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