Florian Marks

Seasonal variation and high multiplicity of first Plasmodium falciparum infections in children from a holoendemic area in Ghana, West Africa

Objectiveu2002 To assess the prevalence and multiplicity of Plasmodium falciparum infections in Ghanaian infants.

Malaria incidence and efficacy of intermittent preventive treatment in infants (IPTi).

BackgroundIntermittent preventive antimalarial treatment in infants (IPTi) is currently evaluated as a malaria control strategy. Among the factors influencing the extent of protection that is provided by IPTi are the transmission intensity, seasonality, drug resistance patterns, and the schedule of IPTi administrations. The aim of this study was to determine how far the protective efficacy of IPTi depends on spatio-temporal variations of the prevailing incidence of malaria.MethodsOne thousand seventy infants were enrolled in a registered controlled trial on the efficacy of IPTi with sulphadoxine-pyrimethamine (SP) in the Ashanti Region, Ghana, West Africa (ClinicalTrial.gov: NCT00206739). Stratification for the village of residence and the month of birth of study participants demonstrated that the malaria incidence was dependent on spatial (range of incidence rates in different villages 0.6–2.0 episodes/year) and temporal (range of incidence rates in children of different birth months 0.8–1.2 episodes/year) factors. The range of spatio-temporal variation allowed ecological analyses of the correlation between malaria incidence rates, anti-Plasmodium falciparum lysate IgG antibody levels and protective efficacies provided by IPTi.ResultsProtective efficacy of the first SP administration was positively correlated with malaria incidences in children living in a distinct village or born in a distinct month (R2 0.48, p < 0.04 and R2 0.63, p < 0.003, respectively). Corresponding trends were seen after the second and third study drug administration. Accordingly, IgG levels against parasite lysate increased with malaria incidence. This correlation was stronger in children who received IPTi, indicating an effect modification of the intervention.ConclusionThe spatial and temporal variations of malaria incidences in a geographically and meteorologically homogeneous study area exemplify the need for close monitoring of local incidence rates in all types of intervention studies. The increase of the protective efficacy of IPTi with malaria incidences may be relevant for IPTi implementation strategies and, possibly, for other malaria control measures.

Expression of Plasmodium falciparum 3D7 STEVOR proteins for evaluation of antibody responses following malaria infections in naïve infants.

Clinical immunity to Plasmodium falciparum malaria develops after repeated exposure to the parasite. At least 2 P. falciparum variant antigens encoded by multicopy gene families (var and rif) are targets of this adaptive antibody-mediated immunity. A third multigene family of variant antigens comprises the stevor genes. Here, 4 different stevor sequences were selected for cloning and expression in Escherichia coli and His6-tagged fusion proteins were used for assessing the development of immunity. In a cross-sectional analysis of clinically immune adults living in a malaria endemic area in Ghana, high levels of anti-STEVOR IgG antibody titres were determined in ELISA. A cross-sectional study of 90 nine-month-old Ghanaian infants using 1 recombinant STEVOR showed that the antibody responses correlated positively with the number of parasitaemia episodes. In a longitudinal investigation of 17 immunologically naïve 9-month-old infants, 3 different patterns of anti-STEVOR antibody responses could be distinguished (high, transient and low). Children with high anti-STEVOR-antibody levels exhibited an elevated risk for developing parasitaemia episodes. Overall, a protective effect could not be attributed to antibodies against the STEVOR proteins chosen for the study presented here.

Editorial: Antifolates in prevention of HIV‐associated opportunistic infections and in intermittent preventive treatment of malaria in Africa

Two recent articles in The Lancet (Mermin et al. 2004; Chintu et al. 2004) report on trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis in HIV positive individuals and favour the respective intervention on a large scale as recommended by UNAIDS/WHO (UNAIDS/WHO 2000; UNAIDS/WHO 2004). Mermin et al. and Chintu et al. suggest that all individuals with clinical manifestations of HIV infection, including children of all ages, should receive TMP/SMX daily to stabilize CD4 cell counts, control the viral load, prevent hospital admission, and reduce mortality due to opportunistic infections. The authors raise, consequently, the issue of potential cross-resistance between TMP and pyrimethamine (PYR) and SMX and sulfadoxine (SUL). HIV-associated opportunistic infectious agents and Plasmodium falciparum are, together with Mycobacterium tuberculosis, the main infectious killers in sub-Saharan Africa, and strategies to fight one may confer severe disadvantages in treating or preventing another. Based on the observation that in vitro cross-resistance between TMP/ PYR and SMX/SUL may result from drug pressure (Iyer et al. 2001; Khalil et al. 2003), extensive application of TMP/SMX in areas of highHIV prevalence has the potential of readily increasing the degree of P. falciparum SUL/PYR resistance. This applies particularly to areas where intermittent preventive treatment (IPT) control strategies with SUL/PYR are currently being implemented and evaluated to prevent P. falciparum malaria (Schellenberg et al. 2001; WHO/UNICEF 2003). The problem is accentuated by our recent observation of a high prevalence of P. falciparum resistance markers in clinically healthy adults in Ghana in the absence of essential SUL/PYR drug pressure, but common TMP/SMXuse in bacterial infections (Marks et al. 2005). This would imply that not only in regions with existing, but also in those devoid of SUL/PYR pressure, resistance to these substances might arise in addition to preexisting levels of resistance. Routine TMP/SMX prophylaxis of HIV-associated opportunistic infections and SUL/ PYR based IPT would then considerably affect each other, also with regard to presumably more frequent occurrence of severe cutaneous adverse drug reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome. As a result of the high levels of resistance to chloroquine and SUL/PYR, several sub-Saharan countries have meanwhile changed their first-line treatment of uncomplicated P. falciparummalaria, and artemisinin-based combinations are now widely used. However, economic conditions must not be neglected. Although an official agreement on the costs of new first-line drugs of WHO with manufacturers of these drugs is effective, malaria treatment courses with artemisinin, e.g., artemether/lumefantrine cost US

Efficacy of a bivalent killed whole-cell cholera vaccine over five years: a re-analysis of a cluster-randomized trial

0.90 (children) and

Characterization of Salmonella enterica from invasive bloodstream infections and water sources in rural Ghana

2.40 (adults), irrespective of distribution and retail expenses. In contrast, SUL/PYR malaria treatment is available for US

Typhoid conjugate vaccines: a new tool in the fight against antimicrobial resistance

0.13/

The global burden and epidemiology of invasive non-typhoidal Salmonella infections

0.25 (children/adults). Obviously, cheaper drugs will preferentially be applied in areas where antimalarial self-treatment, without attending health professionals, is common practice. These considerations stress the urgency of (i) further studying mechanisms that lead to cross-resistance between various antifolates, (ii) intensemonitoring of prevalence and spread of drug-resistant infectious organisms, (iii) probatory studies and evaluation of IPT with alternative drugs, including HIV-positive individuals, (iv) making affordable new first-line antimalarials, considering interactions with current treatment/prophylaxis policies in HIV-positive individuals, and (v) detailed analyses of the primary causes ofmortality, whichmay be either because ofHIV-associated opportunistic infections, malaria, or other conditions.

Sm-p80-based schistosomiasis vaccine: double-blind preclinical trial in baboons demonstrates comprehensive prophylactic and parasite transmission-blocking efficacy: Sm-p80 vaccine efficacy in baboons

BackgroundOral cholera vaccine (OCV) is a feasible tool to prevent or mitigate cholera outbreaks. A better understanding of the vaccine’s efficacy among different age groups and how rapidly its protection wanes could help guide vaccination policy.MethodsTo estimate the level and duration of OCV efficacy, we re-analyzed data from a previously published cluster-randomized, double-blind, placebo controlled trial with five years of follow-up. We used a Cox proportional hazards model and modeled the potentially time-dependent effect of age categories on both vaccine efficacy and risk of infection in the placebo group. In addition, we investigated the impact of an outbreak period on model estimation.ResultsVaccine efficacy was 38% (95% CI: -2%,62%) for those vaccinated from ages 1 to under 5 years old, 85% (95% CI: 67%,93%) for those 5 to under 15 years, and 69% (95% CI: 49%,81%) for those vaccinated at ages 15 years and older. Among adult vaccinees, efficacy did not appear to wane during the trial, but there was insufficient data to assess the waning of efficacy among child vaccinees.ConclusionsThrough this re-analysis we were able to detect a statistically significant difference in OCV efficacy when the vaccine was administered to children under 5 years old vs. children 5 years and older. The estimated efficacies are more similar to the previously published analysis based on the first two years of follow-up than the analysis based on all five years.Trial registrationClinicalTrials.gov identifier NCT00289224

The Dengue virus in Nepal: gaps in diagnosis and surveillance

BackgroundNon-typhoidal Salmonella (NTS) cause the majority of bloodstream infections in Ghana, however the mode of transmission and source of invasive NTS in Africa are poorly understood. This study compares NTS from water sources and invasive bloodstream infections in rural Ghana.MethodsBlood from hospitalised, febrile children and samples from drinking water sources were analysed for Salmonella spp. Strains were serotyped to trace possible epidemiological links between human and water-derived isolates.. Antibiotic susceptibility testing was performed,ResultsIn 2720 blood culture samples, 165 (6%) NTS were isolated. S. Typhimurium (70%) was the most common serovar followed by S. Enteritidis (8%) and S. Dublin (8%). Multidrug resistance (MDR) was found in 95 (58%) NTS isolates, including five S. Enteritidis. One S. Typhimurium showed reduced fluroquinolone susceptibility. In 511 water samples, 19 (4%) tested positive for S. enterica with two isolates being resistant to ampicillin and one isolate being resistant to cotrimoxazole. Serovars from water samples were not encountered in any of the clinical specimens.ConclusionWater analyses demonstrated that common drinking water sources were contaminated with S. enterica posing a potential risk for transmission. However, a link between S. enterica from water sources and patients could not be established, questioning the ability of water-derived serovars to cause invasive bloodstream infections.