Papers by Steffen Borrmann
Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomyci... more Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1.2 g every 8 h), in nine, eight, and ten evaluable patients, respectively. All treatment regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88% (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3 days, respectively. These data suggest that fosmidomycin is a safe and effective treatment for uncomplicated malaria if given for 4 days or more.
Journal of Infectious Diseases, 2002
The hypothesis that repeated treatments enhance acquired immunity against schistosomes by stimula... more The hypothesis that repeated treatments enhance acquired immunity against schistosomes by stimulating strong T helper 2 responses was tested. Schistosoma haematobium-infected schoolchildren were monitored for 3 years. During the first 2 years, children who did not receive chemotherapy were compared with those treated once or repeatedly. After specific immune responses were measured at 24 months, praziquantel was given to all children to clear any schistosome infections. Twelve months later, the infection status of the children was determined and compared with cytokine profiles at month 24, to gain insight into which immunologic profiles can predict resistance or susceptibility to schistosome infections. Repeated treatment led to high specific levels of interleukin (IL)-5 and low interferon-gamma production but did not protect against reinfection. After adjusting for variables, such as sex, age, and infection status at study onset, high levels of parasite-specific IL-10 were a risk factor for reinfection, and high levels of IL-5 were associated with hematuria development.
Infection and Immunity, 2001
We used a panel of nine fusion proteins that contain different Duffy binding-like ␣ (DBL-␣) domai... more We used a panel of nine fusion proteins that contain different Duffy binding-like ␣ (DBL-␣) domains of Plasmodium falciparum-infected erythrocyte membrane protein 1 to assess the levels of antibody activity in serum samples obtained from semi-immune or nonimmune individuals from Lambaréné, Gabon. Recognition was measured in terms of either the prevalence or the magnitude of the response. A strong correlation between the immune status of the patients and reactivity with recombinant proteins was observed, which was interpreted as a reflection of the number of infections acquired over time. The antibody responses were predominantly directed toward variable epitopes of the DBL-␣ domain. Antibody responses could be reduced by preincubation of the sera with various fusion proteins. A portion of individuals who exhibited high-level responses to all fusion proteins also had antibodies which recognized conserved epitopes. The possibility that a synergizing effect of anti-DBL-␣ domain antibodies could support chemotherapy is discussed.
Journal of Infectious Diseases, 2001
Recently, artemisinin derivatives have been shown to be efficacious in chemoprophylaxis of and ch... more Recently, artemisinin derivatives have been shown to be efficacious in chemoprophylaxis of and chemotherapy for Schistosoma japonicum and S. mansoni infections. Therefore, a double-blind, randomized, placebo-controlled study was carried out to investigate the efficacy and tolerability of artesunate plus placebo and the combination of artesunate and praziquantel in the treatment of S. haematobium infections in Gabon. The 300 infected schoolchildren included in the study were randomized to receive artesunate plus placebo (n=90), praziquantel plus placebo (n=90), artesunate and praziquantel (n=90), or only placebo (n=30). End points were efficacy, assessed as cure on day 56, and tolerability. All treatment regimens were well tolerated. The praziquantel plus placebo-treated group attained a cure rate of 73%, artesunate plus placebo a rate of 27%, the combination of artesunate and praziquantel a rate of 81%, and placebo alone a rate of 20%. In summary, earlier findings of efficacy of artemisinin derivitives against S. mansoni and S. japonicum could not be confirmed in S. haematobium infections.
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2004
The Chinese medicinal plant Artemisia annua L. (Annual Wormwood) contains the antimalarial compou... more The Chinese medicinal plant Artemisia annua L. (Annual Wormwood) contains the antimalarial compound artemisinin. The locally grown herb may offer an additional tool for the control of malaria, especially in poor countries where modern antimalarial drugs are often unavailable. In an open, randomized, controlled pilot trial, we investigated the efficacy and safety of traditional tea preparations of Artemisia annua in
Parasitology Research, 2003
In malaria parasites, isoprenoids are synthesised by the mevalonate independent 1-deoxy-D-xylulos... more In malaria parasites, isoprenoids are synthesised by the mevalonate independent 1-deoxy-D-xylulose 5-phosphate (DOXP) pathway. Fosmidomycin, a natural antibiotic originally developed for the treatment of bacterial infections, represents an inhibitor of DOXP reductoisomerase, an essential enzyme of this pathway. In recent clinical studies it was shown that fosmidomycin is effective in curing uncomplicated Plasmodiumfalciparum malaria in humans. The treatment was well
Tissue Antigens, 2004
Several studies have shown an inverse association between helminth infections and atopy, but none... more Several studies have shown an inverse association between helminth infections and atopy, but none have clearly established that the pathogens themselves, rather than other associated factors, cause the suppression of atopy. To show a direct link, prospective intervention studies are required. A randomized, controlled trial was performed to study whether repeated anthelminthic treatment results in increased allergic sensitivity to house dust mites (HDMs) in chronically infected children. The trial population consisted of 317 Gabonese schoolchildren with a high prevalence of intestinal helminths. Intervention consisted of treatment every 3 months with praziquantel and mebendazole and with placebo in the control group. Follow-up lasted 30 months: at 6-month intervals, skin-test sensitivity to mites, helminth infection status, and levels of total IgE were determined. Treatment resulted in a significant increase in the rate of developing skin sensitivity to HDMs (hazard ratio, 2.51; 95% confidence interval, 1.85-3.41), which was mediated, in part, by reductions in Ascaris and/or Trichuris infections. Levels of total IgE were reduced, but this did not mediate the effect of treatment on skin-test reactivity. Anthelminthic treatment of chronically infected children results in increased atopic reactivity, which indicates that helminths directly suppress allergic reactions.
Human vaccines
Eukaryotic pathogens typically follow a complex life cycle, including host switch and morphologic... more Eukaryotic pathogens typically follow a complex life cycle, including host switch and morphologically distinct forms. Parasite stage conversion offers exceptional opportunities for whole organism vaccine development. In case of Plasmodium, the causative agent of malaria, disease is exclusively caused by asexual blood stages that invade and replicate within erythrocytes. Pathogenic blood stage infections are preceded by a silent parasite growth phase inside the liver. Two alternative experimental whole organisms vaccine strategies that lead to arrested Plasmodium liver stages elicit potent, lasting immunity against re-infection. Live irradiation- or genetically arrested parasites are metabolically active and correspond to classical attenuated vaccines. Specific antimalarial treatment during experimental natural sporozoite infections prevents a febrile malaria episode and, simultaneously, induces effective anti-liver stage immunity. Translation of these strategies into a safe, afforda...
PloS one, 2011
In sub-Saharan Africa, Plasmodium falciparum and hepatitis A (HAV) infections are common, especia... more In sub-Saharan Africa, Plasmodium falciparum and hepatitis A (HAV) infections are common, especially in children. Co-infections with these two pathogens may therefore occur, but it is unknown if temporal clustering exists. We studied the pattern of co-infection of P. falciparum malaria and acute HAV in Kenyan children under the age of 5 years in a cohort of children presenting with uncomplicated P. falciparum malaria. HAV status was determined during a 3-month follow-up period. Among 222 cases of uncomplicated malaria, 10 patients were anti-HAV IgM positive. The incidence of HAV infections during P. falciparum malaria was 1.7 (95% CI 0.81-3.1) infections/person-year while the cumulative incidence of HAV over the 3-month follow-up period was 0.27 (95% CI 0.14-0.50) infections/person-year. Children with or without HAV co-infections had similar mean P. falciparum asexual parasite densities at presentation (31,000/µL vs. 34,000/µL, respectively), largely exceeding the pyrogenic threshol...
PloS one, 2014
Recent multi-centre trials showed that dihydroartemisinin-piperaquine (DP) was as efficacious and... more Recent multi-centre trials showed that dihydroartemisinin-piperaquine (DP) was as efficacious and safe as artemether-lumefantrine (AL) for treatment of young children with uncomplicated P. falciparum malaria across diverse transmission settings in Africa. Longitudinal follow-up of patients in these trials supported previous findings that DP had a longer post-treatment prophylactic effect than AL, reducing the risk of reinfection and conferring additional health benefits to patients, particularly in areas with moderate to high malaria transmission. We developed a Markov model to assess the cost-effectiveness of DP versus AL for first-line treatment of uncomplicated malaria in young children from the provider perspective, taking into consideration the post-treatment prophylactic effects of the drugs as reported by a recent multi-centre trial in Africa and using the maximum manufacturer drug prices for artemisinin-based combination therapies set by the Global Fund in 2013. We estimated...
The American journal of tropical medicine and hygiene, 2005
Direct data entry, using handheld computers, may simplify and streamline data management, especia... more Direct data entry, using handheld computers, may simplify and streamline data management, especially in remote settings. We compared the accuracy of data entry using the current standard practice (a paper-based case report form with double data entry) with that using a personal digital assistant (PDA) in a clinical study in rural Gabon. The rate of discrepant entries was 1.7%. Categorical data (presented in "pull down" menus on the PDA) were more commonly discrepant than were continuous "typed in" data (2.4% versus 1.2%; P = 0.001). Both systems functioned smoothly and no data were lost. The clinicians involved in this study preferred the handheld computers, and their use will be considered in future studies in an African clinical research network.
The American journal of tropical medicine and hygiene, 2004
We have evaluated the accuracy of a simple and inexpensive photometric device (DHT) for the estim... more We have evaluated the accuracy of a simple and inexpensive photometric device (DHT) for the estimation of the blood concentration of hemoglobin by comparison with an automated, high-resolution, flow cytometry-based hematology analyzer (CellDyn 3000) and a centrifugal quantitative buffy coat hematology system (QBC I). We have analyzed the hemoglobin values of 163 individual blood samples. Bland-Altman analysis showed that the methods agreed only poorly: mean differences were 1.0 g/dL with limits of agreement (LOA) of -1.2 g/dL to 3.2 g/dL for the comparison of DHT and CellDyn measurements, 0.5 g/dL with LOA of -2.0 g/dL to 3.0 g/dL for the comparison of DHT with QBC measurements, and 0.5 g/dL with LOA of -1.1 g/dL to 2.1 g/dL for the comparison of QBC with CellDyn measurements. We conclude that the poor agreement of the DHT with the CellDyn does not permit the use of the DHT for critical hemoglobin measurements, particularly in transfusion services.
Vaccine, Jan 14, 2014
Experimental whole-parasite immunization through concurrent administration of infectious Plasmodi... more Experimental whole-parasite immunization through concurrent administration of infectious Plasmodium sporozoites with drugs that prevent pathogenic blood-stage infection represents the current benchmark in malaria vaccine development. Key questions concerning translation remain, including the requirement for single-dose drug regimens that can reliably prevent breakthrough infections. We assessed the feasibility and efficacy of immunization with single-dose piperaquine chemoprophylaxis and concurrent sporozoite administration (PPQ-CPS) in the murine P. berghei ANKA/C57BL/6 infection model. We demonstrate that PPQ-CPS is protective with an efficacy comparable to previous findings using whole-parasite immunization under chloroquine chemoprophylaxis. PPQ-CPS immunization resulted in an expansion of intrahepatic and intrasplenic effector memory CD8(+) T cells. In summary, PPQ-CPS appears to be a safe and efficacious immunization regimen in the rodent malaria model and may thus become an i...
Background. Selection by host immunity and antimalarial drugs has driven extensive adaptive evolu... more Background. Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation.
Nature Communications, 2014
Malaria is a major public health problem that is actively being addressed in a global eradication... more Malaria is a major public health problem that is actively being addressed in a global eradication campaign. Increased population mobility through international air travel has elevated the risk of re-introducing parasites to elimination areas and dispersing drug-resistant parasites to new regions. A simple genetic marker that quickly and accurately identifies the geographic origin of infections would be a valuable public health tool for locating the source of imported outbreaks. Here we analyse the mitochondrion and apicoplast genomes of 711 Plasmodium falciparum isolates from 14 countries, and find evidence that they are non-recombining and co-inherited. The high degree of linkage produces a panel of relatively few single-nucleotide polymorphisms (SNPs) that is geographically informative. We design a 23-SNP barcode that is highly predictive (B92%) and easily adapted to aid case management in the field and survey parasite migration worldwide.
eLife, 2014
Malaria transmission is spatially heterogeneous. This reduces the efficacy of control strategies,... more Malaria transmission is spatially heterogeneous. This reduces the efficacy of control strategies, but focusing control strategies on clusters or 'hotspots' of transmission may be highly effective. Among 1500 homesteads in coastal Kenya we calculated (a) the fraction of febrile children with positive malaria smears per homestead, and (b) the mean age of children with malaria per homestead. These two measures were inversely correlated, indicating that children in homesteads at higher transmission acquire immunity more rapidly. This inverse correlation increased gradually with increasing spatial scale of analysis, and hotspots of febrile malaria were identified at every scale. We found hotspots within hotspots, down to the level of an individual homestead. Febrile malaria hotspots were temporally unstable, but 4 km radius hotspots could be targeted for 1 month following 1 month periods of surveillance.
Scientific Reports, 2013
Early identification of causal genetic variants underlying antimalarial drug resistance could pro... more Early identification of causal genetic variants underlying antimalarial drug resistance could provide robust epidemiological tools for timely public health interventions. Using a novel natural genetics strategy for mapping novel candidate genes we analyzed .75,000 high quality single nucleotide polymorphisms selected from high-resolution whole-genome sequencing data in 27 isolates of Plasmodium falciparum. We identified genetic variants associated with susceptibility to dihydroartemisinin that implicate one region on chromosome 13, a candidate gene on chromosome 1 (PFA0220w, a UBP1 ortholog) and others (PFB0560w, PFB0630c, PFF0445w) with putative roles in protein homeostasis and stress response. There was a strong signal for positive selection on PFA0220w, but not the other candidate loci. Our results demonstrate the power of full-genome sequencing-based association studies for uncovering candidate genes that determine parasite sensitivity to artemisinins. Our study provides a unique reference for the interpretation of results from resistant infections.
Tropical Medicine & International Health, 2010
objectives Artemether-lumefantrine (AL) is first-line treatment for uncomplicated malaria in many... more objectives Artemether-lumefantrine (AL) is first-line treatment for uncomplicated malaria in many African countries. Concomitant food consumption may affect absorption of lumefantrine but data in the most important target population, i.e. children, are lacking. Therefore, we evaluated the effect of food intake on oral lumefantrine bioavailability in African children with malaria.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2002
Increasing resistance of Plasmodium falciparum to antimalarial drugs presents a major risk factor... more Increasing resistance of Plasmodium falciparum to antimalarial drugs presents a major risk factor for people living in endemic areas of tropical Africa. In Lambark& Gabon, regular surveillance of chloroquine sensitivity of l? falciparum in vitro has been carried out since 1992 using the WHO standard microtest. Results indicated that from 1994 onwards chloroquine resistance in vitro decreased significantly and that by 2000, about 70% of parasite isolates seemed to be sensitive to chloroquine in vitro. In 2001, we conducted a clinical study to reassess the eficacy of chloroquine in vivo for the treatment of uncomplicated P. falciparum malaria. Twenty-six patients aged 4-15 years were included in this study.
PLoS ONE, 2011
Background: The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highl... more Background: The emergence of artemisinin-resistant P. falciparum malaria in South-East Asia highlights the need for continued global surveillance of the efficacy of artemisinin-based combination therapies.
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Papers by Steffen Borrmann