Tuesday, 6 December 2011

MALARIA: More than a shield: The RTS,S malaria vaccine trial

6 Dec, 2011: Meera Senthilingam
Meera Senthilingam is a freelance science journalist based in London, UK.
Madamani clinic My ride to the clinic

The RTS,S vaccine is one of the most promising malaria vaccine for years, currently doing well in clinical trials. And the benefits of the trial go beyond the vaccine itself, as Meera Senthilingam discovered.
On a recent trip to Kenya, I decided to visit the quiet, coastal town of Kilifi. Unlike the busy, tourist laden beaches of Mombasa just 60 kilometres to the North, Kilifi is scenic, peaceful and far less polluted. But it also has one of the highest prevalences of disease in the country. Its warm, moist climate, combined with a poor population, mean that diseases such as malaria are quite common. As a result, Kilifi is a trial site for many malaria treatments and vaccines, including the RTS,S vaccine, the most developed malaria vaccine to date.
RTS,S has now reached phase III clinical trials involving over 15,000 participants across seven African countries. Of the eleven trial sites across these countries, three are in Kenya, taking place at the Kenya Medical Research Institute (KEMRI) bases in Kisumu in Western Kenya and, of course, Kilifi.
Equipped with a four-wheel drive and a few medical deliveries, Dr Patricia Njuguna, the principle investigator on the Kilifi trial, took me to see how such a large-scale trial works in the field. Our destination was the Madamani dispensary, one of the three clinics conducting the trial within Kilifi.
We passed acres of land where drought was evident by the dry soils followed, surprisingly, by a conserved area of natural forest. But as farmland and forest turned to huts, wells and people going about their daily lives, the car made numerous stops for women and their children to come aboard. Although initially confused as to whether the KEMRI vehicle doubled up as a taxi to increase funding, I soon learned this was all part of the service offered as part of the vaccine trial.
“As well as routine visits, if participants are unwell we provide them access to the facility for free healthcare,” says Njuguna. “Our vehicles come in every day bringing in mothers from various homes. This is coordinated by fieldworkers living within the community who have close contact with the mothers who call them when they need to be seen”.
Our driver was one of these fieldworkers and the women on board had called him that morning about various ailments affecting their children. They joined us for the remainder of the journey so their children could be examined examination by the local clinician.
The trial it seems is not just the testing of a vaccine, but a complete health service, and a very good one at that.
Rapid malaria test Rapid malaria test

Developing a vaccine
In Sub-Saharan Africa, malaria is caused predominantly by infection with the parasite Plasmodium falciparum. Creating a vaccine has been a challenge to date due to the fact that the parasite, and its genome, is larger than bacteria and viruses, the complex nature of the parasite’s life-cycle and the fact that it can alter the proteins on its surface, limiting our ability to design a vaccine to find it and induce an immune response.
“Imagine Joseph and his Technicolor Dreamcoat that’s showing a different colour every time. If you’re trying to take down someone in red and the coat shows blue, you’ll miss it,” says Dr. Njuguna as we draw closer to the dispensary.
“This is the challenge for the vaccine and if it misses it you get malaria. Every time the parasite goes through a life cycle it changes the protein it’s presenting, so your vaccine needs to be very clever”.
Once bitten by an infected mosquito, the parasite enters the body in its immature form, known as a sporozoite, where it then travels to the liver in order to replicate within liver cells before moving on to invade red blood cells. This latter stage is when the main symptoms of disease, such as fever and chills, occur, and it’s also when the rapid production of new proteins takes place as the parasite frantically replicates within the blood cells.
RTS,S aims to overcome these issues of adaptation by targeting the parasite early on in its life cycle the sporozoite stage when the parasite first enters through the skin and travels to the liver This can happen within 3–5 minutes of infection.
When we arrive at the dispensary the first thing I notice is the high degree of organisation on site. As we enter the building, we walk straight into a large waiting room catering comfortably for tens of people at one time. Away from this stems two consultation rooms and a pharmacy. The clinician, Dr Pauline Akoo, is busy examining a child in one of the rooms while the women from our car journey are registered by fieldworkers noting down the symptoms of their children.
The trial targets two age groups of children, both under the age of 5 as this is the group at most risk of infection with malaria. The first cohort is made up of children aged 5 to 17 months and the second are infants aged 6 to 12 weeks all receiving three monthly injections followed by a booster vaccine 18 months later. This is, however, a randomised trial, so half of the participants act as a control group receiving a pretend vaccine. By comparing the number of children experiencing Malaria for the first time within each group, the researchers will see if the vaccine really has an effect.
As I join Dr Akoo for a few of her consultations, mothers bring in children with ear infections, upper respiratory tract infections and fevers. Any child brought in with a fever is given a rapid malaria test to, which diagnoses on site, allowing for immediate prescription of anti-malarials, if need be, while a sample is sent to a lab for confirmation. Medicines for the other ailments are also prescribed.
“Each time the child visits they get an opportunity to be seen by a clinician. Whether they’ve come for screening, vaccination, or some other problem they will always get a thorough medical examination,” says Akoo. This is a complete medical package for participants, and, more importantly, it is free of charge.
With such care provided in an otherwise poor region, it’s easy to imagine the flooding of volunteers to the dispensary but, as with many trials in developing regions, there was some initial anxiety and resistance.
“Initially they were shy because this is a research-naïve area – they don’t understand the difference between research and treatment,” says Akoo. “But with time we have explained the trial and the people realised it would not harm them and there were health benefits.”

Madamani dispensary charter Madamani dispensary charter

Vaccine on the horizon?
RTS,S is the first vaccine to reach Phase III of clinical trials, with Phase II trial results demonstrating 53 per cent protection against malaria in children aged 5 to 17 months. Phase III is currently halfway through its intended timeframe, with encouraging preliminary results published recently in the New England Journal of Medicine.
The early results analysed 6000 of the trial participants across Africa and demonstrated 56 per cent protection against standard clinical malaria and 47 per cent against severe malaria (when the parasite enters the brain). However these results are, again, for a subsection of the study – the cohort aged 5 to 17 months – with results from the infant group expected by the end of 2012.
Without getting our hopes up too high, it does look like a vaccine against malaria could soon become a reality. Even the costs of scaling up and production have been accounted for, with pharmaceutical company GlaxoSmithKline promising to provide it almost at cost price with any return invested back into further improvement of the vaccine.
Although incidence of malaria has been on the decline in recent years, according to the World Health Organization, 781,000 people still died of the disease in 2009 – 90 per cent in Africa. Although a 56 per cent success rate may not sound significant enough to justify rolling the RTS,S out in a wider scale, when the burden of disease is considered globally, it’s certainly worth having. And from what I saw at the dispensary, the RTS,S trial has not only provided a possible shield against malaria, but also improved the understanding, and general well-being, of the people most affected by it.
The KEMRI-Wellcome Trust Research Programme is supported by the Wellcome Trust.

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