Therapy with an HIV vaccine: progress poor, prospects unclear

The use of HIV vaccines to treat people already living with the virus was the subject of several presentations and one dedicated session at the AIDS Vaccine 04 meeting in Lausanne. It remains doubtful whether currently available vaccines will have any substantial clinical effect.

Some animal studies have suggested that vaccines given to animals infected with HIV-related viruses can improve their ability to control viral load and extend disease-free survival.

One study of this kind, reported in Lausanne, involved monkeys that had been infected with an SIV 251 strain of virus for between 15 and 70 weeks before the experiment began, in an experiment designed to parallel chronic HIV infection.

15 animals were treated with three antiretroviral drugs (PMPA – a form of tenofovir, ddI [didanosine], d4T [stavudine]) for 20 weeks, and were immunised at weeks 8, 12 and 16 with one of several related DNA vaccines. The vaccines included gene sequences corresponding to SIV viral proteins (env or gag). This vaccine group was compared to another 16 monkeys that received the antiretrovirals only, without immunisation. Two vaccinated and five unvaccinated animals had to be taken off the ARVs because of drug toxicity.

Animals were followed up for between 7 and 18 months after ARV treatment was stopped. Vaccinees showed a statistically significant reduction in viral load compared to unvaccinated animals, which continued for at least 18 months.

This makes several points which are common to other studies.

One is that any effect from a vaccine is likely to be modest, and only seen in the setting of treatment with antiretrovirals.

Another is that small numbers of animals were used, making interpretation difficult. This study could only reach statistical significance by combining animals treated with different products, which is far from ideal, given that the exact relationship between vaccine and infecting virus should be central to any effect it may have.

A third is that showing any clinical benefit from a vaccine may take a long time, even if people are willing to accept breaks in their HAART treatment, to see if their immune system is able to control the virus unaided.

Finally, it cannot be assumed that DNA vaccines will be equally immunogenic when given to people, in doses that are practical and tolerable. For preventive vaccines there are problems of scaling up dosage which are surely going to apply equally to therapeutic vaccination.

One clinical trial which was reported by a researcher from Lausanne was developed as part of the multi-centre, international Quest study of antiretroviral treatment in primary HIV infection. This was initially designed to look at structured treatment interruption as a strategy to try and improve immune control of the virus in people identified soon after becoming HIV positive. Vaccination with one of two products – the envelope-depleted, inactivated virus known as Remune, or an ALVAC canarypox-based HIV vaccine – was added to the protocol in an effort to increase the chance of success. The results were negative: no significant difference between vaccine recipients and others in the rate at which viral load rebounded when treatment stopped. Again, numbers were small, given the challenge of identifying people in primary infection and recruiting them into clinical trials.

Reviewing this and other studies, Dr Yves Levy – a researcher involved with the largest therapeutic vaccine research programme, sponsored by the French ANRS – concluded that vaccines do not appear to add anything to what may be achieved through treatment interruptions in people treated during primary HIV infection. The implication is that work should focus instead on chronic infection.

An update by Julianna Lisziewicz on DermaVir did not add to what was reported two years ago. This product still seems to be set for an early stage clinical trial through the US AIDS Clinical Trials Group system and also for a paediatric trial in children or adolescents. It is a DNA vaccine administered through a skin-patch after first exfoliating (removing dead outer skin cells) with sand-paper. The theory is that this exposes Langerhans (dendritic) cells specialised in presenting antigens to the immune system.

In the monkey study which was reported (again) DermaVir was given repeatedly to monkeys with SIV 251 before each of a series of short interrruptions in antiretroviral treatment. Viral load rebounds in each interruption but, if these results are to be believed, to a lesser extent on each occasion. After several interruptions, extended control of viral load without antiretroviral drugs may be achieved in at least some monkeys.

There must be a question about the dosage that can be delivered through this system – and how to measure it. Another obvious question concerns the risk of drug resistance during repeated treatment interruptions, which are not planned as part of initial human trials, but would appear to be the only way to obtain clear-cut clinical benefit.

The conclusion at the final plenary session of the Lausanne meeting is that while therapeutic vaccine studies should continue, vaccine design will require as much attention as those for preventive use. One good reason for doing these studies is to develop better understanding of immune responses to HIV and better tools to measure them, which may then inform preventive vaccine research as well as suggesting new treatment options.