Sonderforschungsbereich 544 “Kontrolle tropischer Infektionskrankheiten” Collaborative Research Center 544 “Control of tropical infectious diseases”

Old, new and re-emerging infectious diseases pose a rising threat to global health, economic growth and development, and will complicate global security in the future. Infectious diseases account for one third of the estimated 54 million annual deaths worldwide. Sub-Saharan Africa (SSA) remains the region most affected, with nearly half of all infectious disease-caused deaths. Twenty wellknown diseases, including malaria and tuberculosis, have re-emerged or spread during the past 30 years and at least 30 previously unknown pathogens, including HIV, have been newly identified. Malaria, tuberculosis, and HIV/AIDS account for the majority of deaths in developing countries now, and will continue to do so in the years to come. Recently, however, political will and social support to mount an effective fight against the deadly epidemics have finally begun to materialize. It is the aim of SFB544 “Control of Tropical Infectious Diseases” to contribute to this fight at all levels.  

This SFB constitutes a unique network which combines basic research projects (identifying drug targets and testing compounds), clinical research projects (implementing new therapies through controlled trials) and public health projects (making sure that those interventions reach the people in need). In the last period, several new projects mostly led by young, highly promising scientists were integrated into SFB544 and a concerted effort was made to strengthen clinical research. The new proposal shows the success of these developments with several ongoing and planned clinical studies and a move towards application-oriented research. Since its implementation in 1999, SFB544 has transformed individual projects targeting specific aspects of tropical infectious diseases into a highly interactive network of closely collaborating groups with a successful track record as measured both by publications and awards and by clinical and public health measures introduced. It is thus beginning to bring its research products “from bench to bedside”. This program is only possible through our long-standing and very fruitful collaboration with the Centre de Recherche en Santé de Nouna (CRSN) in Nouna, Burkina Faso. In the current period, this has been extended to Nouna district hospital, which is transforming into a clinical research centre qualified for international phase II/III drug and vaccine trials. The current funding period has also seen extended collaborations with other clinical, laboratory and public health research partners, in particular linking research at Navrongo (Ghana) and at the Centre Hopitalier Universitaire in Ouagadougou with the CRSN in the context of South-South collaborations. Furthermore, the A7 junior group General Information developed a new interdisciplinary clinical research site in collaboration with the KEMRI centre in Kilifi (Kenya), further enhancing our collaborative network. The majority of SFB544 projects work on malaria, while three projects each address trypanosomatids and HIV/AIDS. A new project targets Dengue fever, today the most common arthropod-borne viral disease worldwide. With an annual incidence of more than 500 million clinically manifest cases and a death toll of at least 1 million, malaria is still one of the most important communicable diseases overall, with 80-90% of the global malaria burden in SSA. Drug resistance of P. falciparum has become a major obstacle in the fight against malaria. Accordingly, development of new drugs against new targets, analysing mechanisms of resistance, and measures to evaluate optimal drug regimens and to devise optimal strategies to bring interventions to those who need them, are of prime importance. All these aspects are therefore central to SFB544. Members of the Trypanosomatidae family are the causative agents of sleeping sickness, Chagas' disease and various forms of Leishmaniasis; very few drugs are currently available against these important pathogens. According to the WHO, sleeping sickness affects more than 60 million people in 36 countries of SSA. HIV/AIDS in the last decade became the single most common cause of death in SSA with an estimated 25 million people living with HIV and 2.2 million dying from AIDS every year. Programs to prevent mother to child transmission and increased availability of antiretroviral therapy are first steps to curb this dramatic development, but drug resistance again presents a major obstacle. Accordingly, projects aiming at new drug targets and resistance studies as proposed in SFB544 are of utmost importance. Dengue virus, a topic newly introduced into our SFB, is another important pathogen on the rise: ~40% of the world population live in areas at risk for Dengue infection due to increased presence of the arthropod vector. In summary, infectious diseases are still a major cause of death worldwide and much more so in SSA. Malaria, trypanosomiasis, AIDS and Dengue contribute dramatically to morbidity and mortality. The central aim and the true potential of SFB544 is to contribute to the fight against these diseases using an integrated approach that links drug development and public health research with clinical research and trials, and at the same time connecting research centres in the North with counterparts in the affected countries of the South.  

General Information

1.2.2 Research programme SFB544 has three comprehensive project areas: Immunology and clinical research (A), New targets for antimicrobial drugs (B) and Interdependence between health system and interventions (D). It consists of a total of 19 individual research projects, two central projects providing essential support in biostatistics and epidemiology (Z2) and in clinical research (Z3), respectively, and a central administration project (Z1). The new proposal integrates two new projects (i) on the important tropical pathogen Dengue virus (B19) and (ii) on cost-effectiveness and value of information analysis for malaria interventions (D9). All projects from the current funding period shall be continued into the next period and no projects are terminated. This SFB proposal comprises a wide range of disciplines and expertises; we will therefore provide an overview of the individual project areas and projects in the next paragraphs, followed by a short description of various layers of integration. Collaborations of major importance are also described for each project, while an overview of all established and planned collaborations for the next funding period is depicted in Table 1.  

General Information A) Immunology and clinical research

Project area A has been further strengthened in the last years by developing our capacity to perform clinical research through implementation of the Z3 central project in Nouna on the one side and through recruitment of the A7 junior group working in Kilifi on the other side. Project area A and project area D also depended most heavily on the demographic surveillance system (DSS) and biostatistical support provided through the central project Z2. An important development in capacity building for clinical research was the instalment of a counterpart system with the continuous presence of one clinical researcher funded through Z3 and one clinical researcher funded through the government of Burkina Faso in Nouna. This led to a major improvement of the clinical service and paved the way for further clinical studies. Currently, the emphasis of work on the research infrastructure concerns improving clinical documentation and implementing searchable databases as essential prerequisite for future studies. Projects A7 and A8 have both successfully completed clinical trials during the current funding period and further trials are proposed in the new application.
In the current funding period, clinical research has been further enhanced and the Nouna district hospital and CRSN have formed an integrated structure for clinical and laboratory research. Since its inauguration, the CRSN has thus grown into an increasingly successful research institute which serves as an important counterpart for many projects of SFB 544. Nine individual projects (A6, A7, A8, B2, B12, D1, D2, D4, D9) as well as the two central projects Z2 and Z3 plan to work together with the CRSN in the next funding period. This is similar in the current period and the success of this interaction is shown by the many joint publications and mutual visits. Interaction also involves teaching both in Nouna and in Heidelberg (see 1.5 and Z1) including the implementation of joint clinical and research steering committees on both sides and two important joint workshops. It should also be emphasized, however, that our collaboration with southern research institutes is not exclusively focused on Nouna. Examples are the work on antiretroviral resistance in HIV (A6) with the University Hospital in Ouagadougou, the work of the SFB junior group (A7) in Kilifi, the multi-site study of project A8 involving other sites in Burkina Faso and Kenya besides Nouna, and the epidemiological study in D1 analyzing data from INDEPTH sites from different countries. Importantly, these interactions not only link Heidelberg with its partners in the South, but also strengthen the network of South-South collaborations which is essential for sustained development of research centres. Examples are the collaboration of the CRSN laboratory with the research centre in Navrongo (Ghana) organized through Z3 in cooperation with the Swiss Tropical Institute, which established in Nouna culturing techniques, serology and a multiplex PCR to identify pneumococci, meningococci and haemophilus influenzae B (HiB), and the collaboration between CRSN and the University Hospital in Ouagadougou on HIV viral load testing (done in Ouagadougou for both sites) and PCR from dried blood spots (done in Nouna for both sites) organized through A6.  

The Z-projects Z2 and Z3:

Building a platform for clinical and epidemiological research The central projects Z2 and Z3 provide essential platforms with almost all SFB projects linking in some part of their research to one or both Z-projects. As shown in Table 1, Z2 interacts with twelve individual research projects and Z3 interacts with ten individual research projects. A major focus of the collaboration between the CRSN and SFB544 is the demographic surveillance system (DSS) which allows a prospective follow-up of an entire population over years and provides the basis for several research projects (e.g. D1, D2, D4). Data analysis and management of the data base is performed through the central project Z2. This is also important for maintaining the role of the CRSN within the INDEPTH network and providing access for SFB projects to data from other General Information INDEPTH sites. Z2 also provides epidemiological and biostatistical support to all SFB projects that need it. This is of course of particular importance for the clinical and public health research projects, and in particular A8 and D4, where Z2 is involved in study design as well as in data analysis and presentation. Biostatistical support is also important e.g. for prevalence studies and this is exemplified by several joint publications with A6. The central project Z3 was initiated in the current funding period to enhance the integration of CRSN and the district hospital and develop it into a high quality clinical research centre. During the current funding period, the clinical diagnostic laboratory of the district hospital and the research laboratory of the CRSN have merged into one single structure which is now located in a new building on the hospital ground. This is an important step to advance clinical research in Nouna and to transfer its benefits into improved patient care. Further important developments for clinical research during the current funding period accomplished by Z3 include:

• Instalment of a counterpart system of clinical researchers in Nouna (one from Heidelberg and one from Burkina Faso)
• Upgrading of clinical services at the district hospital. This has been achieved for the ultrasound unit and emergency care unit, and is currently undertaken for the pediatric service.
• Improving diagnostic services including PCR for pneumococci, meningococci, HiB and HIV in the newly created joint laboratory
• Holding annual clinical workshops in Nouna involving representatives from the national government and from the district to develop an action plan for enhancing clinical performance
• Building a sustainable system for case documentation including searchable electronic databases (currently ongoing together with A6)
• Performing phase II/III clinical studies and thus qualifying Nouna as a clinical trials centre e.g. in the European and Developing Countries Clinical Trials (EDCTP) program.

Through these developments, the restructured clinical unit now has the potential to serve as a study site for clinical trials and for clinical research. Projects A6, A7, A8, B12 and D4 will make direct use of this clinical research platform, which will be maintained and improved through the central clinical project Z3.
Ensuring implementation and evaluating the outcome Developing new drugs and testing their efficacy and safety in clinical trials is an essential step, but will not be sufficient to win the fight against tropical infectious diseases. Bringing the interventions to those who need them at a reasonable cost is a further essential task. Ideally, this should be complemented by outcome analysis that determines the benefit and cost effectiveness of individual measures even in a complex network of interventions. Linking this research, which is often far separated from basic and clinical science, together with drug development and clinical research projects is a unique capacity of SFB544. This includes evaluation of the burden of disease in D1, which also provides essential support in epidemiology and statistics to other projects. Implementation of the community-based insurance in February 2004 has been a major step and it will now be important to define and overcome the reasons for insufficient enrolment. This requires a close interaction with all clinically oriented projects (A6, A7, A8) and with D4, which will pursue optimal distribution of insecticide treated bed nets to young children and pregnant women. The new research project D9 will complement our comprehensive approach towards the fight against tropical infectious diseases by performing cost effectiveness and information validation analysis. Interdisciplinary research and its potential to shape new projects Interdisciplinarity is a hallmark of this SFB which links scientists from the disciplines of parasitology, virology, bioorganic and medicinal chemistry, biochemistry, cell biology, epidemiology, health economics, health system research and clinical medicine. Thus, there is no need to further describe the interdisciplinary nature of the SFB as a whole. We will therefore briefly describe examples of interdisciplinary approaches leading to new research projects and thus making best use of the resources of SFB544.

The clinical study project testing the acceptability, safety and efficacy of MB in combination with other antimalarial drugs originated from the research of H. Schirmer (B2) on the effects of MB on the redox system of the parasite. After receiving the “Dream Action Award” from the company DSM together with B. Kouyaté (then director of CRSN), clinical phase I/II studies were planned within the SFB network. O. Müller (D4) served as principal investigator in this trial with support from T. Junghanss (Z3) and further clinicians in Heidelberg. This trial series was successfully performed in 2003 – 2004, and led directly to the new clinical research project A8. Evaluation of the results also involved the central project Z2. During the current funding period, A8 has shown that the BlueCQ combination is not useful due to high CQ resistance, but the combination with AQ was highly effective. This will now be explored in a significantly larger multi-site phase III equivalence trial in A8 (again supported by B2, Z2 and Z3) which may eventually lead to a new registered malaria combination therapy. Project B14 provides essential chemical synthesis capacity to this SFB which has one focus on new drugs against tropical infectious diseases. The importance of redox buffering networks in both Apicomplexa and trypanosomatids allows application of related approaches in both cases. While targets and compounds will probably differ in detail, general approaches may be similar and there may be even some compounds active against both parasites (e.g. MB). Discussions within the internal SFB seminar also linked B14 with the HIV project B17. O. Keppler presented his exciting results on extracts from lamiaceae inhibiting HIV at nanomolar concentrations and this led to an immediate collaboration with E. Davioud-Charvet (B14) who had access to purified compounds from lamiaceae and, subsequently, their potent inhibition of HIV led to the new joint project B17. Integrating important results obtained outside SFB544 into the SFB project has also been a stronghold of this research network. One good example is the development of project B10 which studies Plasmodium liver stages as target for new drugs. The major breakthrough of this group showing that genetically attenuated parasites can induce protective immunity against parasite challenge, combined with their recent result indicating that drugs active against Plasmodium liver stages may allow pharmacological induction of a protective immune response, redirected B10 towards preclinical application of this strategy in the mouse malaria model as a prelude to a planned clinical study. This exemplifies the motto of SFB544 to bring the results of clinical research into application. Achieving this will strongly rely on the established network and this is already reflected by including S. Borrmann as second project leader in B10. Finally, the presence and success of SFB544 and the Heidelberg research focus on tropical pathogens has influenced other researchers to take on new challenges. The most obvious example is project B19 of R. Bartenschlager whose decision to initiate Dengue research after moving to Heidelberg was influenced by the many options for cooperation within SFB544.