Killers offer promise of rescue

June 1, 2001

Matilu Mwau introduces the cells that could lead the way to an Aids vaccine.

The Max Perutz Essay Prize 2001 attracted almost twice as many entries as last year, with 79 Medical Research Council research students and research training fellows attempting to squeeze a clear account of their work into 800 words. Judges included Max Perutz, one of the United Kingdom's most renowned scientists, George Radda, chief executive of the MRC, Philip Campbell, editor of Nature, and Steve Farrar, science correspondent of The THES. The winning entry was penned by Matilu Mwau, at the MRC Human Immunology Unit, Oxford.

"Setback to Aids Vaccine as 'Immune' Prostitutes Catch Virus" - The Daily Nation was at it again. I carefully cut the controversial article from the front page and folded it neatly into my wallet, discarding the rest. Having no wish to drown in the fast-flowing river, I balanced on the makeshift log. I had not been back for six years, but not much had changed in the Kenyan village where I spent most of my childhood. I was here to attend the burial of KimChwere, the most selfless man I had ever met.

Villagers spoke about him in whispers accompanied by shakes of the head. They all agreed that a good man had died. In his last visit to my city home, he was anxious about the lack of progress towards an Aids vaccine. At the time, I had no clue that he was HIV positive and I did not believe an HIV vaccine was possible. When he died, a part of me died too.

The degree of suffering and death caused by HIV infection in the global south cannot be overemphasised. An Aids vaccine is the world's most urgent priority. Studies done using weakened HIV-like viruses have shown that they elicit strong immune responses that protect primates from Aids-like disease. But there is an unacceptable risk that the viruses can revert to the disease-causing form by mutation in healthy recipients and cause Aids. They could possibly cause Aids in people with compromised immunity as well.

Synthetic HIV peptide vaccines stimulate antibody production, but these have largely failed in preventing disease in clinical trials. They are specific to individual strains and ineffective in natural infection. They do not stimulate killer T-cell responses, vital in containing HIV infection.

Six years ago, scientists allied to our unit discovered that a few prostitutes in Nairobi and Gambia remained uninfected despite repeated exposure to HIV. Their blood and certain tissues contained large numbers of HIV-specific killer T-cells that effectively and rapidly killed those cells that got invaded by HIV. The scientists recognised the significance of this finding immediately. They made a vaccine intended to stimulate production of HIV-specific killer T-cells in a human recipient. It consisted of a piece of the genetic code of the HIV virus that would stimulate the strongest immune response. The DNA construct was put into two different "vehicles" to improve delivery, one a plasmid (a larger piece of DNA) and the other a modified Vaccina Ankara (MVA) virus, all harmless. I joined the unit soon afterwards.

We confirmed that killer T-cell responses are strongest when two doses of the plasmid DNA were injected into muscle tissue, followed by a dose of the MVA vaccine into skin tissue, all about three weeks apart. This is called the "prime-boost" approach. Using a "gene gun" to deliver the vaccine gives even better outcomes.

In the past year, we have been able to show that the DNA vaccine is safe and stimulates a strong killer T-cell response in mice. It protects primates from the virus, even at doses as high as ten times those in infectious humans. We began a human trial at Oxford in August 2000. In this trial, my brief was to identify and quantify vaccinee-stimulated killer T-cells from vaccinees' blood. I do this using a special test called the enzyme linked immunospot assay to pinpoint the release of molecules called cytokines from activated cells. I also identify memory T-cells, which retain a memory of the offending agent for rapid response in future. This is vital as people will need protection from repeated exposure to HIV without repeated vaccinations.

I also investigate the ability of vaccinees' killer T-cells to kill HIV-infected target cells. This simulates what they do in the prostitutes found uninfected despite repeated exposure, and tells us whether the vaccine is likely to be any good. Meanwhile, I have been cloning a shorter DNA vaccine to complement that already in clinical trials. Within a few hours of HIV infection, cells show on their surfaces virus proteins called rev, tat and nef. The new construct will cause the body to recognise these early HIV proteins and hence be able to attack the virus before it has time to spread.

We will know with certainty that the vaccine works only when certain vaccinees become exposed to HIV by virtue of their work and remain uninfected.

But I am optimistic that perhaps, when I visit KimChwere's family in Mumias, western Kenya, in early June, I will be able to say: "Yes, an Aids vaccine is possible."

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