Health research ethics in malaria vector trials in Africa.

Malaria mosquito research in Africa as elsewhere is just over a century old. Early trials for development of mosquito control tools were driven by colonial enterprises and war efforts; they were, therefore, tested in military or colonial settings. The failure of those tools and environmental concerns, coupled with the desperate need for integrated malaria control strategies, has necessitated the development of new malaria mosquito control tools, which are to be tested on humans, their environment and mosquito habitats. Ethical concerns start with phase 2 trials, which pose limited ethical dilemmas. Phase 3 trials, which are undertaken on vulnerable civilian populations, pose ethical dilemmas ranging from individual to community concerns. It is argued that such trials must abide by established ethical principles especially safety, which is mainly enshrined in the principle of non-maleficence. As there is total lack of experience with many of the promising candidate tools (eg genetically modified mosquitoes, entomopathogenic fungi, and biocontrol agents), great caution must be exercised before they are introduced in the field. Since malaria vector trials, especially phase 3 are intrusive and in large populations, individual and community respect is mandatory, and must give great priority to community engagement. It is concluded that new tools must be safe, beneficial, efficacious, effective, and acceptable to large populations in the short and long-term, and that research benefits should be equitably distributed to all who bear the brunt of the research burdens. It is further concluded that individual and institutional capacity strengthening should be provided, in order to undertake essential research, carry out scientific and ethical review, and establish competent regulatory frameworks.

Engaging diverse communities participating in clinical trials: case examples from across Africa.

BACKGROUND: In the advent of increasing international collaborative research involving participants drawn from populations with diverse cultural backgrounds, community engagement becomes very critical for the smooth conduction of the research. The African Malaria Network Trust (AMANET) is a pan-African non-governmental organization that sponsors and technically supports malaria vaccine trials in various African countries. CASE DESCRIPTION: AMANET sponsored phase Ib or IIb clinical trials of several malaria vaccine candidates in various Africa countries. In Burkina Faso, Mali and Tanzania trials of the merozoite surface protein 3 -- in its Long Synthetic Peptide configuration (MSP3 LSP) -- were conducted. In Mali, the apical membrane antigen 1 (AMA1) was tested, while a hybrid of glutamate rich protein (GLURP) and MSP3 (GMZ2) was tested in Gabon. AMANET recognizes the importance of engaging with the communities from which trial participants are drawn, hence community engagement was given priority in all project activities conducted in the various countries. DISCUSSION AND EVALUATION: Existing local social systems were used to engage the communities from which clinical trial participants were drawn. This article focuses on community engagement activities employed at various AMANET-supported clinical trial sites in different countries, highlighting subtle differences in the approaches used. The paper also gives some general pros and cons of community engagement. CONCLUSIONS: Community engagement enables two-way sharing of accurate information and ideas between researchers and researched communities, which helps to create an environment conducive to smooth research activities with enhanced sense of research ownership by the communities.

Towards an African-driven malaria vaccine development program: history and activities of the African Malaria Network Trust (AMANET).

The African Malaria Network Trust (AMANET), whose mission is to promote capacity strengthening of African malaria research institutions, was founded in 2002 and is currently focusing on malaria vaccine development. AMANET has trained over 900 African malaria researchers at workshops relevant to clinical trials of candidate malaria vaccines that will meet scientific, ethical, and international Good Clinical Practice standards. African centers selected for developing malaria vaccines initially undergo a needs assessment, followed by filling gaps in short- and long-term training, provision of essential equipment, and infrastructure improvement. Four centers from different malaria ecoepidemiologic settings are being strengthened; two of these have been approved for carrying out malaria vaccine trials. Researchers from prospective trial sites are mentored at northern institutions undertaking Phase 1a and/or 2a trials; five researchers are undergoing doctoral training. AMANET has sponsored one successful Phase 1b trial; three more are underway. Expert site audits will precede launch of phase 2b trials. Several lessons have been learned: the building of comprehensive capacity, essential for undertaking internationally acceptable trials including their sponsorship, is complex and costly. AMANET has spent over US$ 1 million on capacity strengthening of its leading trial center. Despite the high costs, development of three other sites is underway and there are plans to develop two more sites. To succeed, genuine north-south collaboration based on mutual trust and sharing of available information and responsibilities has been essential. AMANET as a sponsor has assumed roles usually reserved for the pharmaceutical industry, yet is operating where regulatory authorities are generally weak or wanting.

Multilateral initiative on malaria: justification, evolution, achievements, challenges, opportunities, and future plans.

Malaria is a major public health problem; about half of the world's populations live under exposure. The problem is increasing in magnitude and complexity because it is entwined with low socio-economic status, which makes African women and children particularly vulnerable. Combating malaria therefore requires concerted international efforts with an emphasis on Africa. The Multilateral Initiative on Malaria (MIM) was founded in 1997 to meet that need through strengthening research capacity in Africa, increasing international cooperation and communication, and utilization of research findings to inform malaria prevention, treatment, and control. The review undertaken in 2002 showed that through improved communication and science-focused institutional networks, MIM had brought African scientists together, opened up communication among malaria stakeholders, and provided Internet access to literature. The achievements were made through four autonomous constituents including the coordinating Secretariat being hosted for the first time in Africa by the African Malaria Network Trust (AMANET) for the period 2006-2010. The other constituents are the MIM TDR providing funding for peer-reviewed research; MIMCom facilitating Internet connectivity, access to medical literature, and communication between scientists inside and outside of Africa; and MR4 providing scientists access to research tools, standardized reagents, and protocols. Future plans will mostly consolidate the gains made under the MIM Strategic Plan for the period 2003-2005.

Sixth Africa Malaria Day in 2006: how far have we come after the Abuja Declaration?

Each year on the 25th April Africa and the rest of the world commemorate Africa Malaria Day as was agreed upon at the African Summit on Roll Back Malaria held in Abuja, Nigeria on 25th April 2000. The summit also called upon the United Nations to declare the period 2001-2010 a decade for malaria. The 1st Africa Malaria Day was commemorated with the theme "Communities Play a Central Role in Tackling Malaria". The 6th Africa Malaria Day was observed in 2006 with the theme "Get Your ACT Together" and the slogan "Universal Access to Effective Malaria Treatment is a Human Right". This article by the Secretariat of the Multilateral Initiative on Malaria (MIM) was also part of the commemorations for the day. MIM was founded in 1997 as an alliance of institutions and individuals concerned with the malaria problem, and aiming at maximizing the impact of scientific research on malaria through strengthening African research capacity and coordinated global collaboration. The MIM Secretariat has been hosted in rotation by the founding institutions, and is being hosted for the first time in Africa by the African Malaria Network Trust (AMANET) in Dar es Salaam, Tanzania. This article reviews the malaria situation in Africa six years after the Abuja Declaration, highlighting the disease burden trends, failures, achievements, challenges, and the way forward.

Malaria: current status of control, diagnosis, treatment, and a proposed agenda for research and development.

Rolling back malaria is possible. Tools are available but they are not used. Several countries deploy, as their national malaria control treatment policy, drugs that are no longer effective. New and innovative methods of vector control, diagnosis, and treatment should be developed, and work towards development of new drugs and a vaccine should receive much greater support. But the pressing need, in the face of increasing global mortality and general lack of progress in malaria control, is research into the best methods of deploying and using existing approaches, particularly insecticide-treated mosquito nets, rapid methods of diagnosis, and artemisinin-based combination treatments. Evidence on these approaches should provide national governments and international donors with the cost-benefit information that would justify much-needed increases in global support for appropriate and effective malaria control.

Safety and immunogenicity of the malaria vaccine candidate GMZ2 in malaria-exposed, adult individuals from Lambaréné, Gabon.

Malaria is still one of the major public health threats in sub-Saharan Africa. An effective vaccine could be a sustainable control measure that can be integrated into existing health infrastructures. The malaria vaccine candidate GMZ2 is a recombinant fusion protein of conserved parts of Plasmodium falciparum Glutamate Rich Protein and Merozoite Surface Protein 3 adjuvanted with aluminium hydroxide. GMZ2 is immunogenic and well tolerated in malaria-naive adults from Germany. To assess safety and immunogenicity in malaria-exposed individuals, 40 adults from Lambaréné, Gabon were randomly assigned to receive either 100 µg GMZ2 or a rabies control vaccine three times in monthly intervals. Both vaccines were well tolerated. One month after a full course of vaccination, GMZ2-vaccinated individuals had 1.4-fold (95% confidence interval: [1.1, 1.7]) higher baseline-corrected anti-GMZ2 antibody levels and more GMZ2-specific memory B-cells compared to the rabies group (p=0.039), despite a high prevalence of GMZ2-specific immune reactivity due to previous intense exposure to P. falciparum.

Health research ethics in public health: trials and implementation of malaria mosquito control strategies.

Health research ethics has its roots in protecting individuals participating in clinical trials. There is, however, nascent interest in ethics in public health, although it does not yet cover ethics in the development of public health products. The paper reviews the history of the development of malaria vector interventions, which initially aimed at promoting colonial interests. Attempts at eradicating malaria in Africa ended in 1969, and DDT, the leading malaria vector control tool was banned soon after. Insecticide Treated Nets, which later gave rise to Long Lasting Insecticidal Nets have resurrected malaria mosquito vector control, and their development has set new benchmarks, which it is suggested should be followed by all vector control tools under development. Furthermore, DDT has been exonerated and is back in the vector control arsenal. New tools under development include the sterile male technique, genetically modified mosquitoes, entomopathogenic fungi, and odorants.The paper proposes that these new tools be tested in community settings, abiding by all the leading bioethical principles, and calls for the development and implementation of international ethical guidelines for trials in public health.

The 10/90 gap in sub-Saharan Africa: resolving inequities in health research.

Sub-Saharan Africa (SSA) is worse off in terms of health indicators than any other region of the world, and suffers badly from the 10/90 gap, whereby 90% of the world's investment in health research addresses only 10% of the global health problems. This anomaly in health research investment in SSA is mainly attributed to rampant poverty, weak educational institutions, deficient health research capacity, feeble communications systems and isolation. Translating research results into action, manufacturing and access are also weak. Furthermore, many diseases of poverty are neglected diseases, they receive scanty research attention; there are no new drugs or vaccines for their treatment or prevention. The situation in SSA is made worse by the surge in noncommunicable diseases and injuries. The paper reviews actions taken over the last two decades to resolve the 10/90 gap through: (i) policies prioritizing funding for health research, (ii) developing capacities of credible public and private SSA health research institutions, (iii) activities of international NGOs undertaking research aimed at resolving the gap, and (iv) the setting up of research based mechanisms to ensure access to new effective products for the treatment and prevention of poverty-related diseases. The paper highlights examples for each of the above, and discusses the overall situation. We conclude that despite the many capacity strengthening actions, and achievements made towards resolving the 10/90 gap, the disequilibrium still persists; there is need for greater investments aimed at closing it.

Data safety and monitoring boards for African clinical trials.

The recent increase in funding for diseases endemic in resource-poor countries has led to a progressive rise in the number of trials conducted in Africa for product development purposes or to answer important questions on reduction of disease burden. This causes an increasing demand for data safety monitoring boards (DSMBs) within Africa, where there is currently a shortage of appropriately skilled people. To address this, and in line with capacity-building efforts directed at improved quality research, AMANET invited the authors to create a curriculum and to train selected Africans with the skills required for members of DSMBs. Based on experience, the facilitators made an overview of clinical trial designs, a comprehensive review of data safety monitoring guidelines and other relevant DSMB governance issues. The wealth of guidelines and recommendations available for establishing and running DSMBs focus mainly on trials set in developed countries. The authors drew from these guidelines a practical summary of those relevant for Africa. This interactive process enabled recommendation of a straightforward set of principles to guide the establishment of DSMBs in Africa, which strike that essential balance between protecting trial participants and allowing investigators to answer their scientific questions.