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TropIKA.net Partnerships

Malaria research: putting African scientists on the front line

23 Apr 2009

Tatum Anderson

Source: TropIKA.net

World Malaria Day this year marks a moment when the international community has intensified its battle against malaria.

From New York to Oslo, the community has launched initiatives aimed at eliminating the disease as a public health problem, and eventually eradicating it. Just one week before World Malaria Day a $225m subsidy for malaria drugs – the Affordable Medicines Facility for malaria (AMFm) – was launched in Norway. It will be administered by the Geneva-based Global Fund for AIDS, TB and Malaria. There are also an increasing number of success stories to report; WHO has announced that Zambia has halved deaths from malaria compared with 2000.

But this sort of global attention is a world away from the experiences of Professor Wen L Kilama, a Tanzanian scientist and professor of parasitology, whose career has run curiously in parallel with recent history of malaria.

A barely-noticed disease

Although his PhD focused on malaria vector genetics in the sixties, Professor Kilama later drifted on to other diseases – because malaria was not considered a major problem in 1970s Tanzania.

That belief persisted for the much of the decades to come but, during his 17-year tenure as founding director-general of Tanzania’s National Institute for Medical Research (NIMR), Kilama’s team began to uncover evidence of some of the first cases of chloroquine-resistance in Africa. Subsequent work revealed a mounting need for a new focus on malaria, not only in Tanzania but across the continent.

The international community barely noticed in those early days. “At that time malaria was a neglected disease,” he says. “Today there is so much in terms of malaria research and control. These things did not exist before.”

But even with today’s attention on malaria, there is far less focus on ensuring that it is African scientists who are on the front line of efforts to eliminate the disease in their own countries. This is despite the fact that Africa is where malaria strikes the hardest. About 800,000 Africans – mainly children younger than five – die from malaria each year, a figure that represents over 90% of the global mortality.

AMANET

This is where the African Malaria Network Trust (AMANET), which Kilama helped to found, plays its part. Based in Dar-es-Salaam, Tanzania, this pan-African, non-governmental organization equips African medical research centres with the kit and skills they need to run malaria vaccine trials in partnership with the international community.

AMANET’s work has so far led to an international stamp of approval for research centres, from Burkina Faso to Tanzania, which now carry out trials. But crucially, AMANET takes on the sponsorship for vaccine trials itself.

So far it has sponsored trials of several candidate vaccines – MSP3, GMZ2 and AMA1.

It’s an unusual situation. “We are the only African institution that has ever sponsored a malaria vaccine trial. It’s an enormous responsibility,” says Kilama, who acts as the managing trustee of AMANET.

Today, a host of other organizations is funding trial site developments all over Africa for the same reason as AMANET. The Malaria Clinical Trials Alliance (MCTA), for instance, is a project run in partnership with the US-based Malaria Vaccine Initiative (MVI) and the Medicines for Malaria Venture (MMV), to train personnel and improve facilities and infrastructure in 10 countries across Africa.

Most recently, both MCTA and MVI have been working on trial sites for the upcoming Phase III trial of the RTS,S malaria vaccine that MVI and GlaxoSmithKline Biologicals have been developing.

However, it is usually the patent holders that assume sponsorship of the trials – as GlaxoSmithKline has done on the RTS,S trials. Occasionally they import clinical research organizations.

AMANET’s role as sponsor is one way to increase participation of African scientists. However it is also working in other ways. It is the first African organisation to host the Multilateral Initiative on Malaria (MIM) secretariat, an alliance created in 1997 to increase African participation in the development of tools and research in malaria endemic counties of Africa. That role has previously been filled by the Wellcome Trust in the UK, Fogarty International Center (FIC) of the National Institutes of Health (NIH) in the US and the Karolinska Institutet in Sweden. (Kilama is also on MIM’s strategic advisory board).

The secretariat role also means organising the world’s largest scientific meeting devoted entirely to malaria research and control in Africa later this year. AMANET is co-organising the Nairobi conference with the Kenya Medical Research Institute (KEMRI).

The results of these appointments are already clear says Kilama. Judging from the number of registered applicants and papers submitted to this year’s conference, African participation has risen considerably. “The running of the conference was not in African hands,” he says. “Now you can see more young and seasoned African researchers taking part.”

Time to change the picture

That there has been insufficient participation for many years is, at least in part, down to a lack of resources and weak infrastructure. Researchers in developing countries have traditionally had very limited capacity to conduct clinical research.

Kilama says it is essential to change the picture. “You need to establish an institution to develop capacity right where it is needed. Otherwise African capacity would be left behind,” he says.

But conducting trials in Africa with more home-grown scientists is also a question of ethics too (1). The rights and wellbeing of research participants, especially of highly vulnerable groups that are victim to high disease rates, low education rates, rampant poverty, and frequent human rights abuses, must be protected.

“We thought it was, in a way, unethical that [researchers] come to Africa and do what they want to do, get involved minimally, and then leave,” he says.

Of course there are well-established, equipped and internationally-renowned clinical research centres in Africa already. However, AMANET’s focus is to bring the many other institutions – sometimes flagship national medical research organizations – up to international clinical trial standards.

Its first project was to turn around Burkina Faso’s Centre de National Recherché et de Formation sur le Paludisme (CNRFP), based in the capital Ouagadougou.

AMANET has so far funded the training of seven CNRFP staff – five up to PhD and two to MSc level. Importantly, the staff at the centre have been offered grounding in research ethics, good clinical practice, data management, institutional management and the procedural techniques to complete trials according to international, clinical and ethical standards. For instance, the staff have received training to handle the relevant immunological assays that support the clinical trials.

The West African site has since participated in the phase Ib trial of the merozoite surface protein – long synthetic peptide (MSP3 LSP) candidate vaccine.

Other sites have also received the AMANET treatment. The Tanga site of NIMR in Tanzania has since participated in this trial too.

The plan is to get two more centres up and running by 2011; Zambia’s Tropical Diseases Research Centre (TDRC) in Ndola and Uganda’s Makerere University.

Other sites have not received the full capacity-building treatment, but qualified for small funds to fill gaps before trials could start – AMANET funded a health centre at the site in Mali for example.

Beyond workshops there are also from workshops to web-based courses in topics as diverse as health research ethics. AMANET has provided funds to strengthen institutional ethics review committees; there’s an online Health Research Ethics discussion forum for members across Africa and AMANET has even received funding to establish an ‘Ask the Expert/Ethicist’ facility so that individual researchers and ethics committee members can pose ethical dilemmas they come across in the field to experts.

Sponsoring trials, however, is also a major focus for the organisation.

Today, AMANET is sponsoring the phase IIb trials of MSP3 in healthy children aged 12-48 months at a trial site in Mali.

Sponsorship works like this: EMVI, which helps accelerate European vaccine science research, helps candidate vaccines get to basic manufacturing stages and then onto Phase Ia trials. It then hands off projects to AMANET.

For instance, EMVI has sponsored initial European trials of a recombinant blood stage candidate vaccine, called GMZ2, which had been developed at Statens Serum Institut (SSI) in Denmark. It is a promising hybrid molecule with two potential targets on the malaria parasite; MSP3 and another called glutamate-rich protein (GLURP).

Now AMANET has begun sponsoring later stage clinical trials of GMZ2 in Gabon, the Gambia, CNRFP in Burkina Faso, and Makerere University in Uganda. (The trials are funded, ironically, by a €5million grant from EDCTP which is headed up by Charles Mgone, ex-deputy of AMANET).

It is now about halfway through the Phase Ib trial in children and will progress onto IIb trial of children between one and five years old during the second quarter next year says Egeruan Babatunde Imoukhuede, director of clinical and regulatory affairs at EMVI, who works closely with AMANET.

Some result in failed candidates. Trials of the antigen AMA1 which AMANET has sponsored have been abandoned and the candidate returned to the drawing board.

Challenges lie ahead

A number of problems loom large on the horizon.

A massive surge in demand for malaria vaccine trial sites is imminent – ironically - because of successful malaria control efforts. A few years ago, a few thousand people might have been sufficient for a Phase III trial but trials of the RTS,S vaccine will, in contrast, require around 16,000 children and 11 trial sites (with an option for one more).

Increased malaria controls such as malaria treatments and insecticide-treated bed nets, have had the effect of reducing malaria transmission dramatically in many areas. As a result, clinical researchers need thousands more trial participants to be able to detect statistically significant changes in the incidence of the disease in the population resulting from a trial vaccine.

“When you look at the clinical trials map, you find places where clinical trials have been going on for some time but we are also seeing declining incidence rates of malaria there,” says EMVI’s Imoukhuede.

As a result, other vaccines reaching Phase III trials later than RTS,S may run into problems. Finding research participants near existing sites, where many have already have taken part in the first phase III trial, is going to be a challenge. As Imoukhuede puts it, “I have a fear that there will be volunteer fatigue.”

The problem is not just one for AMANET, but for the malaria research community in general. There are still not enough viable trial sites in many countries. Nigeria, Africa’s most populous country, has none he adds.

AMANET’s six main sites are unlikely to be sufficient for such large-scale trials, admits Kilama. He reckons that it is hard to do more because training and equipping sites is such a costly business. Each site requires up to €1 million to develop fully and AMANET is entirely dependent on grants. And although the financial situation at the NGO is fine currently, the global recession has yet to make its effects clear.

But developing sites is not just about equipping researchers with the skills and infrastructure they need to carry out their jobs. There must be ways to entice them away from taking their newly-acquired skills to highly-paid posts in the North too, says Kilama. That means areas where researchers live with their families, and educate their children must also have investment.

A busy and crucial role

What is clear is that AMANET’s role will be crucial in future international efforts to eliminate malaria. It is still looking for more vaccine candidates – perhaps orphan projects and plans to focus too on diagnostic tools that will be necessary as malaria transmission decreases further.

That’s because the traditional ways to spot malaria – the presence of fever – are no longer good indicators that a child has malaria in many areas.

“Now we are getting to the point where those with a fever do not necessarily have malaria and we need new tools that will tell you what it is,” he says.

It is even considering whether to develop the really promising leads from the many phyto-chemists and ethno-botanists scanning natural products for anti-malarial properties.

What’s clear is that there is plenty of work to do. Putting off a proper retirement to work at AMANET has been a good move says Kilama. “I am busier than before I retired. I have a very competent team from Kenya, Zimbabwe, Congo; English and French. It is much more enjoyable than if I went to my home.”

Reference

1. Nyika A, Kilama W, Chilengi R, Tangwa G, Tindana P, Ndebele P, Ikingura J (2009). Composition, training needs and independence of ethics review committees across Africa: are the gate-keepers rising to the emerging challenges? J Med Ethics; 35(3): 189-193. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19251972

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