In a webcast here, the US biotechnology company VaxGen has set out its strategy for further development of AIDSVAX.
Although the trial, as reported here found no efficacy in White or Hispanic trial volunteers, the suggestion that it may have protected Black, Asian and 'other' (mostly mixed-heritage) ethnic groups will be investigated further.
It is still possible that there are non-racial differences between the 'ethnic groups' of volunteers within this trial, which may account for these findings. These must be considered further, before the US Food and Drug Administration could even think of licensing a product for use by people from selected ethnic groups.
The AIDSVAX B/E trial now being carried out in Thailand, with results due towards the end of this year, will also be of great importance in deciding whether, or how rapidly, and for which populations, AIDSVAX could be licensed.
VaxGen has stored blood sera from multiple clinic visits by all trial volunteers, which can be tested for levels of neutralising antibodies. The company reports that eight different tests are planned for each sample.
Preliminary analysis of the serum stored from vaccinated volunteers who later became infected, compared with those of a sample of volunteers who did not, have shown that infected volunteers had significantly lower levels of antibodies than those who did not become infected, according to the company. Indeed, according to the company, this even applied to White and Hispanic volunteers - which makes it very odd, that they still found no significant protection for the vaccinated volunteers compared to those who received placebo.
There is also a suggestion that there were higher levels of antibodies in the Black, Asian and 'other' volunteers than there were in the White and Hispanic volunteers in the trial. This can be tested through analysis of more of the 40,000 stored samples available.
At present, the only analysis that has been performed for the trial is the 'intent to treat' analysis, which is a proper way to minimise bias in such trials. Additional analysis, comparing the levels of infection between volunteers who attained different levels of neutralising antibodies, might still be of interest in validating that test as a correlate of protection.
VaxGen has said that, based on such work, it would wish to explore ways to make AIDSVAX more immunogenic, which could include partnerships with other companies to use different adjuvants in place of the alum used in AIDSVAX.
An additional kind of analysis that VaxGen has begun to carry out, but from which no results are yet available, will look at the viruses that infected placebo recipients during the trial and compare them to those which infected vaccine recipients. All of the viruses have been isolated and their envelope protein genes have been sequenced, but this analysis is complex - and any conclusions based on it will doubtless be contested.
VaxGen has promised to provide additional data, including from these studies, at a vaccines meeting in April to be held in Keystone, Colorado.
Beyond analysing existing data, VaxGen is actively planning additional clinical studies. The company says it remains fully committed to supplying vaccine for the planned trial in Thailand, co-sponsored by the Royal Thai Army and the US National Institutes of Health (formerly a US military AIDS research programme) which plans to test a combination of Aventis Pasteur's ALVAC canarypox vaccine followed by AIDSVAX B/E.
As part of its plans for manufacturing AIDSVAX in large quantities, VaxGen is building facilities in south San Francisco, California, which still might be able to produce large quantities of product from early 2005 (although this needs to be confirmed). It is also building facilities in South Korea in partnership with Celltrion. The Korean facility is fully funded, and can be used for other products should there be limited demand for AIDSVAX.
VaxGen would have expected to run additional clinical studies to demonstrate that their scaled-up process yields vaccine that is fully equivalent to that used in their Phase III trials. They would now seek advice from the US FDA, on how to use such studies to expand the evidence base to support licensing of AIDSVAX for specific populations at risk.
Even if it is confirmed that AIDSVAX B/B was able to offer some protection to Black and Asian participants in this trial, it does not follow that the vaccine will be of any use to people in Africa and Asia, where different viruses are circulating and where exposure to other infections and parasites may alter immune responses to the vaccine.
VaxGen is currently in discussion with the Gates Foundation, World Health Organization, Global Alliance on Vaccines and Immunization and others on how to find out whether AIDSVAX can, in fact, be of wider use. In particular, it is in discussion with African researchers with a view to running small scale trials to assess safety and immunogenicity using remaining stocks of the AIDSVAX B/B vaccine. These would be followed, if they appeared to show good immune responses, by trials of an AIDSVAX product including a gp120 derived from subtype C viruses, which is now being prepared. Subtype C is the predominant group of viruses circulating in Southern Africa, Ethiopia, India and much of China.