BioWorld International Correspondent

LONDON - Effective vaccines against diseases as diverse as malaria and certain cancers have edged closer, tests of an experimental malaria vaccine suggest.

The results, which showed that the vaccine was able to induce a substantial response by the cellular arm of the immune response, also are encouraging for those working on developing a therapeutic vaccine to treat people already infected with HIV.

Adrian Hill, head of the cellular immunology and vaccine development group at the University of Oxford in Oxford, UK, told BioWorld International, "Our latest study shows that this approach, which we discovered in animal studies five years ago, is the most effective way we have, so far, of inducing protective T-cell responses in humans."

Hill collaborated with researchers in Oxford and London; at the Walter Reed Army Institute of Research in Silver Spring, Md.; at PowderJect Vaccines, of Madison, Wis.; and at Oxxon Pharmaccines Ltd. in Oxford. Their work appears in the June issue of Nature Medicine under the title "Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans."

Hill and his team already began clinical trials to test the protective efficacy of the vaccine in The Gambia, West Africa, and hope to announce results later this year.

The vaccine relies on a technology called PrimeBoost, which has been licensed to Oxxon Pharmaccines. It involves priming the immune system to recognize a target antigen with a DNA vaccine, and then boosting the immune response with a modified vaccinia virus expressing the same antigen.

For the vaccine against malaria, the researchers decided to try to stimulate an immune response against the parasite's initial stage of infection, which takes place in the liver. That strategy is attractive, because it is only when the parasite migrates out into the bloodstream that the infected person experiences the symptoms of malaria.

To make the vaccine, the researchers first took a leading malaria antigen called TRAP, together with a string of epitopes from other malaria antigens, which are known to stimulate cytotoxic T cells, and manufactured DNA encoding those components. That genetic material formed the DNA vaccine that comprised the first part of the vaccination schedule.

Secondly, the team engineered the same stretch of DNA into a strain of vaccinia virus called MVA, to form a recombinant viral vaccine. MVA is a strain of vaccinia that does not replicate in humans, so it is much safer than the strain normally used in smallpox vaccination. The engineered MVA comprised the second part of the vaccination schedule.

"When you give the engineered MVA alone, it has 150 to 200 of its own antigens that are competing with the malaria antigens when stimulating the immune response," Hill said. "The idea of PrimeBoost is to start an immune response with the DNA vaccine, then when you give the recombinant MVA, the immune system is primed to direct the bulk of its response against the malaria antigens."

That explains why, he said, when either the DNA malaria vaccine or the MVA recombinant vaccine were given alone to human volunteers, only a modest immune response resulted. "But when we gave DNA followed by MVA with the right dosing," Hill said, "we got an immune response that was 10 times stronger than either one alone, and much stronger than anything that has ever been seen before in a human clinical vaccine trial of a subunit vaccine."

The team also challenged the volunteers who took part in the trial with malaria infection. For the challenge, the researchers used a strain different to that they had used to develop the vaccine. They found that the volunteers who had received either the DNA vaccine or MVA alone were not protected from infection, but those who had received DNA followed by MVA were significantly protected.

Hill said it remained to be seen whether the vaccine as is would provide enough protection in the field, or whether it might be necessary to combine the PrimeBoost approach with other antigens and other types of malaria vaccine. "Nevertheless, these are some of the best results we have seen in terms of a malaria vaccine working in humans," he said.

He added that PrimeBoost also is one of the leading approaches to vaccination to protect against HIV infection, and is being evaluated for safety and immunogenicity in trials in Oxford, London and Nairobi, Kenya. Trials are also under way in Oxford of a vaccine against tuberculosis, using the same strategy.

In April, Oxxon Pharmaccines Ltd announced that it had raised £15 million (US$23 million) in a private financing round. The company has already begun Phase II trials to test PrimeBoost therapeutic vaccines to treat malignant melanoma and hepatitis B.