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 Medical Center 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 vaccines:
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 success.
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:
- Antibodies to envelope proteins (Env) appear to be critical for blocking acquisition of infection.
- The 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.
- The immune system’s mechanisms for controlling infection are different from the mechanisms used to prevent infection.
- Adenovirus 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.
Barouch D et al. Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys. Nature, advance online publication, 4 January 2012.