AIDS vaccines in 2003

The biggest vaccine-related story of 2003 is likely to be the outcome of VaxGen’s first AIDSVAX trial. This is the first time that any HIV vaccine has been put to the final test, to see if it works. The results from the first and largest study, which drew mainly on American gay men for volunteers, will be reported in the first quarter of the new year. The second trial, among injecting drug users in Thailand, should be reported towards the end of the year.

Antibodies are found in almost everyone to whom AIDSVAX is given. What no-one knows is whether those antibodies will protect anyone from HIV. Many vaccine experts have predicted failure and it is already clear, from the infection of vaccinated volunteers in earlier trials, that AIDSVAX will not be 100% effective. Nonetheless, the vaccine has passed a series of reviews from the trial’s independent Data and Safety Monitoring Board, including an interim analysis of results. This suggests that while it has not been proven effective, the possibility of a positive result remains open.

If the results of this first trial are negative, both the company itself and the whole HIV vaccines field will need to regroup. The company has put another product in the pipeline (an anthrax vaccine) to ensure its survival, without diminishing its commitment to AIDSVAX. The company has already agreed to a trial using AIDSVAX in combination with another product, to see if that can give better results. Alternatively, their expertise in running trials might be deployed to test other candidates. Other vaccine designers are looking both for vaccines to stimulate more powerful antibody responses and vaccines that could protect in entirely different ways.

If, confounding VaxGen’s critics, the results of the first trial are positive (an apparent efficacy of 50% or better, and a proven efficacy of at least 30%), then the challenge to both the company and the whole field will be even greater. The company is preparing to scale up production, with new production plants in California and South Korea. This will take time – in practice at least two years – which can be used to decide how to make best use of their product.

The US Food and Drug Administration, which will have a pivotal role in licensing any vaccine for sale in North America and Western Europe, declared this month that AIDSVAX will be put on fast track for evaluation if the early trial results are positive. Other US Federal agencies, especially the US Centers for Disease Control and Prevention, which sponsored studies of volunteer behaviour in the VaxGen trials, are also geared up for a rapid response.

AIDSVAX has been tested in combination with other HIV prevention efforts, and would need to be deployed in the same way. Deciding on the shape of those services, and getting them ready for AIDSVAX, would be a major task.

The challenge to AIDS vaccine research would also be substantial. If AIDSVAX must be used in place of placebos – and even compared to a combination of AIDSVAX with any new vaccine - then future vaccine trials will need to be far larger, and more costly, than the first round of trials. This would be an ideal opportunity to set up and test the infrastructure needed to deliver HIV vaccines and other prevention methods on a scale that could really turn back the epidemic. But will funders see it that way?

Further trials and follow-up studies would be needed in any case. How long would any protection last? How far can AIDSVAX protect against HIVs that differ from those on which the vaccines are based? The first trials use gp120 (the outer envelope protein) from subtypes B and “E”; a subtype C version is in preparation, but what is to be done in Uganda (subtypes A and D) or Nigeria (AG and other recombinants)? These subtype variations may or may not matter, but decisions – to test or to deploy – would be hard ones.

The first results should emerge from clinical trials, in London, Oxford, Nairobi and the USA, of vaccines designed to induce a totally different kind of immune response, using a prime-boost regimen that includes a DNA vaccine. Indications from animal studies, and early clinical studies of non-HIV vaccines on the same principle, are that these can induce levels of cellular immunity that have not been seen before. The question remains, whether even this will be enough to block infection with the virus or transform the prospects for people infected despite vaccination. And would these vaccines boost or undermine any protection that can be gained from antibodies?

Efforts to establish national HIV vaccine efforts in a number of key countries are moving steadily forwards. The first Phase I vaccine trials in South Africa, testing new ideas with antigens based on HIV subtype C, have great significance for the progress of all of these efforts.

We may also be seeing the first animal studies of potentially usable vaccines, inducing broadly neutralising antibodies by using a combination of HIV and other proteins, possibly a modified scorpion toxin, to mimic the intermediate states of HIV that form during the docking process between the virus and its host cells.