A new vaccine approach provided monkeys with a high level of
protection against a virulent form of SIV, the monkey equivalent of HIV.
Vaccine researchers say the findings are promising, and provide important
pointers on how to design an HIV vaccine.
In particular the study found that two potential vaccine
regimens reduced the per-exposure risk of infection by an estimated 80-83%.
The study was a collaboration between Crucell Holland B.V.,
the Beth Israel Deaconess
and Ragon Institute of MGH, MIT and
Harvard, and the U.S. Military HIV Research Program at the Walter Reed
Army Institute of Research. It was funded by the Ragon Institute, the US Military HIV Research Program and the US National Institute of Allergy and Infectious Disease.
The study used a vaccine approach called prime-boost, in
which monkeys received a “priming” dosing regimen of one vaccine, followed by a
booster shot of a different vaccine 24 weeks later.
The study also tested the impact of different vectors, the
harmless viruses which deliver the non-infectious sequences of HIV or SIV genes
that are designed to stimulate an immune response to the virus. Vectors are
chosen on the basis of their suitability for delivering gene sequences to
cells, or for their ability to provoke strong immune responses. (See Types of HIV vaccine for further information).
The study tested a number of different combinations of
A DNA prime vaccine containing SIV Gag, Pol and
Env immunogens at weeks 0, 4 and 8, followed by a booster using modified
vaccinia Ankara (MVA) to deliver the same immunogens at week 24.
The MVA-based vaccine as both prime and boost
vaccine, at weeks 0 and 24.
An adenovirus type-26 vector (Ad26) delivering the same
immunogens at week 0, with an MVA-vectored vaccine booster at week 24.
An MVA vaccine as prime at week 0, with an Ad26 vaccine booster at week 24.
Each vaccine combination was given to eight animals.
The adenovirus vector has been developed by Crucell, a Dutch
company that forms part of the Johnson & Johnson group, and uses adenovirus
type 26, which is not commonly found in humans. A previous adenovirus-vectored
vaccine, using the Ad5 serotype that is widespread in humans, was tested in the STEP trial, and may have
contributed to the greater risk of infection observed in participants with
higher levels of immunity to Ad5.
Six months after the boost immunisation monkeys were exposed
to a rectal inoculation using a type of SIV that was genetically different from
the SIV genes contained in the experimental vaccines in order to test their
potential for preventing infection with a virus of a different genetic profile.
This virus was also chosen for its ability to evade
neutralisation by antibodies.
This stringent approach was designed to set a high bar for
Three-quarters of the animals in the control group became
infected after the first exposure to SIV, compared with less than a quarter of
animals that received one of the vaccine combinations. Animals continued to
receive regular exposures to SIV, and not all monkeys became infected, even
after four challenges.
Animals that received the two vaccine combinations containing Ad26 proved
particularly hard to infect. After three rounds of exposure, only 50% of
animals that received the Ad26/MVA or MVA/Ad26 regimens had become infected,
compared to a 50% infection rate after one round of exposure in the control
group. This represented an 80-83% reduction in the per-exposure probability of
infection, although the confidence intervals were fairly wide, due in part to
the small number of animals studied (95% confidence intervals 0.05-0.57 and
0.06 – 0.063).
The Ad-26-containing regimens were also associated with
significantly lower viral load setpoints in animals that did become infected. The
point at which viral load stabilises after the early months of infection is a
strong predictor of the subsequent risk, and speed, of HIV disease progression.
Two hundred and fifty days after infection animals immunised
with an Ad26-containing regimen had mean viral load setpoints 2.32 log (Ad26/MVA) and 1.08 log (MVA/Ad26) below
those of animals in the control group (P=0.0037).
In addition three of the seven infected animals in the
Ad26/MVA group rapidly demonstrated that their immune systems were controlling
the virus to such an extent that they had sustained undetectable viral loads.
After analysing the immune system responses that were
correlated with protection from infection, delayed infection or virological
control after infection, the researchers have concluded:
to envelope proteins (Env) appear to be critical for blocking acquisition
findings are consistent with the results of the RV144 human HIV vaccine
study, which showed modest protection against HIV infection, and in
particular suggested that antibodies against the V1/V2 region on the HIV
envelope may be associated with reduced risk of infection.
immune system’s mechanisms for controlling infection are different from
the mechanisms used to prevent infection.
and adenovirus/MVA vector-based vaccines can offer significant protection
against highly pathogenic strains of SIV.
Plans are now underway for early-stage human studies of
vaccine candidates adapted from one of the most successful prime-boost
combinations used in this study.