The recent report in Nature journal1 about
the CMV-based vaccine was picked up by the mainstream press
and, as with many recent scientific advances in the HIV field, was hailed as if
it was the next step to a cure.
It’s not. What happened
in this trial is that, in three separate batches, 46 rhesus monkeys were given
the RhCMV/SIV vaccine. Then, 13 months later, they were exposed to SIV: 24 male
and female monkeys with up to ten weekly shots of virus in the rectum to mimic
anal sex, 16 females similarly infected vaginally, and six with up to three
direct low-dose injections of SIV to mimic needle sharing. They all acquired
SIV, as blood and cellular assays taken soon after infection show.
The bad news, and the
reason this is not ‘the cure’, is that for 22 (48%) of the monkeys, the vaccine
did not work. (By October, 96 had been infected and the vaccine did not work in
48 of them.) They developed SIV infections with high viral loads, including
four of the six monkeys infected via injection. That also means they would die
within a year or two unless treated with antiretrovirals: the SIV strain chosen
is highly pathogenic and typically maintains long-term blood viral loads of a
million copies/ml or more. Another reason that this is not ‘the cure’ is that
this is an animal study and, so far, promising signs of success in animal
studies have often failed to translate into anything more.
A third reason for more
cautious reporting, is that some researchers are concerned that CMV is not safe
enough to use in a vaccine for humans; the very fact that it is so active and
stimulates such a strong immune response worries people that, through
recombination (the so-called ‘viral sex’ where these little entities swap
genes), HIV could reconstruct itself from the vaccine.
The good news is this: the
other half of the vaccinated monkeys also became infected with SIV. There was
no doubt that SIV was there: as we said above, it showed up in cells. But it
was such a pathetic, low-key infection that these monkeys never even made
antibodies to the virus – meaning they would test SIV negative. The blood viral
load in most of these 24 monkeys was never above five copies/ml, though five
showed irregular blips up to 10,000 copies/ml in the first three months after
infection but never after (with one crucial exception, which we’ll hear more
Five vaccinated monkeys
were put down five weeks after being vaccinated so they could be autopsied.
They had traces of SIV in 2% of samples of immune tissue (from lymph nodes,
spleen, gut, bone marrow and liver). That compares with 100% of samples in an
infected but unvaccinated monkey; 16% of samples in a monkey that spontaneously
controlled its viral load; and 6% of samples in a monkey on antiretroviral
drugs (tenofovir, raltegravir and boosted darunavir).
By excluding the viral
protein vif from the vaccine, the researchers were able to show that it was
immune responses generated by the vaccine, and not ones generated by the virus,
that were controlling the infection.
Although strong immune
responses to the other proteins were already present at the date of infection – an immune response to vif did not reach similar levels till
two weeks after infection.
The exciting thing about
this vaccine, however, is that even this low-level infection disappeared over
time. When aidsmap.com first reported on this study two years ago,
any trace of viral infection had disappeared in 72% of the monkeys infected
rectally a year after infection. Now, three years after infection in the
rectally infected monkeys and after at least a year in the monkeys infected
vaginally and via injection, blood tests and cell samples could find no trace
of virus in any of the monkeys that
had an undetectable blood viral load. Furthermore, while levels of immune
response to the vaccine remained strong, levels of immunity to SIV itself had
dwindled to nothing by a year after infection, because by that time there was
so little virus around the immune system couldn’t sense it.
More stringent tests
were done on some monkeys. Even more ultrasensitive assays on six autopsied
monkeys found no trace of virus. Three had their CD8 cells depleted by
immunosuppressant drugs: no virus reappeared. And finally, in an experiment you
could never do in humans, immune cells were transplanted from seven vaccinated
monkeys, two monkeys on ART, and the one ‘elite controller’ monkey, into ten
uninfected monkeys. None of the seven monkeys receiving cells from vaccinated
monkeys developed SIV infection; the other three all did.