultural factors and the levels of social infrastructure,” says Andrew McMichael of Oxford University, who is leading the development of a vaccine that’s being tested in Oxford and Nairobi. “There are no simple answers on whether we should use low-efficacy vaccines.”
But McMichael says he would be “very happy indeed” if his vaccine turned out to be 50 per cent effective. He points out that this kind of vaccine might not just stop some people getting infected in the first place. It might also slow down the disease in people who are already infected.
“And if people stay healthier for longer, then they are less likely to be infectious and less likely to pass the virus to someone else,” says McMichael. People with HIV tend to be most infectious in the later stages of the illness, when there are higher levels of the virus in their blood. That means a vaccine that only stops 35 per cent of people who take it becoming infected might nevertheless reduce the number of infections by, say, 50 per cent if given to an entire population.
In the absence of any solid data, researchers are turning to modelling. Statistician Roy Anderson of Imperial College London has produced models that suggest that low-efficacy vaccines that give protection for only a few years could prevent millions of infections in high-risk populations. But he told the recent AIDS conference in Barcelona that it might be quite difficult to work out how effective a partially effective vaccine is, requiring larger trials over longer periods than normal vaccines.
Despite these difficulties, the World Health Organization is already using such models to estimate where the vaccines should be employed and how much will be needed. In a paper submitted to a leading medical journal, Jose Esparza, who leads the WHO/UNAIDS vaccination programme, and his colleagues stress that a low-efficacy vaccine should be given only to “at-risk” populations. These include gay men, intravenous drug users and sex workers, as well as people in countries where infection is widespread.
Esparza calculates that 260 million people worldwide fall into these high-risk categories, including nearly half of sub-Saharan Africans aged between 15 and 49. These populations should be given any vaccine within five years, he says.
But Esparza acknowledges that officials will have their work cut out to avoid any stigma being associated with the vaccinations. He adds that the cost-effectiveness of such vaccination programmes will have to be carefully compared with that of, say, vaginal creams that prevent HIV infection.
The problems won’t end if the WHO decides to go ahead with vaccination. Esparza’s paper, based on consultations with experts and community leaders from Latin America, Asia, Africa and Europe, suggests that uptake (defined as people getting a full course of three shots plus a booster) would be very low, with fewer than one in five of the target population complying (see Table). The big obstacle, the authors say, is the lack of public health infrastructure in poor countries.
And there’s another problem. Giving someone a partially effective vaccine could drastically reduce their ability to benefit from more powerful ones that will inevitably follow. “It is possible that if people received our vaccine, it could alter their response to a better vaccine that came along later,” agrees McMichael. But of course, no one knows when such a vaccine will be developed.
Another, remoter possibility is that crude, early vaccines could make a few people more susceptible to HIV infection by encouraging the production of so-called “enhancing antibodies”, through immune mechanisms that are poorly understood. Such an effect might not be spotted in a small clinical trial.
Despite all the potential dangers, most experts agree that there’s little point in waiting around for the definitive vaccine. The vaccines being tested now will either, like VaxGen’s, induce antibodies against the virus, or make people produce special immune cells that destroy HIV-infected cells, like the Oxford vaccine. A highly effective vaccine would probably have to combine the two approaches. For most diseases, this would mean creating a weakened version of the live virus, but with HIV this is out of the question for safety reasons.
Instead, we will have to squeeze out every last bit of effectiveness from a bunch of imperfect vaccines until we finally work out what it takes to offer complete protection. Esparza firmly believes we’ll get vital new insights by giving the early vaccines to those at risk. “This would help slow the spread of HIV and tell us more of what we need to make better vaccines.”
Gotch agrees. “We still don’t know what it takes to protect against HIV,” she says, “and we never can do until we try these vaccines in lots of people.”
So the first few million vaccinations against HIV will not only be something of a gamble. They might also be the biggest medical experiment ever undertaken.