Deep down immunity

September 10, 1999

Malaria has proved tougher than many of the antibiotics deployed against it. However, the latest vaccine against the parasite responsible for malaria, which begins preliminary testing in humans soon, is a first. This trial, taking place in Oxford, is the latest of a rising number of forays into the use of DNA to protect against disease.

Conventional vaccines are of two types: those relying on live but attenuated variants of the organism under attack, and those that use natural or synthetic fragments of it. Both aim to provoke an immune response without causing the full disease, thus generating an immune memory that will allow the body's natural defences to swing promptly into action should the microbe turn up at some later date.

With a DNA vaccine, the individuals being protected do more of the work themselves. To mount the required immune response against this or that microbe, their own cells have first to synthesise the microbial material required to provoke that response. The information that the cells need to perform this trick is carried by the vaccine in the form of copies of the genes that the microbe itself uses to make this same material. It is as if instead of giving people swords to defend themselves, you give them instructions for making their own.

The man running the Oxford malaria project is Wellcome principal research fellow Adrian Hill. As he points out, the malaria parasite has a complicated, multi-stage life cycle. "What our DNA vaccine encodes is a selection of small fragments of some of the proteins that the parasite produces. The vaccine is targeted against the liver stage of the infection. It is designed to attack the parasite when it is growing inside the liver cells. That is early on, before you develop any symptoms."

Assuming the vaccine passes its initial safety trials in England, Professor Hill and his colleagues will ship it to Africa for more tests and, eventually, for a study of the protection it offers against the disease.

Over the years, various researchers tried to convince a sceptical scientific community that injection of DNA could provide protection against the microbes from which it came. The person usually credited with showing that DNA vaccines work is Margaret Lieu. In the early 1990s, working for the drugs company Merck, she and her colleagues immunised mice against flu by injecting them with genes from an influenza virus. Since then, researchers have quickly developed prototype vaccines against hepatitis B, herpes, tuberculosis, rabies, HIV and other diseases.

The spur to this work is that DNA vaccines are said to have many advantages. "DNA is very stable, easy to produce in large quantities, and can be transported at room temperature," says Peter Beverley, director of the Edward Jenner Vaccine Institute. "This is a considerable improvement over live attenuated vaccines, which have to be handled more carefully. Also, by using a string of genes, you can combine all sorts of things in one vaccine." Delivery seems to pose no great problem. You can inject genes, spray them up the nose or attach them to tiny gold particles and blast them through the skin using a pressurised canister known as a gene gun. Professor Beverley thinks it will soon be possible

to put them in capsule form to be swallowed.

Quite how the DNA gets to where each cell's metabolic machinery can read and then act on its message is not yet clear. The process is probably quite inefficient - which would explain why the DNA vaccines developed so far are relatively weak. Andrew McMichael, director of the Medical Research Council's Human Immunology Unit in Oxford, has developed a vaccine against one of the proteins of HIV. "The big advantage for us is that DNA vaccines are very focused, so we can select just the bit of the virus we want an immune response to. On the other hand, they don't seem to be that potent on their own." That is why Professor McMichael plans to use it in combination with a modified form of another virus that gives the body's immune response a more general boost.

In view of the scares that have cast a succession of shadows over conventional vaccines, everyone in the field is conscious of safety. Professor Beverley is offering no guarantees, but he is reassuring. "There are no acute effects that I am aware of. The question is whether the DNA might persist for a long time or even integrate with the recipient's genome. The worry is then that it might be one step on the road to the formation of a cancer. But so far the frequency of integration seems to be vanishingly small." And even if the new DNA did integrate, it would not necessarily do harm.

With animal studies completed, a number of research groups are embarking on human trials. Professor McMichael hopes to start the first phase, the safety trials, of his HIV vaccine in the spring.

Being dosed with a DNA vaccine is not unlike being infected naturally with a virus. "That's why the penny should have dropped sooner," Professor Beverley says. "We should have believed the early reports saying you can get effects when you transfer nucleic acid." DNA vaccines promise many advantages: they are focused, stable and easy to make in quantity. And, as Geoff Watts reports, human trials of them are about to start

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