First results from Oxford-Nairobi vaccine trials

The first results from clinical trials now taking place in Oxford and Nairobi were presented on Friday at the AIDS Vaccine 2001 conference in Philadelphia. The talk was given by Dr Matilu Mwau, a Kenyan physician working as a graduate student in Oxford with Professor Andrew McMichael’s team.

The Oxford and Nairobi trials are looking at the safety and immunogenicity of two vaccines incorporating the same artificial “HIV-A” gene sequence designed by Dr Tomas Hanke in Oxford. HIV-A represents a small part of HIV based on subtype A viruses which are the second most widespread of the subtypes worldwide. It includes a gag sequence representing the main internal protein of the virus and a series of epitopes chosen to generate killer T-cell (CTL) immune responses against a wide range of HIV strains.

One vaccine consistes of DNA which is injected into the skin as a primer and another uses Modified Vaccinia Ankara (MVA), a bird-adapted smallpox vaccine strain, injected into a muscle. So far, these vaccines have only been tested separately, although animal studies show that they are most effective when the DNA is followed by the MVA in a prime-boost regimen. A prime-boost trial is due to start in Oxford later this month (September), and later in Nairobi, where the principal investigator is Dr Job Bwayo of the University of Nairobi.

Safety findings so far confirm that these vaccines should be safe for widespread use, though larger trials are essential.

Cellular immune responses have already been seen, mainly directed to elements of the gag protein rather than the selected smaller components of the vaccine, probably just because it presents more targets for an immune response.

These CTL responses have been measured using ELISpot tests which show the ability of cells to produce interferon gamma when exposed to particular fragments of the vaccine proteins. 16 out of 18 given the DNA vaccine and 5 out of 8 given the MVA vaccine showed positive responses, although the DNA responses were weaker than the MVA ones. 10 of the 16 and 4 out of the 5 responders to each vaccine also showed measurable CD4+ (T-helper cell) responses to the vaccine. These findings persisted over the six months of follow-up within the trial.

These responses compare very favourably to those reported from extensive clinical trials of canarypox-based vaccines, where at most 30 per cent of vaccine recipients show any CTL responses at any time over sometimes very lengthy periods of follow up, with responses which are not consistently detectable.

Dr Mwau also reported that initial early evidence from Kenya was that they were seeing weaker responses among Kenyan trial volunteers than they saw in Oxford. He speculated that this could be due to exposure to malaria or other infections, dampening cellular immune responses. However, in answer to questions, he strongly doubted whether malnutrition would have anything to do with this, given that the volunteers recruited in Nairobi as in Oxford were low-risk healthy adults.

The next step will be to design and produce a second pair of vaccines using a new gene sequence called "RENTA" based on fragments of different HIV proteins, including tat, nef and the envelope protein gp41, again from Kenyan subtype A strains. The aim is to use these with HIV-A to broaden the CTL response. The hope is that when high-risk vaccinees are exposed to HIV, infection can either be cut short or turned into a “long-term non-progressor” state with low viral load and reduced infectiousness.

Dr Mwau outlined the impact of AIDS on Kenya, which included an estimate that 0.9 per cent of the population will die during 2001 from AIDS-related illness. More than ten per cent of all AIDS-related deaths worldwide so far are believed to have been among Kenyans. The need for a vaccine, alongside other responses, is clear.

Dr Mwau declared that the target date for beginning a Phase III trial would be 2004 although he was unable to answer a question about precisely which population would be selected to take part in that trial.

Clearly there is still a great deal of work which must be done, very rapidly, if Kenya is to be able to mobilise the community support which will be essential for any such trial to take place.

The International AIDS Vaccine Initiative (IAVI) which is co-sponsoring the Oxford-Nairobi project with the UK’s Medical Research Council, has recently signed an agreement with the Ugandan Ministry of Health and the Uganda Virus Research Institute to conduct clinical trials of vaccines based on HIV-A in Uganda. In addition to the DNA and MVA vaccines used in Nairobi, they hope to test a bacterial DNA vaccine which can be taken orally, based on a vaccine strain of Salmonella or Shigella, using a technology developed by Dr Robert Gallo’s Institute of Human Virology in Baltimore, Maryland.