therefore a welcome surprise when the much-criticised RV144 trial reported some
degree of efficacy in September 2009, the first vaccine efficacy trial ever to
However the result hovered tantalisingly close to the boundary of statistical
insignificance, and exactly how the vaccine exerted its effect is still the
subject of study.
compared vaccine to placebo in 16,402 adults, starting in 2003 and ending in
2006. It recruited adults aged 18 to 30 in two provinces of Thailand with high
HIV prevalence but did not specifically target people at high risk of HIV
vaccine combined a ‘prime’ vaccine called ALVAC‐HIV (vCP1521) with a boost of
the AIDSVAX gp120 vaccine, an envelope protein segment from HIV subtypes B and
E. VaxGen, IDSVAX’s original manufacturers, had dissolved soon after the
original AIDSVAX trials but executives from VaxGen went on to form Global
Solutions for Infectious Diseases, a non-profit organisation. The presence of
AIDSVAX in the vaccination regimen was one reason why many vaccine experts had
not expected the trial to show a positive result.
developed by Sanofi Pasteur, consists of a viral vector containing genetically
engineered versions of three HIV genes (env, gag and pro). The ALVAC vector is
an inert form of canarypox, a bird virus, which cannot cause disease or
replicate in humans; it has been used in trials of cancer vaccines too.
prime-boost combination of ALVAC(R)-HIV and AIDSVAX(R) B/E lowered the rate of
HIV infection by 31.2% compared with placebo. This reduction was statistically
significant, meaning that the possibility of the result being due to chance is
low, but the confidence intervals for the estimate in the reduction in risk
were wide (p=0.039, 95% confidence interval 1.1%-51.1%). This means that there
was a 95% chance that the ‘true’ vaccine efficacy lies somewhere between these
placebo recipients became infected with HIV compared to 51 in the vaccine
regimen arm. The vaccine regimen had no effect on the amount of virus in the
blood of volunteers who became HIV-infected during the study.
were surprising to many. In a press conference call after the results were
announced, Colonel Nelson Michael, Director of the US Military HIV Research
Programme (MHRP), which funded 25% of the $119 million trial, said that the
most surprising and probably significant aspect of the result was that the
vaccine appeared to produce a mild protective effect while producing no effect
on the viral load in those who were infected.
humbled by this finding,” he said. “This may have turned several key assumptions
in HIV vaccine research on their heads.” He added that the trial showed that
“human experimentation trumps everything we do in animals and test tubes.”
Michael was referring to is that the RV144 trial consisted of two vaccines with
two modes of action. The ‘prime’ vaccine, ALVAC, consisted of HIV genes
contained in a canarypox virus vector. This model of vaccine delivery was
designed to stimulate a cellular immune response. This does not prevent initial
infection, but the scientific model – supported by data from some monkey
studies - was that the cytotoxic T-lymphocytes (CTLs or CD8 cells) thereby
generated would subsequently reduce HIV proliferation, contain viral load, and
slow or stop progression to AIDS.
appears to have made no difference to viral load at all, a finding at least in
harmony with the failure of the STEP trial. But at the start of RV144 study,
CTL vaccines appeared promising.
on the other hand, was designed to produce an antibody response against the
gp120 protein on HIV’s surface, a concept thought to have been discredited in
2003, just after RV144 started, when it failed its earlier trial. The
assumption was that HIV’s genetic hypervariability would mean that any antibody
response would be hopelessly specific; at the time HIV research pioneer Dr
Robert Gallo said: “This is not a vaccine approach that was based on science.”
what RV144 appears to have done is block infection without containing viral
load in those infected, which looks like an antibody response, though Nelson
Michael added that a longer-term study, RV152, was following up a proportion of
trial participants to see if there were longer-term effects on viral load.
asked what was causing the vaccine’s efficacy, Anthony Fauci, director of the
National Institute of Alliergies and Infectious Diseases (NIAID) commented:
“Simply, we don’t know. We did not see broadly neutralising antibody responses,
though there is an indication of a small antibody response. We also saw a
lympho-proliferative response but didn’t see an increase in CTLs (CD8 cells).
may not even have started to measure the correct immune parameters in the body
that in fact indicate protection against HIV.”
said there were a number of further questions left unanswered by the trial.
the vaccine’s effect durable or would further boosters be needed?
there ways of improving this model’s efficacy?
we see similar results in high-risk populations such as men who have sex with
men, injecting drug users, and high-risk heterosexual people?
the last question, MHRP Deputy Director Jerome Kim said that, contrary to some
reports, RV144 did not exclude high-risk people. At baseline a small number of
participants did turn out to be MSM and sex workers. The trial was designed to
vaccinate a “community sample”, in other words a truly representative
cross-section of the Thai population, “ranging from people at high risk to
people at no risk”.
Kim also speculated, one reason for the positive result may have been that “the
average intensity of exposure to HIV may have been lower than in high-risk
populations…we know a sufficiently large inoculum of virus can overcome any