How to stop a killer

A vaccine to combat the spread of HIV is the 'holy grail' of medical science. So why is it taking so long? Steve Connor explains the problems facing researchers

Developing a vaccine against Aids is described as one of the most difficult challenges facing biomedical science. It is also the most pressing. With tens of millions of people at risk of being infected with HIV in the coming decades, an Aids vaccine is seen as imperative if this disease is ever to be controlled. The big question is how near are we to realising this goal?

Developing a vaccine against Aids is described as one of the most difficult challenges facing biomedical science. It is also the most pressing. With tens of millions of people at risk of being infected with HIV in the coming decades, an Aids vaccine is seen as imperative if this disease is ever to be controlled. The big question is how near are we to realising this goal?

Chancellor Gordon Brown has pledged to raise £100bn for the treatment and prevention of Aids over the next 10 years, and he has specifically mentioned the need to set aside money for the development of a vaccine as part of this strategy. Yet it would be a rash person who would predict that we would have a vaccine within a decade.

When the US government announced the discovery of the Aids virus in 1984 (a year after the French), it said that the isolation of HIV would lead to a vaccine within five years. When Britain announced its own research project into HIV in the early 1990s, some of those behind it said that a vaccine would be developed in 10 years. In 1997 President Clinton announced that he wanted to see an Aids vaccine by 2007 - but the body he set up to oversee this admitted last year that his deadline will not be met.

This month the open-access journal produced by the Public Library of Science, PLoS Medicine, published what amounts to the latest manifesto of those who are working towards an Aids vaccine. It has been written by the Coordinating Committee of the Global HIV/Aids Vaccine Enterprise, which includes representatives of just about every major Aids-research funding organisation in the world, from the Wellcome Trust and the Bill & Melinda Gates Foundation, to the US National Institutes of Health and UNAids. What is perhaps most striking about its scientific strategic plan is that this time there is no mention of timelines, deadlines or milestones. Everyone accepts that making an Aids vaccine is a long-haul mission.

"It is not that there are no vaccine candidates in clinical trials, but there is little hope that any of the current candidates will turn out to be a cheap and safe vaccine that affords long-term protection," write the editors of PLoS Medicine. As they say, one of the problems of putting a timeframe on developing an Aids vaccine is a fundamental one: we do not actually know whether it is possible to develop a safe and effective vaccine. Neither is it possible to predict when the necessary scientific advances will happen, they say.

Scientifically, it is difficult to conceive of an infectious disease virus that would be harder to develop a vaccine against than HIV. The problem can be divided into three parts. First, the virus mutates rapidly which means that a vaccine against one strain is unlikely to work against another. Then HIV integrates itself into a patient's genetic material. Once someone is infected, he or she is almost certainly infected for life. Thirdly, the virus infects the very cells sent out by the body's immune defences to patrol the body's perimeter and defend it against attack. In effect, these T-cells act like a Trojan Horse carrying the virus back to the lymph glands, where it can replicate without fear of attack for many years.

Vaccines normally work by stimulating the immune system to recognise and attack an invading microbe or virus. This is why the vaccines against polio and smallpox have performed so well, but these viruses are very different from HIV. Indeed, Albert Sabin, who developed the world's first oral polio vaccine, said in 1993 just before he died that he thought that HIV was so different from most viruses that he thought a conventional vaccine would probably never work against it.

His prophecy has turned out to be true in the case of the only putative Aids vaccine to reach the final, "phase three", stage of clinical trials. VaxGen, a company based in California, began the trial in 1998 involving 5,400 participants in North America, Puerto Rico and the Netherlands, and a further 2,500 volunteers in Bangkok. The vaccine that was being tested was based on the outer envelope protein of HIV, a protein called gp120, which mutates dramatically from one HIV molecule to the next.

VaxGen was hoping that its vaccine would protect, at the very least, between 45 per cent and 65 per cent of the participants. This would have been enough to persuade the US Food and Drug Administration to give the vaccine a licence. In fact, the protection rate for the group overall was a disappointing 3.8 per cent, which was not even statistically significant.

Many medical researchers were not surprised when the results of the trial, published in 2003, showed that the vaccine did not work. "The VaxGen vaccine was designed 20 years ago," says Andrew McMichael, Professor of Immunology at Oxford University, who acts as spokesman for the Medical Research Council on Britain's Aids vaccine research. Simply injecting parts of the outer protein coat of HIV into people and expecting their bodies to launch an immune response will not work against this virus, he says.

Understanding the complex nature of the immune response is key to understanding the problems of developing an Aids vaccine. There are in fact two ways the immune system can respond to an invasion of foreign particles such as viruses. One is the humoral, or antibody response, when complex molecules called antibodies are tailor-made to fit around the invader, binding to it and rendering it harmless. These are called "neutralising antibodies" and they are something of a holy grail for Aids researchers because unfortunately the antibodies that people normally make against HIV are ineffective - they do not neutralise the virus.

The other type of immune defence is the "cell-mediated" response, when the soldier cells of the body - such as killer T-cells - are sent out to recognise and destroy the invaders. Professor McMichael said that this aspect of immunity is the one that is giving scientists the most hope for developing an Aids vaccine. The idea is to protect not against infection as such but against the onset of disease once the virus has gained entry to the body. Professor McMichael likens the situation to the way most people manage to harbour potentially dangerous viruses, such as Epstein-Barr, which causes glandular fever, without getting ill. They do so by having a good cell-mediated immunity that prevents the virus from getting out of control. "If we can get into that situation with HIV then it wouldn't be that bad," Professor McMichael says. "It would of course be better to have a fully prophylactic vaccine that prevents infection, but for that I think we also need an effective antibody vaccine."

Professor Frances Gotch, an immunologist at the Chelsea and Westminster Hospital in London, and head of the British arm of the International Aids Vaccine Initiative, says the aim is still to develop a prophylactic vaccine against Aids. "We are moving faster than we were three years ago. There has been a worldwide effort. We have not cracked the problem but the pipeline is widening. We are beginning to understand what immune response might work," she says. "We recognise the first vaccine [to be developed] may not stop the infection but enable people to live with HIV. This is not ideal. But it will curb the epidemic by reducing the viral load. But the aim of the international vaccine initiative is still to have a prophylactic vaccine."

Most scientists believe that a vaccine that triggers a cell-mediated response that protects against developing Aids, but is not prophylactic, is much closer than the holy grail of a vaccine that stimulates an attack on HIV with fully neutralising antibodies. David Ho, a leading Aids researcher at the Aaron Diamond Aids Research Centre in New York, says there are many explanations for why the holy grail is likely to remain just that for many years to come: "In the natural course of HIV infection, the virus wins 99 per cent of the time, showing that specific immunity in an infected person is unable to completely clear the virus," he explains. "We have also known for over a decade that primary HIV isolates are relatively resistant to antibody neutralisation, probably because of a protective shield on the viral envelope glycoproteins," he says.

"Arguably, the reason for the lack of an effective HIV vaccine today is rooted in the basic problems posed by the virus itself."

An Aids vaccine is rightfully depicted as the greatest public health need. But unfortunately it is also the one that raises some of the greatest problems for medical science.