The AIDSVAX trials

The first HIV vaccine to enter full-scale efficacy testing was the AIDSVAX gp120-based vaccine. This was designed to induce neutralising antibodies in the hope of preventing or aborting infection with HIV.

One AIDSVAX version, based on two different isolates of subtype B viruses, was tested among 5400 people at risk of sexual transmission of HIV in a randomised placebo-controlled trial in the United States, Canada, Puerto Rico and the Netherlands. The trial produced no evidence of protection among the trial volunteers as a whole, although the vaccine did elicit HIV antibodies.¹ A second trial, of an AIDSVAX formulation based on Thai subtype E and subtype B viruses,  recruited 2500 injecting drug users in Thailand, and also found no evidence of protection.² The trials began in 1998 and 1999 respectively, with both ending in 2003.

The AIDSVAX vaccines were developed by VaxGen, a leading biopharmaceutical company. VaxGen was a spinoff from Genentech (a biotech company now largely owned by Roche), founded to develop Genentech’s gp120 recombinant vaccine after the US government refusal to support Phase III trials of a prototype in 1994. VaxGen succeeded in raising private funds to run Phase III trials in the USA, Canada, the Netherlands, Puerto Rico and Thailand. It is greatly to their credit that they completed the trials despite many expert opinions to the effect that it would be impossible to recruit or retain volunteers. In fact, trial volunteer retention was higher than predicted in all settings and higher in Thailand than in North America.

The first VaxGen trial recruited 5417 volunteers at risk of HIV infection from sexual transmission, around 90% of whom were gay men. One third of the volunteers were randomised in a double-blind trial to receive placebo injections and two thirds a ‘bivalent’ vaccine based on a genetically engineered version of the gp120 surface protein from two different HIV-1 subtype B isolates.

The protocol for the trial involved seven injections over thirty months (0, 1, 6, 12, 18, 24 and 30 months) with follow-up visits for blood tests two weeks after each injection and six months after the last injection. All volunteers were given prevention advice and counselling.

The results of the trial showed that AIDSVAX offered no significant protection against HIV infection in the study population as a whole. Although there was a tiny excess of infections in placebo versus vaccine recipients over the whole course of the trial, when this was expressed as the annual incidence of infection, it was 2.7% in both arms, whether subjects received vaccine or the placebo. The efficacy of the vaccine was therefore zero.

The second VaxGen Phase III trial commenced in Thailand during 1999, using a gp120 vaccine based on ‘subtype E’ (now classified as circulating recombinant form 01_AE) and subtype B isolates of the virus. This recruited 2500 volunteers from drug treatment centres around Bangkok, to evaluate protection from direct blood exposure, with an equal number of placebo recipients and vaccine recipients. The annual infection rate was exactly the same in vaccine and placebo recipients: 3.4% a year for both arms.

Despite these non-results, the AIDSVAX gp120 vaccine continued to be used as the ‘boost’ in the RV144 Phase III trial in combination with the ALVAC vCP1521 canarypox vector as prime (see below). At the time, this attracted fierce criticism from scientists and activists alike, though the choice was later vindicated by the trial results. In 2004, 22 of the most prominent researchers in the HIV vaccine field wrote to Science stating that the US government was wasting its resources on funding a trial of a vaccine combination where there was no evidence that either component worked well on its own.³

“There is no credible scientific justification for the inclusion of gp120 in the trial,” commented co-author John Moore. “It’s an expensive, inert component that complicates any analysis of the final outcome.”

The trial’s sponsors, NIAID, defended the decision to proceed with the trial.⁴ NIAID’s Margaret Johnston said that, although the results were arguably modest, early studies showed that the combination used in RV144 was augmenting immune responses relative to those produced by each vaccine alone, and that the combination vaccine induced CD8 responses in 25to 45% of individuals.

However the critics said the enhanced responses seen could be just as well studied in a smaller trial and it was a waste not only of money but of human resources – in the shape of the volunteers who would probably be excluded from a future vaccine trial.

A central dilemma in AIDS vaccine research seems to be embodied by the RV144 trial controversy. The field is split between two points of view.

One is that vaccine development is incremental and that ‘more immune protection than the last one’ is sufficient reason for a trial to move ahead. People arguing this point of view say that the only ‘failed’ vaccine trial is one that produces no information and that even the numerous candidate vaccines that have produced little immune response or, if they have, have yet to show that translates into efficacy, are part of an immense scientific project that is teaching us huge lessons about virology and immunology.

The opposite point of view is that, historically, successful vaccines have not been developed incrementally, but have usually come out of the serendipitous success of an often new approach. Like Robert Gallo, they argue that we are at too early a stage in HIV vaccine development to start incrementally developing anything; the incremental stage comes when we have strong candidates that will provide real efficacy. It is a waste of human and financial resources to put on large trials of products that are, at best, only likely to be marginally efficacious and it may be unethical if it provides volunteers with a false sense of security against HIV infection.

Ironically, while the modestly positive result in the RV144 trial was a triumph against the odds for the incrementalists, the unexpectedness of this result has thrown HIV vaccine development into one of its phases of going back to the drawing board – the focus is currently on basic research rather than large-scale efficacy trials.