One of the most worrying questions about the vaccine trials is
whether some of them really did increase participants’ susceptibility to HIV. A
new meta-analysis by Peter Gilbert of the Fred Hutchinson Cancer Research
Center in Seattle, USA attempted to shed some light on this. It looked at all 8500 participants in the
STEP, Phambili and HVTN 505 trials and established that, over the whole group,
participants who were given a vaccine were 33% more likely to become infected
with HIV than placebo recipients. However,
the increased risk in HVTN 505 was only 9% and this was not remotely
statistically significant (p = 0.7).
There was a 41% raised risk of acquiring HIV for vaccine
recipients over placebo recipients in STEP and Phambili taken together. This was
statistically significant (p = 0.005). However, if STEP was taken by itself, the raised
risk for all participants was only 22% and this was not significant. So in
terms of whole trials, it was Phambili, where vaccine recipients were 74% more
likely to acquire HIV than placebo recipients, which remained significant.
Based on the results at the end of the blinded
phase of vaccine trials, when participants did not know whether they were on
vaccine or placebo (which is what has been published before) – pre-existing
adenovirus immunity, especially in uncircumcised men, seemed to be implicated (being male and having ad5 immunity raised your risk by 68% in both trials taken together).
Both trials, however, continued after unblinding: participants were
followed for three years after they found out whether or not they had actually
been on the vaccine.
During the unblinded phase, a very odd thing started
to happen: while the increased risk of vaccine over placebo remained, especially in Phambili, and the risk for men over women persisted in that trial too, the risks associated with adenovirus immunity
and circumcision actually reversed. People without
immunity to Ad5 and circumcised men became
more likely to acquire HIV than Ad5-immune and uncircumcised participants.In fact this actually started happening before
unblinding, after 18 months from the first vaccine or placebo shot.
appeared that, whatever was causing the excess infections in vaccine recipients,
it either wasn’t Ad5 immunity after all, or the Ad5 risk only contributed to
the overall risk in the first 18 months after people were given the vaccine, for some
unknown biological reason. This doesn't explain why the risk reversed, though – and it would be very unusual for a vaccine to suddenly
start producing a biological risk that hadn’t happened before as long as
18 months after the vaccine was given.
It may have been behaviour in the unblinded phase. Trials are
blinded so that participants' knowledge of whether they are on the treatment or the placebo
does not influence their behaviour. As a result, it is much more
difficult to tease out influences on outcomes in the unblinded phase.
difference in infection rates in the unblinded phase of STEP and more markedly
in Phambili was characterised by another odd thing: the difference later on was
not so much driven by vaccine recipients acquiring more HIV so much as placebo
recipients ceasing to acquire it. In
Phambili in particular, in the last year of follow-up no infections were seen
in the placebo group.
What was happening? Did placebo recipients reduce their risk
behaviour after unblinding, or vaccine recipients increase theirs? Conversely,
what about people who dropped out of the study? Somewhat more placebo recipients dropped out of the study
after it had been unblinded than vaccine recipients, a common phenomenon in
vaccine trials. What if the high-risk placebo recipients had been the ones that
dropped out? That would also keep infections in the remaining placebo group down. Conversely,
high-risk vaccine recipients might have been more likely to stay in the study.
Glenda Gray, Principal Investigator of the Phambili trial,
said that self-reported behaviour did not differ between vaccine and placebo
recipients and that even if there was differential drop-out in high-risk placebo
recipients, it would only make a single infection's difference to the Phambili result.
Gilbert said that based on the drop-out rates in all three trials, there
would have to be 33% more infections in placebo drop-outs than those who stayed
in the trials, and 28% fewer in
vaccine drop-outs than in those who stayed, to even out the vaccine/placebo
difference seen during the unblinded phases of the trials.
For now, then, the explanation for the higher rates of
infection seen in some groups in the STEP and Phambili trials remains