/ 23 September 2004

Africa learns from Aids vaccine setbacks

Disappointing results of clinical trials for a promising pair of new Aids vaccines have highlighted the dilemmas faced by those determining strategy in this field. Fortunately, reactions on all sides indicate a willingness to use science as the principle basis of their decisions.

Recently, a prominent Kenyan newspaper carried a news story with the headline “Aids vaccine trials flop”. The following day, the same newspaper carried a second news story, this time with the headline “Search for Aids cure ‘not a flop'”.

At first sight, the two headlines appear contradictory.

In fact, between them they accurately convey the complex and sometimes tortuous path of progress towards what one leading authority in the field has called “the hardest challenge we’ve ever faced in terms of a vaccine.”

Both headlines refer to the news that a pair of vaccines intended to boost the body’s immune response to the Aids virus had failed to demonstrate a sufficiently promising effect in preliminary trials in Kenya, the United Kingdom and Uganda.

The failure was all the more disappointing because the vaccines — based on the discovery that some sex workers in Nairobi appear to have a natural immunity to the disease — promised a defence against the subtype of the virus that is particularly prevalent in Africa.

The first news story was a straightforward account of the announcement of the outcome of the trials, describing the inevitable disappointment among both the researchers involved and others who had been hoping to see a significant step towards controlling a disease that continues to decimate much of the African continent.

One blow is that the main sponsor of the research into the two vaccines — the International Aids Vaccine Initiative (IAVI) — is expected to shift its support to other candidates.

The second story was based on an interview with one of the first Kenyan volunteers to sign up for the trials.

Pamela Mandela, a Kenyan doctor, pointed to the positive results it had provided, in terms of demonstrating the apparent safety of the potential vaccines. And she also emphasised the fact that setting up and carrying out the trials had provided several African countries, particularly Kenya, with both the experience and infrastructure that are vital for new trials of other candidates in the future.

Taken together, the two news stories capture an important truth about Aids vaccine research: that progress in the field is going to be a protracted and iterative process as investigators discover slowly what does and doesn’t work in people.

This is especially true given that the ultimate goal is to develop a vaccine that is protective against HIV infection — and not merely successful in either triggering or strengthening a relatively low level of immunity.

The two vaccines that failed to achieve this in the latest tests have been developed in a partnership between the University of Oxford (supported by the UK Medical Research Council) and the University of Nairobi (supported by the Kenyan Aids Vaccine Initiative), subsequently joined by the Uganda Virus Research Institute.

They have been designed not to stimulate the production of antibodies to attack the virus — the standard approach of many vaccines — but to produce what is called a “cell-mediated response” to HIV.

This strategy is based on attempts to find ways of stimulating the human body to kill the cells that become infected with HIV to prevent further spread in the body.

The first of the two vaccines, known as the “prime”, consists of a copy of one of HIV’s nine genes stitched into a ring of DNA taken from a bacteria (the gene contains genetic sequences of subtype A of the virus, which accounts for most infection in East Africa).

The second, the “boost” vaccine, involves inserting the same gene into a modified smallpox virus that is unrelated to HIV.

The hope had been that, when delivered one after the other to enhance each other’s effectiveness, the two vaccines would stimulate the body into rejecting the HIV virus.

Such a result has already been successfully achieved in monkeys — one of the main reasons for the high hopes that they had raised.

But tests carried out since 2000 on 439 volunteers in Kenya, South Africa, Switzerland, Uganda and the United Kingdom, have now shown a similar immune response in, at most, only 25% of those receiving the vaccines. Furthermore, the effects appear to die away relatively quickly.

For the researchers involved, the result is clearly a significant setback. But they insist that it does not necessarily mean that the approach they are pursuing is doomed to failure. Rather, they are now seeing whether a different delivery technique — still using the same genetic sequence to produce the immune response, but with a modified delivery system – will prove to be any more effective.

There seems to be considerable evidence, for example, that the main problem may lie with the first vaccine, a conclusion that would correlate with similar disappointments elsewhere with vaccines that seek to promote immune responses by using disease-related genes inserted into “naked” strips of DNA.

Hopes remain that the second vaccine can be significantly improved. And both candidate vaccines are still being studied as a way of slowing down the progression of the disease in those already infected, ie as a therapeutic, rather than preventative, measure.

All this is as it should be. Developing an effective vaccine against HIV remains a major scientific, as well as technical, challenge.

In the long-term, however, only a vaccine strategy that is guided by science in both its short- and medium-term decisions is likely to succeed.

This may itself be an uncomfortable lesson for those involved to accept; African politicians who are demonstrating their commitment to combating the disease are among the front ranks of those who had been hoping desperately for a more positive result from the latest trials.

But, when the price of going too far down the wrong track is so high, African governments are also coming to learn that even failed experiments can remain important ones. — SciDev.Net