BioWorld International Correspondent
LONDON - A clinical trial to test the safety of a new candidate vaccine to protect against malaria is expected to begin in about a year's time, following promising results in tests on mice.
The vaccination protocol will involve giving volunteers two recombinant poxviruses, which contain DNA encoding a string of antigens from the liver stage of Plasmodium falciparum.
Earlier this year, that same team reported that they could induce a substantial cellular immune response against the malaria parasite in a human clinical trial, with significant protection against challenge with malaria.
Now, their latest study, published in the Dec. 15, 2003, issue of the Proceedings of the National Academy of Sciences (PNAS), reports that mice that received the experimental poxvirus vaccines produced immune responses to all of the antigens included. The title of the paper is "A Plasmodium falciparum candidate vaccine based on a six-antigen polyprotein encoded by recombinant poxviruses."
Sarah Gilbert, university research lecturer at the Nuffield department of medicine at the University of Oxford in the UK and one of the authors of the paper, told BioWorld International: "We have already shown partial protection in humans using a single antigen. What we now hope to be able to do is to stimulate a broader immune response that will improve on this level of protection. This is very exciting because the latest results suggest that we have got a better chance of improving on something that already works partially."
Gilbert and colleagues, including Eric Prieur, the first author of the paper, work in the group of Adrian Hill, head of the cellular immunology and vaccine development group at the University of Oxford. In May, Hill's team reported in Nature Medicine that a vaccine strategy called PrimeBoost could stimulate a "substantial" immune response against P. falciparum. That strategy 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.
The antigens in the vaccine were chosen for their ability to stimulate an immune response against the parasite's initial stage of infection, which takes place in the liver. The strategy is attractive because it is only when the parasite migrates into the bloodstream that the infected person begins to feel ill.
Gilbert said, "We knew from the Nature Medicine study that we were going in the right direction, but we needed a vaccine that could be used in the field, that would give complete protection."
They decided to make a piece of DNA encoding six different antigens from the liver stage of P. falciparum, which could make a "polyprotein" of six fused proteins. They also engineered the same stretch of DNA into two different poxviruses: MVA, which is a strain of vaccinia that does not replicate in humans, making it much safer than the strain normally used in smallpox vaccination; and FP9, an attenuated strain of fowlpox virus, which also is incapable of causing an infection in humans.
"The important finding of this paper is that it can be done - we have shown it is possible to link together all these antigens and make a DNA vaccine, and engineer it into two different poxvirus vectors and to get immune responses to all the antigens used," Gilbert said. The group had been concerned that the immune response to such large proteins would be too diffuse, or that the immune system would respond only to one dominant part of the polyprotein, although - as the results from the mice showed - that was not the case.
However, unlike their earlier study, they found that giving the naked DNA to prime the immune system before giving modified poxvirus was not very effective in stimulating the immune response they wanted. When they tried giving the recombinant FP9 followed by recombinant MVA, they found that the mice produced strong CD8+ T-cell responses.
Hill's group collaborates with Oxxon Pharmaccines Ltd, of Oxford, UK, and Oxxon's Joerg Schneider is among the authors of the PNAS paper. The PrimeBoost technology is licensed to Oxxon, which announced in April that it had raised £15 million (US$23 million) in a private financing round.
Gilbert said the group now is having the recombinant MVA and FP9 viruses manufactured for the forthcoming Phase I trial. That is expected to involve about 20 people and will take place in Oxford.