International AIDS Vaccine Initiative abandons lead vaccine candidate, citing poor responses

The International AIDS Vaccine Initiative (IAVI) has announced that it does not plan to carry out further trials of its lead HIV vaccine candidate, following the presentation of disappointing results at this week's AIDS Vaccine 2004 meeting in Lausanne.

In a statement issued on August 30^th IAVI said: "The data fall short of expectations, and they show that the promise manifest in preclinical studies of DNA.HIVA and MVA.HIVA has not held up in humans."

"Over the next six to nine months, IAVI will complete a small number of clinical trials that have already started of DNA.HIVA and MVA.HIVA, in order to learn as much as possible from the candidates. Unless there are new immune response data that are dramatically different, IAVI will not develop the candidates further, and will focus on its other research and development projects."

There were a number of other disappointing reports on recombinant poxviruses at the AIDS Vaccine 04 meeting. Despite this, clinical trials are set to continue using several HIV vaccines based on poxvirus vectors. Some of the problems may have been due to the HIV-related components, not the vectors, and there may be ways to improve the vectors too.

The vaccine picked by the International AIDS Vaccine Initiative, IAVI, as its lead project, has given disappointing results in clinical trials reported from Oxford and London in the UK and from Kenya and Uganda.

In a complex randomised double-blind trial, 119 volunteers were treated with placebo and/or one of two doses of DNA, followed by a recombinant MVA or a placebo.

MVA stands for modified vaccinia Ankara, a smallpox vaccine adapted to grow in chicken embryo cells.

The DNA and the MVA both included "HIV-A" gene sequences corresponding to an HIV core protein (Gag) plus other very small fragments of viral protein, designed for immune responses to kill HIV-infected cells.

Immune responses were measured primarily using an ELISPOT assay. This detects the release of a substance (in this case, gamma interferon) when T-cells from a blood sample are added to a pool of protein fragments (peptides) matching elements of the vaccine or other antigen. A positive response to any one of these peptides is counted, though real-life immune protection is likely to depend on multiple responses of different kinds to different peptides. While there is controversy over how well this test measures working and useful T-cells, it is generally a repeatable test which gives positive results in animal models.

The disappointing outcome of the various trials was that in no group did the response rate exceed 20%, and in some the response was down to 10%. This is no better than has been seen in trials of canarypox-based vaccines and is not good enough, according to IAVI, to justify moving the vaccines forwards into larger trials.

In mice and monkeys, a simple strand of DNA, injected as a vaccine, is able to prime immune responses with viruses such as MVA, giving much better results than when either is used on its own. However, in this trial there was no evidence that either of the doses used - 0.5mg or 2mg - had any priming effect.

Some have argued that to match the doses that are effective in monkeys, human doses would need to be substantially higher. For example, Dr Stephen Kent, reporting his work on DNA – fowlpox prime-boost system, said that to match the minimum effective dose in monkeys they would need to give 6mg of DNA to their trial volunteers. This is close to the limit that could be tolerated as a single injection, and also raises cost and manufacturing issues.

Professor McMichael expressed reservations about taking DNA doses substantially higher than 2mg, but also commented that it would not be practical to take the dose of MVA much higher than he had used. One reason why adenovirus-based vaccines appear to give better results than MVA may simply be that it is possible to produce and administer much higher doses of adenovirus.

Another blow for poxviruses was reported by Merck scientists, who had hoped that a canarypox-based vaccine in the ALVAC series from Aventis Pasteur could be used to boost their adenovirus-based product. In monkeys, there seemed to be a synergistic effect, but this was not replicated in human trials. When an ALVAC product was administered as a booster to volunteers who had previously received the Merck vaccine, the results were identical to those seen when a repeat dose of the Merck vaccine itself was given.

In addition, a case was reported of a vaccine trial volunteer who had a clear-cut cellular immune response to an ALVAC vCP205 product, after receiving four injections in the course of a clinical trial. Two years later, the volunteer contacted medical services with a primary HIV infection, and chose to go on to antiretroviral treatment. The treatment was discontinued as the volunteer was unable to adhere to it, and their immune responses to the virus were assessed in detail. Initially, infection led to a recall of the vaccine-induced responses, but this failed to control the virus. Examined in great detail, the immune response was very similar to that of two other individuals with shared genetic factors (similar MHC varieties) who went on to progress to HIV disease.