Adenovirus-based T-cell vaccine prevents AIDS in monkeys, offering fresh hope for approach

An adenovirus-based vaccine prevented six out of six monkeys from developing an animal equivalent of AIDS, according to findings published this month in Nature. The authors of the study believe that vaccine approaches based on adenovirus vectors still have potential to prevent or control HIV infection, despite the failure of Merck’s adenovirus-based HIV vaccine last year.

Merck’s vaccine used an adenovirus (a common cold virus) as a carrier to deliver HIV gene sequences to immune system cells in order to trigger a strong immune response to HIV by the cellular arm of the immune system, which should recognise HIV-infected cells and kill them.

Although Merck’s vaccine showed promise in animal studies, it failed to protect against HIV infection in a large international study called the STEP trial. The study was halted in September 2007 when it became clear that people receiving the vaccine were just as likely to become infected with HIV as people receiving a dummy vaccine.

Subsequent analysis revealed that people with high levels of antibodies to adenovirus-5 (the strain used in the Merck study) were significantly more likely to become infected, and laboratory experiments have shown that adenovirus-5 antibodies accelerate the spread of HIV between cells when the Ad5 vaccine is also present.

The Merck study findings led to considerable despondency in the field about the prospects for an HIV vaccine designed to stimulate cellular immune responses, especially any approach employing adenoviruses.

The study published this month in Nature, carried out by the Beth Israel Deaconess Medical Center at Harvard University, Boston, and the Dutch biotechnology company Crucell, shows that Crucell’s vaccine elicits greater magnitude, breadth and quality of immune responses in monkeys than the Merck vaccine, according to lead investigator Dr Dan Barouch.

The Crucell vaccine uses a rare adenovirus strain, adenovirus-26, that was originally selected because of concerns that the adenovirus-5 vector would prove ineffective for many people because of widespread human exposure to adenovirus-5. At that stage no one anticipated that prior exposure to adenovirus-5 might be harmful for people exposed to the Merck vaccine, although Crucell founder Dr Jaap Goudsmit warned two years ago that adenovirus vectors would need to be managed carefully as complementary vaccines for HIV, TB and malaria are developed using adenovirus vectors.

In the experiment carried out by Beth Israel Deaconess Medical Center monkeys were exposed to a priming dose of a vaccine that used a recombinant adenovirus-26 vector to deliver SIV genes, and then received a follow-up booster dose with an adenovirus-5 vector.

“In most cases, the immune response induced by a single dose of a vaccine isn’t strong enough or sustainable enough to provide effective protection,” said Dr Barouch.

Six monkeys without genetic characteristics that might afford protection against SIV were vaccinated. The vaccine protected all six from developing simian AIDS after exposure to a highly virulent form of simian immunodeficiency virus (SIV). Although the vaccine did not prevent infection, the animals all controlled SIV infection after an initial burst of SIV replication, and were still alive and controlling SIV infection after 500 days of follow-up. In contrast four out of six monkeys that received a placebo vaccine were dead within a year.

The peak of viral load was reduced by 1.4 log (around 95%) from around 100 million copies/ml in the control group to around 4 million copies/ml), and the viral load set point was 2.4 log lower, when compared to the control group. Two of the six animals had viral load below the limits of detection for a substantial part of the follow-up period, while the remaining animals showed no trend towards rising levels of virus after the viral load set point was achieved.

The animals also displayed strong T-lymphocyte responses to the sequence of HIV’s Gag gene used in the vaccine, and had well-preserved populations of central memory and gastrointestinal CD4+ lymphocytes, two populations of lymphocytes that are usually depleted quickly after infection with SIV or HIV.

The authors note that theirs is the first study of a vector-based vaccine to demonstrate a significant reduction in the viral load set point in vaccinated animals using stringent criteria. However they say it is too early to tell whether the protective effect of the vaccine against disease progression is due to the adenovirus-26 vector or the prime-boost regimen, or both. Interestingly, six animals that received the same Gag immunogen delivered by an adenovirus-35 prime/adenovirus-5 boost showed consistently poorer immunological and virological responses after vaccination. Three out of six died during the follow-up period, as did two of four animals that received an ad5/ad5 prime-boost vaccine.

A study of the Crucell vaccine in 48 human volunteers is now underway at Beth Israel Deaconess Medical Center, but that study will not use adenovirus-5 as the vector for the booster dose.

``It certainly is better than the previous animal models, but we still don't know -- and it's a big if - whether this is going to translate into a meaningful and useful human model,'' Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, told Bloomberg.com in an interview.

Dr Bruce Walker, director of Harvard University Center for AIDS Research, was more encouraging. “This is an extremely important study because it shows there is still hope for vaccines currently in the pipeline. It also gives the first clear indication of the level and type of immunity that will likely be needed for an AIDS vaccine to work.”