Tropical Health Matters

Wen Kilama of the African Malaria Network Trust brought a challenging idea to the malaria researchers gathered at MIM’s 5th Pan-African Malaria Conference on Tuesday. He explained that while we have a strong tradition of biomedical ethics that protect the individual from harm in research trials, we do not have a clear code of ethical processes, not the mechanism to oversee and regulate these for public or population health research.

His thoughts are also expounded in a current article in a supplement to Acta Tropica and ask us to consider difficult questions such as weighing individual protection and public benefit of an intervention beijng tested.  Examples of these have included immunization regimens, water fluoridation and iodization of salt. In malaria research we also must consider individual freedoms and choices balanced against the community protective effects of indoor residual spraying or wide coverage long lasting insecticide treated net (LLIN) campaigns.

Dr Kilama raised an interesting ethics about the distribution of two different types of LLINs.  One is a polyester multifiber net with insecticide coated yarn has received only Phase 2 approval from WHOPES, which approves insecticides for human safety. The other is a polyethylene monofilament net with insecticide incorporated into the yard. This has received Phase 3 WHOPES approval.  Ironically three times as many of the former were made available to the public than the later in recent years. Is this ethical?

Dr Kilama also raised an equity issue – how can we justify testing health interventions like LLINs on rural poor people who bear the greatest malaria burden when at the start of most programs, it is better off urban people who can afford the nets?

Corporate social responsibility also plays a role after research and testing for regulatory approval have been done. The manufacturers of the monofilament polyethylene nets have made provision for royalty free transfer and have already set up operations in one African country and are ready to move into others.  Their first African factory employs 6,000 people locally and has a positive economic impact on at least 30,000 in the community.

Ethical considerations in a population/public based research like vector control is complex. Community awareness and consent processes come at the start, but then effort must be made to enlist the informed participation of households and individuals.  Ghana’s Navrongo community research facility was mentioned as an example of an institution that has a codified community ethics process.

Dr Kilama called on the public health research community, and especially community malaria researchers, to develop consensus ethical procedures for community studies.

The first Plenary session of the Multilateral Initiative for Malaria’s 5th Pan African Malaria Conference in Nairobi started with Awa Coll-Seck, the Executive Director of Roll Back Malaria, emphasizing the role of malaria research in the Global Malaria Action Plan (GMAP).  She explained that the GMAP drew on malaria programming experiences over recent years to outline six main needs and directions for malaria research that will guide us from current control efforts into the future. These needs include –

• continuous research at each stage along the pathway, as well as continuous training of malaria researchers and all levels of malaria programming staff
• knowledge to help focus interventions locally and the burden of disease is changing and varies within and among countries
• how to achieve sustainability that reduces cases, reduces deaths and leads to eradication
• continuous advocacy for research and programming funds to see us through 2040 and beyond and based on evidence generated by program research and evaluation
• greater attention to social and cultural aspects of malaria control including community ownership and community systems strengthening
• maintaining a strong malaria partnership of diverse members including the research community

The importance of operations research (OR) in this process was stressed by Dr Robert Newman, the Director of WHO’s Global Malaria Program. Tying in with Dr Coll-Seck’s call for generating local research, Dr Newman noted the importance of enhancing the local decision making about program choices by using locally generated data.

A major concern expressed during the session was not just the need for more research funds designated specifically for malaria OR.  Very few countries use the availability of up to 10% of funds in their Global Fund Grants to conduct program relevant OR.

In contrast, Dr Newman reported that programs involved with Neglected Tropical Diseases use between 9-20% of their funds on OR.  He saw OR as a was to protect the investment of funds in disease control.

Today’s plenary session emphasized that research in malaria is not just an academic exercise. It generates new tools and helps us overcome program implementation bottlenecks.

Jambo

The Permanent Secretary of the Ministry of Public Health and Sanitation (MPHS), Mark Bor livened up the opening ceremony of the 5th MIM Pan African Malaria Conference in Kenya by encouraging the participants to greet each other in Kiswahili. He then introduced the Honorable Minister of MPHS, Beth Mugo.

The Minister stress key points in a malaria research agenda for the future and the importance of adequate investment in scaling up current and new malaria interventions so that eradication can one day be achieved.  She stressed research needs for …

• better diagnostic tools
• effective and affordable medicines
• vaccine development AND deployment
• community level vector control
• health systems strengthening including human resource capacity development

The Minister reminded the participants of the substantial increases in malaria funding over the past 10 years and the results that are becoming visible such as a 40% reduction in child mortality from malaria in Kenya.  Without sustaining this funding for research and intervention, she noted, we could see a backlash that made the resurgence of malaria after the failed eradication efforts of the 1950s and ‘60s look tame by comparison. Interventions must not only be sustained, but also improved, hence the need for continued research.

A regional approach is needed, the Minister stressed, since ‘mosquitoes don’t know boundaries.’ The Minister called on the malaria community to guarantee equal access of all countries to malaria resources as one country that lacks funds needed for control could help reintroduce malaria to its neighbors.  A regional approach to both funding and research is needed.

Karibu

see MIM Press Center here

Of course the answer to this rhetorical question is a resounding “NO”, but the issues of both equitable and adequate funding for disease research and control efforts continues to be debated. From the following press release one might get a different impression:

The first survey of global public and private investment into R&D (Research and Development) for new products for neglected diseases has found that funding was over US$ 2.5 billion in 2007. The lion’s share of funding – almost 80% – went towards HIV/AIDS, TB, and malaria. Many significant diseases responsible for killing millions of people in developing countries – including pneumonia and diarrhoeal diseases – remain underfunded and collectively received less than 6% of total funding. These are the results of the G-FINDER ‘Global Funding of Innovation for Neglected Disease’ survey, released and published in London today by The George Institute for International Health.

Malaria, according to the report, received 18% of R&D funding.  Just as a reality check, Unicef’s State of the World’s Children in 2008 indicated that globally malaria accounts for directly 8% of under-five age child mortality.  Neonatal and infant deaths attributable to malaria in pregnancy are not differentiated. The impact of malaria is much higher in endemic countries than global estimates imply.

No one is arguing that the solution is a redistribution of the existing pie so that there is more money to search for better treatment for pneumonia, for example. We need a larger pie, which could be a major challenge in these tough economic times.  In fact the impact of the economic downturn on water, sanitation, nutrition and housing, to name a few areas, themselves may have a bigger impact on disease control that R&D dollars.

Recent events such as those at Davos and TED show that some corporations and foundations are trying to keep up their support for disease control and research. More partners need to join the effort.

Mosquito species have clear biting times. The US Centers for Disease Control and Prevention notes that, “Most Anopheles mosquitoes are crepuscular (active at dusk or dawn) or nocturnal (active at night).” Das and Dimopoulos studied one of the most common malaria vectors in Africa and explain that, “Anopheles gambiae mosquitoes exhibit an endophilic (after blood feeding, prefer to rest indoors), nocturnal blood feeding behavior. CDC says that insecticide treated bednets are especially helpful in reducing bites from these night time feeders.

But can mosquitoes tell time? Foster and Kreitzman have written in the Rhythms of Life and “describe how organisms measure different intervals of time, how they are adapted to various cycles, and how light coordinates the time within to the external world.” They review the implications of the ‘biological clock’ for humans but also explain that, “it has played an essential role in evolution and … continues to play a vitally important role in all living organisms.”

In reviewing Rhythms of Life, Harman describes how an understanding of the genetics of time works: “a clock can be constructed of a gene that codes for a protein which acts to inhibit its own production, and a second protein that delays this self-inhibition by a reliable amount of time.” Harman explains that, “the light/dark cycle, provid(es)the crucial link between inner (genetic) and outer worlds,” or an organism.

Das and Dimopoulos studied night time mosquito feeding behavior after exposure to light pulses. They found that “The temporary feeding inhibition after short light pulses may reflect a masking effect of light, an unknown mechanism which is known to superimpose on the true circadian regulation. Nonetheless, the shorter light pulses resulted in the differential regulation of a variety of genes including those implicated in the circadian control, suggesting that light induced masking effects also involve clock components. Light pulses (both short and long) also regulated genes implicated in feeding …”

What can be done with the finding that shows “that the mosquito’s feeding behavior is under circadian control?” Bringing light pulses to the rural Africans may not be feasible, but understanding the genetics behind feeding behavior can have important implications for the development of future mosquito control technologies. As we’ve mentioned many times before, research is continually needed to understand all aspects of malaria transmission since it is not safe to rely on only one tool to eliminate malaria. More funding for malaria research would certainly make 2009 a ‘happy’ new year.

While universal coverage of existing malaria control tools is necessary to achieve 2010 and 2015 targets, moving beyond such scale-up toward elimination requires a thorough examination and reappraisal of these tools and the way they are applied. A special supplement to Malaria Journal addresses these concerns.

In his introductory editorial to the special supplement, Marcel Hommel warns that, “The move from control to elimination is actually a quantum leap. If it were once possible to state that all the tools for control were available and that no further research was required, it is doubtful whether elimination could be achieved with those same tools. There is now a need to define a new research agenda and to identify the differences between control and elimination.”  The ten review articles included show that this research agenda includes both basic and applied or operational research. A few highlights follow.

Galinski and Barnwell point out that, “Plasmodium vivax, which has long been neglected and mistakenly considered inconsequential, is now entering into the strategic debates taking place on malaria epidemiology and control, drug  resistance, pathogenesis and vaccines. Thus, contrary to the past, the malaria research community is becoming more aware and concerned about the widespread spectrum of illness and death caused by up to a couple of hundred million cases of vivax malaria each year. ”

Ann Mills and colleagues discuss the economic, financial and institutional challenges that face the renewed call for eradication and intensified control. They point out that some of the key issues requiring research include 1) allocative efficiency of malaria eradication, 2) costs and consequences of the various tools and mixes, 3) extension of coverage of interventions and service delivery approaches, 4) processes of formulating and implementing malaria control and eradication policies, and 5) research on financing issues. They are concerned about equity and decision making at both national and international levels.

Brabin et al. look at the role of monitoring and evaluation in malaria in pregnancy (MIP) control and conclude that, “Large-scale operational research is required to further evaluate the validity of currently proposed (MIP) indicators, and in order to clarify the breadth and scale of implementation to be deployed.” This is especially urgent because MIP interventions currently vary by the type and stability of malaria transmission, which itself may be changing due to large scale intervention to date.

Other reviews address malaria research issues surrounding global warming, vaccines, ACT deployment, the role of drugs in elimination, diagnostics, and integrated vector management.

Finally, the Executive Director of the Roll Back Malaria Partnership calls attention to the research agenda inherent in the newly adopted ‘Global Malaria Action Plan.’ As she explains …

Armed with the Plan’s globally agreed research agenda, partners and advocates can now bring more investment to malaria research and foster further dialogue and innovation. The Global Plan requires a long-term commitment: continued funding is essential in both country implementation and R&D to prevent a re-emergence of malaria. However, the investment is worthwhile.

During the first day of the 2008 Global Ministerial Forum on Research for Health in Bamako we were told that while not every country needs a national airline, all need indigenous health research capacity. How else could the unique ecological, cultural and administrative context for providing appropriate health services be discerned? The objectives for the forum follow:

• Strengthening leadership for health, development and equity
• Engage all relevant constituencies in research and innovation for health
• Increase accountability of research systems

While the forum is featuring improtant processes such as capacity building research ethics, civil society involvement, operations research application, among others, specific health issues like malaria are a subtext running throughout.  Mali itself has been developing strong malaria research capacity, and not surprisingly Ogobara Doumbo, the Director of the Malaria Research and Training Center (MRTC), University of Bamako, is a member of the program committee.

This month in The Lancet Stephen Pincock presents a short biography of Ogobara Doumbo, which starts with a childhood commitment to health care from someone clearly rooted in his culture and thus, able to ground his future health research in his country’s needs.

“One day towards in the late 1960s, a doctor came to visit a small village in eastern Mali where the young Ogobara Doumbo and his family lived. He asked the 10-year-old what he wanted to be when he grew up. “I said, ‘I am planning to be a doctor like you’”, Doumbo recalls. “He was very surprised for a small child to be so convinced he wanted to be a doctor.” Considering Doumbo’s father and grandfather were both traditional healers, perhaps his response was not really so surprising. From that year, Doumbo began travelling with his grandfather to other mountain villages, absorbing his strongly ethical approach to treating ailments ranging from infectious diseases to breast inflammation. “I spent enough time to see his practice and follow him carefully.”

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According to US National Institutes for Health, which is one of the supporter the MRTC, “The MRTC is viewed by many as a model for research centers in developing countries, as its research is planned, directed, and executed by African scientists.” Thus the MRTC can certainly hold pride of place equal to if not greater than a national airline. A small sample of findings from recent MRTC publications include –

• Artesunate-mefloquine is well-tolerated and is as effective as artemether-lumefantrine for the treatment of P. falciparum malaria. Artesunate-mefloquine also prevented more new infections (AMJMH).
• Maps provide valuable information for selective vector control in Mali (insecticide resistance management) and may serve as a decision support tool for the basis for future malaria control strategies including genetically manipulated mosquitoes (Malaria Journal).
• The magnitude of antibody response against Plasmodium falciparum may not be as important as it is believed to be. Instead, the fine specificity or function of the response might be more critical in protection against malaria disease (Acta Tropika)
• Given the delay in the time to first malaria episode associated with HbAS, it would be advisable for clinical trials and observational studies that use this end point to include Hb typing in the design of studies conducted in areas where HbAS is prevalent. (J Infect Dis)
• Altogether, these results suggest that indoor mating is an alternative mating strategy of the M molecular form of An. gambiae. Because naturally occurring mating couples have not yet been observed indoors, this conclusion awaits validation. (J Med Entomol)

Keep track of the Bamako Forum via TropIKA.net and learn more about health systems research, the challenges of eHealth and other health research issues that will affect the future of malaria research.

McRobert and colleagues have published promising findings in PLoS Biology on enzymes needed for malaria parasites to produce gametocytes. They explain that, “Our data predict that in addition to targeting asexual erythrocytic stages, a drug inhibiting Plasmodium PKG could also block parasite transmission to the mosquito, a highly desirable property that would help limit the spread of any drug-resistant parasites. Transmission-blocking drugs would be a powerful tool for reducing the malaria burden in areas endemic for P. falciparum.”

David Baker, a co-author, noted in a press release from the London School of Hygiene and Tropical Medicine that, “The enzyme we have discovered, a protein kinasea, is essential for the development of malaria parasite gametes. Working with genetically modified parasites, in combination with inhibitors of this enzyme, we have demonstrated that it is feasible to block the sexual stage of the life cycle of the malaria parasite. This has exciting implications in terms of improving how we go about tackling malaria. If a drug can be developed that targets this stage of the life cycle, and combined with a curative drug, it would be an important new approach for controlling malaria transmission and the spread of drug resistance.

A 2-in-1 drug that not only treats the disease but prevents transmission would be a most valuable addition to the malaria arsenal. And while the time from drug discovery to a drug on the market may take years, it is important to keep the research pipeline flowing in order to keep ahead of drug resistance. For example, researchers are looking far and wide, and Prudhomme et al. suggest that a “source of marine natural products (may be) marine microorganisms.” Simultaneously it is also important to evaluate continually possible resistance of malaria parasites to existing drugs.

We cannot afford to rest on the laurels of ACTs or sit back in hopes of the perfect vaccine. Research funding for all aspects of malaria control must be boosted.