Double, not quits

A big AIDS-vaccine trial reports encouraging results

SOME good news about AIDS. After more than two decades of research those labouring to find a vaccine against HIV, the virus that causes the disease, have found a method that might actually work.

This method, known as “prime-boost”, has been tested on more than 16,000 volunteers in Thailand. The volunteers were drawn from the general public, rather than specifically from groups at particular risk such as gay men, recreational-drug injectors or prostitutes. The preliminary results of the trial, which was called RV144 and was organised by Thailand’s Ministry of Public Health, were announced on Thursday September 24th.

The upshot is that the technique on trial seems to reduce the risk of an uninfected individual contacting the virus by about 31%. That is below the 50% reduction rate defined as showing “unequivocal clinical benefit”, and the margin of error is wide, so it does not suggest that the experimental vaccine should now be deployed for general use. It is, however, enough to justify putting effort into improving this approach.

Traditional vaccines work mainly by priming the immune system so that it knows how to make antibodies to a particular infectious agent. Antibodies are proteins that stick onto a pathogen and gum up its works. The active principle of the vaccine, known as an antigen, is the bit of the pathogen that the immune system recognises and that the antibody sticks on. Prime-boost techniques, which are also being developed to attack malaria, work mainly by stimulating another part of the immune system—one that kills infected body cells rather than “naked” pathogens. This cell-killing system, too, recognises antigens, but it finds them on the surface of an infected cell.

The experimental evidence suggests that a particularly good way of activating the cell-killing arm of the immune system is to use two vaccines based on different antigens. One primes the response and the other boosts it—hence the technique’s name. In the case of RV144 the boosting vaccine, AIDSVAX, had been the subject of a previous trial in Thailand, and also of one in North America and Europe. Those two trials, intended to raise a traditional antibody-based response, were regarded at the time as the best hope for an effective vaccine. They were a bitter disappointment. When they reported in 2003 they showed no benefit whatsoever. They did, however, show that AIDSVAX was safe, and although it was abandoned by its commercial backers at the time, it was picked up by a Californian charity called Global Solutions for Infectious Diseases.

The antigen in AIDSVAX is a genetically engineered version of gp120, a protein that HIV uses to lock onto the cells it subsequently infects. By contrast the priming vaccine, called ALVAC and made by Sanofi Pasteur, a French firm, contains synthetic versions of three HIV genes. It, too, had been tested for safety in previous trials, but none of those trials were designed to see if it was also efficacious. Unlike AIDSVAX, ALVAC is made of highly engineered viruses into which the antigenic genes have been incorporated. These viruses are versions of canarypox, which is nothing like HIV (so there is no risk of someone contracting AIDS from them) and, in any case, they have been tinkered with so that they cannot reproduce. A full course of the RV144 regime lasted six months and consisted of four shots of ALVAC and two of AIDSVAX.

One criticism of RV144 is that the versions of the antigens it used came from subtypes B and E of HIV. These are the most common forms in, respectively, North America and Europe, and in South-East Asia (including Thailand). Given where the trial was carried out, that makes sense. But the place crying out for a vaccine is sub-Saharan Africa, where two-thirds of the world’s HIV-infected people live, and two-thirds of new infections are happening. This continent, the place where HIV originated, has the greatest variety of subtypes. Subtypes B and E, though, are not common there.

There is also some doubt about how much actual boosting is going on. AIDSVAX, after all, failed the first time round and since ALVAC has, until now, been tested only for safety and not for efficacy, how well it would work by itself (and thus how much contribution the AIDSVAX is making) remains unknown.

But these are minor quibbles about what was intended as an experimental proof of principle. The RV144 trial suggests that an AIDS vaccine can indeed work in principle. Now it is time to get down to the nitty-gritty of making it work in practice.