Disappointing Results for HIV Vaccine Trials

Although more than a dozen HIV vaccines will soon face human trials, Simon Grose finds pessimism among researchers.

HIV vaccine trials are always greeted with hope when they are announced, but we should keep our hopes down when it comes to developing a weapon to thwart the global epidemic that is infecting at least five million people per year.

In February, American and Australian vaccine trials delivered disappointing results. California’s VaxGen said it’s third stage trial - which involved 5108 homosexual men and 309 at-risk women in the US, Canada, Puerto Rico and the Netherlands - had delivered a mere 3.8% reduction in the comparative infection rate.

A first stage trial by Australian research-based start-up Virax, involving 34 participants, found that its treatment was safe, the main goal of first stage trials. But the drug “did not elicit immune responses in the trial participants”.

Dr Ian Ramshaw of the John Curtin School of Medical Research at the Australian National University (ANU) devised the technology behind the Virax vaccine. The company was formed around the technology but Ramshaw says he fell out with the company several years ago after licensing the technology to it.

He later joined another group comprising researchers from the ANU, CSIRO, and the universities of Melbourne and NSW, which won a $27 million grant from the US National Institutes of Health (NIH) 2 years ago. By the end of April they hoped to have final approval for a first stage trial of an HIV vaccine involving more than 20 people in Sydney and Melbourne.

The Australian group is leading three US groups - which received NIH funding at the same time - in its progress towards clinical trials. But Ramshaw is not optimistic about the chances that this or any one of more than 20 other vaccine projects around the world will deliver an effective treatment to prevent HIV infection.

“We aren’t near producing a preventative vaccine at this stage. We’ve still got many, many years to go,” he told a video conference hosted by the US Information Service late last year.

Another member of the group, Dr Tony Kelleher of UNSW, said their vaccine technology will not prevent infection but will hopefully prevent the disease developing once a person is infected. “We’re being very honest here,” Kelleher said.

“The two main measures we want to get out of the trial is that it is safe, with no significant adverse effects, and that it induces robust T cell immunity of the nature that we have seen in the preclinical experiments done in mice by Ian Ramshaw and David Boyle and in monkeys by Stephen Kent [at the University of Melbourne].”

Talking from Washington, Dr Stuart Shapiro told the Australian researchers why they should not set their expectations too high. “Your vaccine doesn’t have two-thirds of the envelope of the surface protein [of the virus],” Shapiro said. “It has only got one-third of it and it doesn’t even have the part that has the binding site, so you’re not going to get antibodies that would be broadly cross-reactive.”

Shapiro works in the AIDS Prevention Research Program at the US National Institute of Allergy and Infectious Disease, where he supervises US funding of HIV vaccine research. The Australian group is one of several around the world to have benefited from the ongoing US commitment to aggressively bankroll this research at a cost of several hundred million dollars per year.

Shapiro said he expects up to 15 HIV vaccine projects to reach the human trial stage in the next 2 years. Like the Australian group’s, these second generation vaccines aim to attack the virus when it enters the bloodstream and when it invades cells in the body. But Shapiro was clear that they are not expected to provide the kind of protection normally associated with a vaccine.

“I don’t think they will be anywhere near 80-90% effective in preventing people from getting infected, but I do think they will prevent some infections,” he said. “Even if they don’t prevent people getting infected, by giving people the prior resistance to the virus, they will slow down the viral infection.

“The virus load in the blood will be lower. This means the disease will progress slower and they will be less infectious to others. It should be comparable to putting them on a good drug therapy.”

The first stage of the two-part vaccines generally aim to trigger white blood cells to produce antibodies that attack the infectious agent in the bloodstream before it enters the body’s cells. However, it is unlikely that this approach will be successful on its own because enough of the virus is expected to evade any such barrier and enter the cells of the new host. Once this occurs, antibodies cannot get through the cells’ membranes to attack their target.

The second stage of the vaccines aims to prepare the immune system to recognise infected cells and kill them. One approach involves using segments of HIV DNA, enough to enter cells but not enough to cause a real infection. The idea is to cause the cells to produce some of the proteins that an HIV-infected cell would produce, preparing the immune system to attack cells whenever they produce those proteins.

“The body is already primed by the vaccine - it has those white blood cells armed and waiting for an invader to come in,” Shapiro said. “Theoretically, they can kill infected cells before they get to reproduce and spread the virus within the body.”

Another method is to use the shell of another virus as a carrier for a vaccine. Fowlpox, which does not infect humans but does provoke an immune response, is being trialled by several research projects. When engineered to retain its surface structure after most of its DNA has been removed and replaced by segments of HIV DNA, this can similarly prime the immune system to attack when it recognises HIV proteins in the body.

One approach that has been used to develop vaccines to other viruses - using a disabled or attenuated version of the live virus - is not a viable strategy with HIV. “This virus is so cunning that, even if you inactivate genes or take genes out of it so it doesn’t replicate, the virus can reconstitute itself when it is injected,” Ramshaw said.

By the end of this year his group will know their stage one trial results. If these are positive they will then need to organise and gain approval for further trials, a complex and expensive task Ramshaw described as “horrendous”.

Just recruiting sufficient numbers of participants is a major challenge. As John Kaldor, Deputy Director and Professor of Epidemiology at the National Centre in HIV Epidemiology and Clinical Research, pointed out in Australasian Science last year (AS, Jan/Feb 2002, p.18-20), it would be necessary to recruit around 2500 gay men from inner Sydney and follow them for an average of 2 years to be able to demonstrate with 80% certainty the effectiveness of a vaccine that reduces risk by 90%. “But if the vaccine is only 50% effective, the number of subjects required would be more than 10,000,” Kaldor wrote.

If any of the HIV vaccine technologies now in the laboratories get to this stage of testing and prove successful, it would then take up to a decade before a vaccine was widely available. Even then, it is unlikely that it would fully prevent infection.

In the meantime, and thereafter, Shapiro recommends more basic preventitive measures to ward off HIV infection: “Condoms, education, and clean needles.”