To prove a
vaccine’s efficacy, it has to be given to thousands of people. This is partly
because the majority would probably not have caught HIV anyway, and partly
because we don’t have a reliable ‘surrogate
marker’ – an immune response that tells us the vaccine is working. Because
of this, and cost, there have been few large efficacy trials: only three have provided
was of a vaccine called AIDSVAX.
This recruited 5417 volunteers identified
as being ‘at risk’ of HIV. AIDSVAX was a generalised antibody vaccine. It found
that the annual infection rate in vaccinated participants was only 2.7% lower
than those receiving placebo, nowhere near significant.5 A
similar trial of a different AIDSVAX formulation in Thailand fared no better.6
The next big
used a CD8 vaccine in volunteers at high risk of HIV infection. Their ad5 vaccine consisted of pieces of HIV in
the shell of an adenovirus – a type of cold virus.7
trial, immune responses thought to be protective were seen in volunteers. There
was shock, then, when the trial was ended prematurely. The vaccine actually appeared to
make some people more vulnerable to HIV.
A 48% higher
rate of infection in vaccine recipients was not statistically significant.
However, there was a significant
difference in those with immunity to pre-existing adenovirus infections.8
It seems that the body ‘recognised’ the adenovirus in these people and the
resulting inflammatory response rendered immune cells more vulnerable to
were low, then, for the third trial, RV144. This was a huge trial in
Most volunteers were heterosexuals at relatively low risk of HIV. It was controversial
because it used the AIDSVAX antibody vaccine, which many scientists considered
useless, in combination with ALVAC, a vector vaccine based on canarypox virus.
It was another
surprise, then, when it produced a
positive result. The group that took at least one dose had 31% fewer
infections than those receiving a placebo. This was just significantly significant: the ‘true’ difference in infection
rate could have been between 1 and 52%.9
the protection seemed to be generated by cells that recognised AIDSVAX and
produced antibodies to it – despite that failing in the original trial.10
generated did look weak. It did not seem to protect volunteers at high risk of
HIV and it waned over time: if the study had stopped six months after the first
dose, instead of continuing for 3.5 years, the protection rate would have been
After debate about a possible statistical
fluke, most immunologists now accept that the RV144 vaccine did have a real
effect – which might be improved. Two studies will start this year: one, RV152, giving ‘booster shots’ to people who
received RV144. In another, yet to start, 125 recipients new to RV144 will get
a double dose. A trial using a different vector is also planned.11
These will be
small studies that can’t prove ‘real world’ efficacy. There are tentative plans
for big efficacy trials, but there’s no widespread appetite for them, given
that there is so much we don’t know about RV144.
don’t know why some vaccines work and others don’t, time-consuming and
expensive investigatory trials are still needed. A paper from the International
AIDS Vaccine Initiative12 revealed it takes US$500 million to
develop a typical vaccine, but the AIDSVAX and RV144 trials alone cost $235
There is pressure
from funders to speed things up. Bill Gates, a major funder of HIV vaccine
research, has demanded that researchers “minimise the length of trials and the
time between trials”.
being considered is ‘adaptive trials’: the aims and strategy of your trial change
as you go along. You build in criteria for stopping fast if the vaccine looks
harmful, ineffective, or even highly effective, and if you anticipated the
vaccine would do one thing, but it does another, you change its ‘primary
endpoint’, the main thing it measures.
controversial because of the danger of biased results: searching long enough
for evidence will probably find some. There are ethical debates too - is it wrong
to keep giving a placebo if your vaccine may be working?
result has regenerated a degree of low-level excitement in HIV vaccine researchers.
We still don’t know the way to an HIV vaccine – but there are signs there is