AIDSVAX trial not the end of the story

The news this week that VaxGen's AIDSVAX Phase III trial gave only 3.8% protection from HIV infection dampened the hopes of many. The result was described as "disappointing" by Seth Berkeley, President of the International AIDS Vaccine Initiative (IAVI). But there are some grounds for optimism. AIDSVAX may have worked in black women and, in addition, 19 different vaccines are in the pipeline for trials, while several new AIDS vaccine concepts are in development.There were 5009 people in the AIDSVAX trial, of whom 314 were black. Of these, 111 received placebo, of whom nine became infected; 203 received the vaccine, of whom four became infected. The placebo and vaccine groups had roughly equal numbers of men and women: 58 men and 53 women in the placebo group; 110 men and 93 women in the vaccine group. But whereas in the placebo group there were five infections in men and four in women, in the vaccine group there were four infections in men and none in women.These may seem to be tiny numbers on which to hang hopes but, "with numbers like these vaccines have [gone on to] be licensed," José Esparza, coordinator of the WHO–UNAIDS HIV Vaccine Initiative, told The Scientist. "WHO is not proposing that. But they indicate a direction research might take."The vaccine used a simple antigen, the gp120 "mushroom top" protein by which HIV attaches itself to the CD4 molecule on the surface of the cell it will infect. "There's a scientific bias against using simple gp120, based on a lot of data in animals and so on, but there are so few leads to follow in HIV vaccines, it would be irresponsible not to follow this one," said Esparza.One exciting lead comes out of the Institute of Virology at the University of Maryland, headed by Robert Gallo. There, Anthony DeVico and Timothy Fouts are about two years from Phase I trials of a complex between gp120 and the CD4 molecule. Binding to CD4 changes the shape of gp120 to reveal a second binding site, with which it eventually binds to co-receptors on the cell. Only then can the virus enter the cell. The hope is to generate antibodies against the second site.But "we've been working on this 10 years," DeVico told The Scientist. There have been problems with steric hindrance — most antibodies can't get to the site when the virus has bound to the CD4 molecule — and with the stability of the complex.Nevertheless, says DeVico "right now these complexes are recognized by all the human monoclonals, including broadly cross-reactive neutralizing antiserum. So they've got all the right epitopes exposed. "Our hope is to have some sort of Phase I trial going in the next two years. The rate-limiting step is going to be convincing the Food and Drug Administration that the complex is safe."At the Scripps Research Institute in California, another approach to the problem is moving forward. IAVI has appointed Scripps' Dennis Burton as director of the Neutralizing Antibody Consortium, which has brought together labs across the United States to "double or triple," said Burton, the speed of work on "broadly neutralizing antibodies." These are a group of antibodies from laboratory cell lines that neutralize most wild strains of HIV. "The idea's pretty simple really," said Burton. "First, these broadly neutralizing antibodies work. They protect monkeys and we have every reason to believe they will protect humans. If you have enough antibody they'll protect monkeys completely." But the levels needed for protection are quite high, and probably not achievable by vaccination. So the hope is that they would be used in combination with cellular immunity.The trouble is "we still can't elicit these antibodies. There's an odd glimmer of hope, but nothing you could yet describe as a breakthrough," said Burton. But the consortium is working on understanding how the antibodies recognize the virus at a molecular level, in the hope of designing molecules to elicit antibodies like them.IAVI's leading vaccine candidate is the "prime–boost" DNA–MVA (attenuated modified Vaccinia Ankara) vaccine, currently in Phase I/II trials in London and Kenya. The vaccine was developed by Tomas Hanke and Andrew McMichael of the MRC Human Immunology Unit, University of Oxford, with scientists at the University of Nairobi. It contains most of the gag gene, fused to a string of 25 partially overlapping regions of gag, pol, nef and env, which encode epitopes for cell-mediated immunity. IAVI has selected it, in principle, for its next Phase III trial in 2005, but there's no final decision yet.Although the results of the Phase I trials are not yet published, "The vaccine was well-tolerated," according to McMichael. "And as far as the immune response was concerned, it's encouraging; we're still analyzing. There are immune responses for sure. We'll probably publish in weeks."The vaccine draws on evidence from Nairobi sex-workers exposed 60–100 times a year to HIV but who have remained uninfected. Omo Anzala, programme manager of the Kenya AIDS Vaccine Initiative, told The Scientist that "research among the resistant sex-workers has not stopped, to understand their natural history and what exactly entails their resistance."According to Anzala, so far in Nairobi the HIV and MVA components of the Oxford vaccine have been tested alone for safety, and "now we are testing the prime–boost strategy, using both. In animal studies the best immune responses came with the combination," he said. The Kenyan results should be available around the end of 2003.According to McMichael "We've got a second vaccine coming through the pipeline that we intend to mix with our current one, to give a broader response. It's very similar in concept but contains different parts of the HIV genome — parts of reverse transcriptase, tat, nef and gp41… We have to accelerate this one through if we are going to get it ready for Phase III in two or three years."Anzala said "We are preparing a cohort in Kangemi" [a Nairobi slum] "for the Phase III trials. It's expensive, and this will be just one of the many cohorts we need. But it takes a while to get the infrastructure in place, get the community educated and interested." According to Esparza, Phase III trial sites in developing countries are one of the key bottlenecks to vaccine development, with a single trial costing up to $50 million.Meanwhile, the world's next Phase III AIDS vaccine trial should begin at the end of 2003 in Thailand, with an Aventis Pasteur canary pox vaccine plus a vaccine like AIDSVAX, but based on a different HIV sub-type.According to IAVI's database there are plenty more trials on the way: 24 ongoing trials and several pending for early 2003, collectively involving 19 different vaccines. (Of these, seven are DNA-based, five use recombinant viral vectors, four are protein subunits and three are lipopeptides.)Most are in Phase I. VaxGen's two trials are the only Phase III studies in progress; both will be completed this year, with efficacy data from the North American trial expected early in the year. The majority use HIV clade B strains from the northern countries, but a few candidates (especially among the newer ones in the pipeline) are based on African and Asian clades A, C, D and E. The effect of clades — with 35% genetic variation between them — on vaccine effectiveness is not yet known.

AIDSVAX trial not the end of the story

Results of AIDSVAX trial disappointing but 19 more AIDS vaccines in pipeline.

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