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Background: A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant Na-GST-1 and catalytically inactive Na-APR-1 (Na-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area., Methods: This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered Na-GST-1 on Alhydrogel plus Na-APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 μg, 30 μg, and 100 μg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with ClinicalTrials.gov, NCT02839161, and is completed., Findings: Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 μg of the co-administered antigens (n=8 for each injection schedule), 30 μg (n=8 for each schedule), 100 μg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti-Na-APR-1(M74) and anti-Na-GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for Na-APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for Na-GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for Na-APR-1[M74] and Na-GST-1, respectively)., Interpretation: Co-administration of recombinant Na-APR-1(M74) and Na-GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas., Funding: European Union Seventh Framework Programme., Competing Interests: Declaration of interests PJH, MEB, JMB, and DJD are named as inventors on a patent for a multivalent helminth vaccine (US8211438B2). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Competing Interests: We declare no competing interests.

Background: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate., Methods: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 μg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing., Findings: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group., Interpretation: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates., Funding: German Federal Ministry of Education and Research and CureVac., Competing Interests: Declaration of interests MB declares institutional funding from CureVac during the conduct of this study, institutional funding from Janssen Vaccines, Molecular Partners, and Merck outside the submitted work, and consulting fees from Janssen Vaccines outside the submitted work. EJLDB, MFM-R, TJO, and XS-L declare institutional funding from CureVac during the conduct of this study. LE and LG declare institutional funding from CureVac during the conduct of this study and outside the submitted work. CFL declares institutional funding from CureVac during the conduct of this study and outside the submitted work and is a member of the WHO Covid-19 Vaccine Effectiveness Working Group and the WHO Product Development for Vaccines Advisory Committee. CL declares institutional funding from CureVac during the conduct of this study and is a member of the German Society of Infection board. IL-R declares institutional funding from CureVac during the conduct of this study and institutional funding from Johnson & Johnson and OSE Immunotherapeutics outside the submitted work. PGK declares institutional funding from CureVac during the conduct of this study and is a member of the scientific advisory board for the HERALD clinical trial. VVRH declares institutional funding from CureVac during the conduct of this study and speakers fees from Gilead outside the submitted work. HJ declares consultant fees from CureVac, is the qualified physician for the HERALD clinical trial, and is co-chair of the DSMB for the HERALD clinical trial. AK and PM are employed by CureVac and hold stock options. OS-K declares consultant fees from CureVac during the conduct of this study and is a member of the DSMB for a CVnCoV phase 1 trial. TV declares consultant fees from CureVac during the conduct of this study, and consultant fees from CureVac, AstraZeneca, Pfizer, Johnson & Johnson, and Moderna outside the submitted work. LO is employed by CureVac and holds stock options and is the holder of a pending patent. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The GMZ2/alum candidate malaria vaccine had an efficacy of 14% (95% confidence interval [CI]: 3.6%, 23%) against clinical malaria over 6 months of follow-up in a phase2b multicentre trial in children 1-5 years of age. Here we report the extended follow up of safety and efficacy over 2 years., Methods: A total of 1849 (GMZ2 = 926, rabies = 923) children aged 12-60 months were randomized to receive intramuscularly, either 3 doses of 100 μg GMZ2/alum or 3 doses of rabies vaccine as control 28 days apart. The children were followed-up for 24 months for clinical malaria episodes and adverse events. The primary endpoint was documented fever with parasitaemia of at least 5000/μL., Results: There were 2,062 malaria episodes in the GMZ2/alum group and 2,115 in the rabies vaccine group in the intention-to-treat analysis, vaccine efficacy (VE) of 6.5% (95%: CI -1.6%, 14.0%). In children aged 1-2 years at enrolment, VE was 3.6% (95 %CI: -9.1%, 14.8%) in the first year and -4.1% (95 %CI: -18.7%, 87%) in the second year. In children aged 3-5 years at enrolment VE was 19.9% (95 %CI: 7.7%, 30.4%) in the first year and 6.3% (95 %CI: -10.2%, 20.3%) in the second year (interaction by year, P = 0.025, and by age group, P = 0.085). A total of 187 (GMZ2 = 91, rabies = 96) serious adverse events were recorded in 167 individuals over the entire period of the study. There were no GMZ2 vaccine related serious adverse events., Conclusions: GMZ2/alum was well tolerated. Follow-up over 2 years confirmed a low level of vaccine efficacy with slightly higher efficacy in older children, which suggests GMZ2 may act in concert with naturally acquired immunity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hookworms cause substantial morbidity in children and women of reproductive age. The control strategy of mass drug administration is suboptimal, hence the need for a vaccine. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are involved in the digestion and detoxification of haemoglobin in the hookworm digestive tract. In animal models, vaccination against these antigens resulted in protection from challenge infection. Both vaccine candidates were shown to be safe and well tolerated when administered separately to healthy adults. We assessed the safety and immunogenicity of co-administered Na-GST-1 and Na-APR-1 (M74) vaccines in healthy Gabonese adults., Methods: This randomised, controlled, double-blind, phase 1, dose-escalation trial was done at the Centre de Recherches Médicales de Lambaréné, in a region of Gabon where N americanus and other helminths are prevalent. Healthy adults aged 18-50 years and living in Lambaréné or the surrounding areas were recruited to the study. Participants were enrolled consecutively into two dose cohorts (30 μg or 100 μg of the experimental vaccines) and randomly assigned in blocks (block size four) to receive three doses of either co-administered Na-GST-1 plus Na-APR-1 (M74; 30 μg or 100 μg of each), adjuvanted with Alhydrogel (aluminium hydroxide gel suspension) together with an aqueous formulation of glucopyranosyl lipid A, or hepatitis B vaccine plus saline (control group). Vaccines were administered intramuscularly on days 0, 28, and 180. The primary endpoint was safety, with immunogenicity a secondary endpoint. The intention-to-treat population was used for safety analyses, whereas for immunogenicity analyses, the per-protocol population was used (participants who received all scheduled vaccinations). Control vaccine recipients for both dose cohorts were combined for the analyses. The trial is registered with ClinicalTrials.gov, NCT02126462., Findings: Between Oct 27, 2014, and Jan 31, 2015, 56 individuals were screened for eligibility, of whom 32 were enrolled and randomly assigned to one of the three study groups (12 each in the 30 μg and 100 μg experimental vaccine groups and eight in the control group). Both study vaccines were well tolerated in both dose groups. The most common adverse events were mild-to-moderate injection-site pain, headache, myalgia, and nausea. No severe or serious adverse events related to the vaccines were recorded. 52 unsolicited vaccine-related adverse events occurred during the study, but there was no difference in frequency between vaccine groups. IgG antibodies were induced to each of the vaccine antigens, with mean IgG levels increasing after each vaccination. Vaccination with 100 μg of each vaccine antigen consistently induced IgG seroconversion (IgG levels above the reactivity threshold). Peak IgG responses were observed 2 weeks after the third vaccine dose for both antigens, with all participants who received the 100 μg doses seroconverting at that timepoint. IgG levels steadily declined until the final study visit 6 months after the third vaccination, although they remained significantly higher than baseline in the 100 μg dose group., Interpretation: Vaccination with recombinant Na-GST-1 and Na-APR-1 (M74) in healthy adults living in N americanus-endemic areas of Gabon was safe and induced IgG to each antigen. To our knowledge, this study is the first to report results of Na-APR-1 (M74) co-administered with Alhydrogel in participants from an N americanus-endemic area. Further clinical development of these vaccines should involve efficacy studies., Funding: European Union Seventh Framework Programme., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Despite appreciable immunogenicity in malaria-naive populations, many candidate malaria vaccines are considerably less immunogenic in malaria-exposed populations. This could reflect induction of immune regulatory mechanisms involving Human Leukocyte Antigen G (HLA-G), regulatory T (Treg), and regulatory B (Breg) cells. Here, we addressed the question whether there is correlation between these immune regulatory pathways and both plasmablast frequencies and vaccine-specific IgG concentrations., Methods: Fifty Gabonese adults with lifelong exposure to Plasmodium spp were randomized to receive three doses of either 30 µg or 100 µg GMZ2-CAF01, or 100 µg GMZ2-alum, or control vaccine (rabies vaccine) at 4-week intervals. Only plasma and peripheral blood mononuclear cells isolated from blood samples collected before (D0) and 28 days after the third vaccination (D84) of 35 participants were used to measure sHLA-G levels and anti-GMZ2 IgG concentrations, and to quantify Treg, Breg and plasmablast cells. Vaccine efficacy was assessed using controlled human malaria infection (CHMI) by direct venous inoculation of Plasmodium falciparum sporozoites (PfSPZ Challenge)., Results: The sHLA-G concentration increased from D0 to D84 in all GMZ2 vaccinated participants and in the control group, whereas Treg frequencies increased only in those receiving 30 µg or 100 µg GMZ2-CAF01. The sHLA-G level on D84 was associated with a decrease of the anti-GMZ2 IgG concentration, whereas Treg frequencies on D0 or on D84, and Breg frequency on D84 were associated with lower plasmablast frequencies. Importantly, having a D84:D0 ratio of sHLA-G above the median was associated with an increased risk of P. falciparum infection after sporozoites injection., Conclusion: Regulatory immune responses are induced following immunization. Stronger sHLA-G and Treg immune responses may suppress vaccine induced immune responses, and the magnitude of the sHLA-G response increased the risk of Plasmodium falciparum infection after CHMI. These findings could have implications for the design and testing of malaria vaccine candidates in semi-immune individuals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Controlled Human Malaria Infection (CHMI) is the most practiced controlled human infection model nowadays and there is an exponential increase in implementation of the model worldwide. During the Controlled Human Infection Models Workshop in Leiden, one day was dedicated to the discussion of the advances made and gaps in Controlled Human Malaria Infection (CHMI) trials. Factors contributing to this impressive expansion in the number of CHMI trials have been related to the ability to perform CHMI using injectable cryopreserved sporozoites (a product from Sanaria Inc. - PfSPZ Challenge), the development of a transmission blocking CHMI model and the need to test more vaccine candidates particularly in the field of whole-sporozoite vaccine development. However, with an increasing number of CHMI trials being undertaken, in an ever-growing number of trial sites, heterogeneity in trial design may compromise universal interpretation of results and require an ongoing dialogue on the need and feasibility of standardization. At the workshop, CHMI investigators convened to share their experiences in CHMI trials and discuss the possibilities for future trials., (Copyright © 2017.)

The principle of deliberately infecting humans with infectious agents in a controlled setting, so-called controlled human infections (CHI), is not novel. Many CHI models have a long history and were established decades ago such as the intentional exposure to yellow fever and dengue performed in the 1900's (Reed, 1902) [2]. In these times bioethics and scientific reasoning were in their infancy. Nowadays, clinical trials are highly regulated and CHI are executed worldwide. Controlled human malaria infections and influenza infections are the two most frequently practiced. Others are experiencing a revival or are being carefully developed. Because CHI models test the efficacy of promising vaccine or drug candidates early in clinical development, they offer the potential to decrease the number of failing phase 2 and 3 trials, reducing risks for patients and saving costs and efforts. In addition, CHI models provide unprecedented opportunities to dissect the physiological, immunological and metabolic changes that occur upon infection. However, it is clear that controlled infections require careful deliberation of safety, ethics, quarantine, scientific output and the production of infectious material. An independent international workshop was hosted by the Leiden University Medical Centre in The Netherlands, bringing together clinical investigators, basic scientists, regulators, funders and policy makers from 22 different countries to discuss the opportunities and challenges in CHI. The aim of the workshop was to discuss CHI as a tool to advance science, drug and vaccine development, share the challenges of establishing a CHI model with specific focus on neglected tropical diseases and the possibilities to transfer models to endemic sites. Noticeably, among the 128 participants were clinical investigators from ten different countries in Sub-Saharan Africa. An important dimension of the meeting was to give the floor to young established clinicians and scientists to voice their perspective on the future of CHI models., (Copyright © 2017.)

Background: A drug for causal (ie, pre-erythrocytic) prophylaxis of Plasmodium falciparum malaria with prolonged activity would substantially advance malaria control. DSM265 is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase. DSM265 shows in vitro activity against liver and blood stages of P falciparum. We assessed the prophylactic activity of DSM265 against controlled human malaria infection (CHMI)., Methods: At the Institute of Tropical Medicine, Eberhard Karls University (Tübingen, Germany), healthy, malaria-naive adults were allocated to receive 400 mg DSM265 or placebo either 1 day (cohort 1A) or 7 days (cohort 2) before CHMI by direct venous inoculation (DVI) of 3200 aseptic, purified, cryopreserved P falciparum sporozoites (PfSPZ Challenge; Sanaria Inc, Rockville, MD, USA). An additional group received daily atovaquone-proguanil (250-100 mg) for 9 days, starting 1 day before CHMI (cohort 1B). Allocation to DSM265, atovaquone-proguanil, or placebo was randomised by an interactive web response system. Allocation to cohort 1A and 1B was open-label, within cohorts 1A and 2, allocation to DSM265 and placebo was double-blinded. All treatments were given orally. Volunteers were treated with an antimalarial on day 28, or when parasitaemic, as detected by thick blood smear (TBS) microscopy. The primary efficacy endpoint was time-to-parasitaemia, assessed by TBS. All participants receiving at least one dose of chemoprophylaxis or placebo were considered for safety, those receiving PfSPZ Challenge for efficacy analyses. Log-rank test was used to compare time-to-parasitemia between interventions. The trial was registered with ClinicalTrials.gov, number NCT02450578., Findings: 22 participants were enrolled between Oct 23, 2015, and Jan 18, 2016. Five participants received 400 mg DSM265 and two participants received placebo 1 day before CHMI (cohort 1A), six participants received daily atovaquone-proguanil 1 day before CHMI (cohort 1B), and six participants received 400 mg DSM265 and two participants received placebo 7 days before CHMI (cohort 2). Five of five participants receiving DSM265 1 day before CHMI and six of six in the atovaquone-proguanil cohort were protected, whereas placebo recipients (two of two) developed malaria on days 11 and 14. When given 7 days before CHMI, three of six volunteers receiving DSM265 became TBS positive on days 11, 13, and 24. The remaining three DSM265-treated, TBS-negative participants of cohort 2 developed transient submicroscopic parasitaemia. Both participants receiving placebo 7 days before CHMI became TBS positive on day 11. The only possible DSM265-related adverse event was a moderate transient elevation in serum bilirubin in one participant., Interpretation: A single dose of 400 mg DSM265 was well tolerated and had causal prophylactic activity when given 1 day before CHMI. Future trials are needed to investigate further the use of DSM265 for the prophylaxis of malaria., Funding: Global Health Innovative Technology Fund, Wellcome Trust, Bill & Melinda Gates Foundation through Medicines for Malaria Venture, and the German Center for Infection Research., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

An estimated 40 million women of childbearing age suffer from schistosomiasis. Animal models indicate a deleterious effect of maternal schistosomiasis on pregnancy outcomes. To date there is a lack of epidemiological evidence evaluating schistosomiasis-related morbidity in pregnancy. This study was designed to describe the impact of urogenital schistosomiasis on pregnancy outcomes in a highly endemic region of central Africa. Pregnant women attending antenatal clinics in Fougamou and Lambaréné, Gabon, were consecutively screened for the presence of Schistosoma haematobium eggs in diurnal urine samples. Maternal and newborn characteristics assessed at delivery were compared between infected and uninfected mothers. The impact of maternal schistosomiasis on low birth weight and preterm delivery was assessed using logistic regression analysis. Urogenital schistosomiasis was diagnosed in 103 (9%) of 1115 pregnant women. Maternal age was inversely associated with the prevalence of urogenital schistosomiasis, with a higher burden amongst nulliparous women. Low birth weight was more common amongst infants of S. haematobium-infected mothers. This association was unaffected by controlling for demographic characteristics, gestational age and Plasmodium infection status (adjusted Odds Ratio 1.93; 95% confidence interval: 1.08-3.42). Other risk factors associated with low birth weight delivery were underweight mothers (adjusted Odds Ratio 2.34; 95% confidence interval: 1.12-4.92), peripheral or placental Plasmodium falciparum infection (adjusted Odds Ratio 2.04; 95% confidence interval: 1.18-3.53) and preterm birth (adjusted Odds Ratio 3.12; 95% confidence interval: 1.97-4.96). Preterm delivery was not associated with S. haematobium infection (adjusted Odds Ratio 1.07 95% confidence interval: 0.57-1.98). In conclusion, this study indicates that pregnant women with urogenital schistosomiasis are at an increased risk for low birth weight deliveries. Further studies evaluating targeted treatment and prevention programmes for urogenital schistosomiasis in pregnant women and their impact on delivery outcomes are warranted., (Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.)

Background: GMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda., Methods: Children 12-60months old were randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL., Results: A cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value=0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value=0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%)., Conclusions: GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Apart from outbreak reports, little is known about the endemicity of dengue and chikungunya virus in African countries. We investigated serum samples collected in Gabon before major outbreaks in 2007 and 2010 in order to identify pre-outbreak-circulation of both viruses., Methods: Serum samples from Gabonese infants (162) were analyzed at 3, 9, 15 and 30 months of age by commercial ELISA for dengue and chikungunya IgG-antibodies. If samples were positive medical records of participants were analyzed for symptoms concordant with dengue and chikungunya infections during the time period of assumed seroconversion., Results: IgG-antibodies against dengue were found in 12.3%, and IgG-antibodies against chikungunya in 0.6% of infants tested. Using the four measuring time points, we estimated corresponding incidences of 51/1.000 person-years and 2.5/1.000 person-years, respectively. Symptoms in positive-tested infants were mostly non-specific., Conclusion: Seropositivity suggests that both viruses circulated before the well-noticed outbreaks. Clinical diagnosis of dengue and chikungunya is difficult especially in infants, underscoring the need for accurate and reliable diagnostic tests as well as awareness of medical personnel., Clinical Trials Registration: NCT00167843., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falciparum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectable PfSPZ-based vaccine that provides high-grade, durable protection against infection with Pf malaria. Several candidate vaccines are being developed and tested, including PfSPZ Vaccine, in which the PfSPZ are attenuated by irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant administration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout. Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-C), are collaborating to advance this program by providing intellectual, clinical, and financial support. Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are underway and at least 12 more are planned for 2015-2016 in the US (four trials), Germany (2 trials), Tanzania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license a first generation product as early as late 2017, initially to protect adults, and a year later to protect all persons >6 months of age for at least six months. Improved vaccine candidates will be advanced as needed until the following requirements have been met: long-term protection against natural transmission, excellent safety and tolerability, and operational feasibility for population-wide administration. Here we describe the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licensure and deployment, and long-term objectives for a final product suitable for mass administration to achieve regional malaria elimination and eventual global eradication., Competing Interests: TLR, PFB, BKS, ERJ, SC and SLH are salaried, full time employees of Sanaria Inc., the developer and sponsor of Sanaria PfSPZ Vaccine, PfSPZ Challenge, and the PfSPZ-CVac vaccine approach., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Artemisinin-based combination therapies (ACTs) are the recommended first-line treatment for uncomplicated Plasmodium falciparum malaria. Ferroquine is a new combination partner for fast-acting ACTs such as artesunate. We aimed to assess different doses of ferroquine in combination with artesunate against uncomplicated P falciparum malaria in a heterogeneous population in Africa., Methods: We did a phase 2, multicentre, parallel-group, double-blind, randomised, dose-ranging non-inferiority trial at eight African hospitals (two in Gabon, three in Burkina Faso, one in Benin, and two in Kenya). We recruited patients presenting with acute P falciparum monoinfection (1000-200,000 parasites per μL), and a central body temperature of at least 37·5°C or history of fever in the past 24 h. We assessed patients in two sequential cohorts: cohort 1 contained adults (bodyweight >50 kg) and adolescents (aged ≥14 years, >30 kg), and cohort 2 contained children (aged 2-13 years, 15-30 kg). We randomly assigned patients (1:1:1:1) to receive artesunate 4 mg/kg per day plus ferroquine 2 mg/kg, 4 mg/kg, or 6 mg/kg, given double-blind once per day for 3 days, or ferroquine monotherapy 4 mg/kg per day given single-blind (ie, allocation was only masked from the patient) once per day for 3 days. We did 14 patient visits (screening, 3 treatment days and 48 h post-treatment surveillance, a visit on day 7, then one follow-up visit per week until day 63). The primary endpoint was non-inferiority of treatment in terms of PCR-corrected cure rate against a reference value of 90%, with a 10% non-inferiority margin, assessed in patients treated without major protocol deviations for parasitologically confirmed malaria. We assessed safety in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00988507, and is closed., Findings: Between Oct 16, 2009, and Sept 22, 2010, we randomly assigned 326 eligible patients to treatment groups, with last follow-up visit on Dec 1, 2010. 284 patients (87%) were available for per-protocol analyses. At day 28, PCR-confirmed cure was noted in 68 (97%, 95% CI 90-100) of 70 patients treated with ferroquine 2 mg/kg plus artesunate, 73 (99%, 93-100) of 74 with ferroquine 4 mg/kg plus artesunate, 71 (99%, 93-100) of 72 with ferroquine 6 mg/kg plus artesunate, and 54 (79%, 68-88) of 68 with ferroquine 4 mg/kg monotherapy. The three dose groups of ferroquine plus artesunate met the non-inferiority hypothesis. The most common adverse events were headache in cohort 1 (30 [19%] of 162 patients) and worsening malaria in cohort 2 (23 [14%] of 164 patients); occurrences were similar between treatment groups., Interpretation: Ferroquine combined with artesunate was associated with high cure rates and was safe at all doses tested, and could be a promising new drug combination for the treatment of P falciparum malaria. Ferroquine could also partner other drugs to establish a new generation of antimalarial combinations, especially in regions that have developed resistance to ACTs., Funding: Sanofi., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Aquatic environments are the most important source for Legionella spp. infections such as Legionnaires' disease and Pontiac fever. The reservoirs of Legionella spp. are mostly unclear in sub-Saharan Africa. The aim of this study, conducted in 2013, was to identify geographical areas of an increased risk for exposure to Legionella spp., and to describe the population structure of Legionella spp. from different water sources in a cross-sectional study in Gabon. Fresh water samples (n = 200) were cultured on Legionella selective agar; species were confirmed by MALDI-TOF, a Legionella pneumophila specific real-time PCR and 16S RNA gene sequencing. Serogroups were identified by agglutination test. The population structure was assessed by multilocus sequence typing (MLST). Legionella spp. isolates (n = 29) were frequently found in the hospital setting particularly in hot water systems. Open water bodies (i.e. rivers, lakes) were not contaminated with Legionella spp. Isolated L. pneumophila mainly belonged to serogroups 2-14 (n = 19) and MLST sequence type ST1, ST75 (and related STs) and ST1911. In conclusion, hospitalized patients might have an increased risk to become infected with Legionella spp. in the studied areas in Gabon, particularly if they have risk factors such as comorbidities. Both broadly extended (ST1, ST75) and local lineages (ST1911) were present in our setting., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Artesunate has replaced quinine as the recommended first-line treatment of severe malaria as it clears parasites faster and lowers mortality. After artesunate's introduction, however, reports of delayed haemolysis have emerged. Typically, this adverse haemolytic event peaks two to three weeks after the acute phase of malaria, and can be severe enough to make blood transfusions necessary in the management of some patients. Delayed haemolysis has been detected in prospective studies in 7-21% of patients treated with artesunate. A confirmed risk factor in travellers is hyperparasitaemia, while additional in malaria-endemic countries young age has been shown to increase risk. The pathophysiology of this phenomenon has not yet been fully elucidated, but may include various combinations of delayed destruction of "pitted" erythrocytes and autoimmune aetiology. All patients treated with parenteral artesunate should be followed up for at least four weeks to detect signs of haemolysis and to allow appropriate symptomatic treatment., (Copyright © 2015. Published by Elsevier Ltd.)

Background: Travellers' diarrhoea causes substantial acute and long-term morbidity. Chemoprophylaxis with fluoroquinolones or rifaximin is effective in prevention of diarrhoea in individuals travelling to Latin America and Africa. Little evidence is available to support the protective effect of antimicrobial drugs in south and southeast Asia, where enteroinvasive and antibiotic-resistant bacteria cause a substantial proportion of diarrhoeal episodes. We aimed to assess the effectiveness of rifaximin in prevention of diarrhoea in individuals travelling to south and southeast Asia., Methods: We did this double-blind, placebo-controlled, single-centre, parallel-group, clinical trial in Tübingen, Germany, between Nov 12, 2009, and Sept 3, 2012. Individuals aged 18-64 years who were planning a 6-28 day journey to south and southeast Asia were randomly assigned (1:1), according to a randomisation list (permuted block size of eight) generated by an independent statistician, to receive placebo or rifaximin 200 mg tablets twice daily. All members of the study team, including investigators, those assessing outcomes, and data analysts, were masked to treatment allocation. The primary endpoint was time to the first episode of classic travellers' diarrhoea, defined as three or more loose stools in 24 h, accompanied by one or more enteric symptoms. Analyses were by intention to treat and per protocol., Findings: We randomly assigned 258 participants to rifaximin (n=129) or placebo (n=129), of whom 239 (93%) returned a completed diary and were included in the primary effectiveness analysis. 48 (41%) of 117 participants in the placebo group and 30 (25%) of 122 in the rifaximin group reported classic episodes of travellers' diarrhoea. From departure to 7 days after return, rifaximin provided 48% protection (95% CI 16-68) by lowering the incidence of travellers' diarrhoea from 1·99 (1·50-2·64) per 100 person-days in the placebo group to 1·04 (0·72-1·48) in the intervention group (incidence rate ratio 0·52, 95% CI 0·32-0·84; p=0·005). The number needed to treat was 5·70 (95% CI 3·44-16·69) to prevent one case of classic travellers' diarrhoea during the first 3 weeks of follow-up. The per-protocol analysis essentially corroborated the findings from the intention-to-treat analysis. We recorded one serious adverse event in a participant in the rifaximin group who had grade 3 right lower quadrant abdominal pain 72 h after the last intake of study drug. The complaints were considered unlikely to be related to use of the drug., Interpretation: Rifaximin is moderately effective in prevention of diarrhoea in individuals travelling to south and southeast Asia. Similar studies are needed to inform travellers and practitioners about the effectiveness of this drug at other popular destinations., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Lyme borreliosis is caused by Borrelia burgdorferi sensu stricto in the USA and by several Borrelia species in Europe and Asia, but no human vaccine is available. We investigated the safety and immunogenicity of adjuvanted and non-adjuvanted vaccines containing protective epitopes from Borrelia species outer surface protein A (OspA) serotypes in healthy adults., Methods: Between March 1, 2011, and May 8, 2012, we did a double-blind, randomised, dose-escalation phase 1/2 study at four sites in Austria and Germany. Healthy adults aged 18-70 years who were seronegative for B. burgdorferi sensu lato were eligible for inclusion. Participants were recruited sequentially and randomly assigned to one of six study groups in equal ratios via an electronic data capture system. Participants and investigators were masked to group allocation. Participants received three vaccinations containing 30 μg, 60 μg, or 90 μg OspA antigen with or without an adjuvant, with intervals of 28 days, and a booster 9-12 months after the first immunisation. The coprimary endpoints were the frequency and severity of injection-site and systemic reactions within 7 days of each vaccination, and the antibody responses to OspA serotypes 1-6, as established by ELISA. This study is registered with ClinicalTrials.gov, number NCT01504347., Findings: 300 participants were randomly assigned: 151 to adjuvanted vaccines (50 to 30 μg, 51 to 60 μg, and 50 to 90 μg doses), and 149 to non-adjuvanted vaccines (50 to 30 μg, 49 to 60 μg, and 50 to 90 μg doses). Adverse reactions were predominantly mild, and no vaccine-related serious adverse events were reported. The risk of systemic reactions (risk ratio 0·54 [95% CI 0·41-0·70]; p<0·0001) and of moderate or severe systemic reactions (0·35 [0·13-0·92]; p=0·034) was significantly lower for adjuvanted than non-adjuvanted formulations. The 30 μg adjuvanted formulation had the best tolerability profile; only headache (five [10%, 95% CI 4-20] of 50), injection-site pain (16 [32%, 21-45]), and tenderness (17 [34%, 23-47]) affected more than 6% of patients. All doses and formulations induced substantial mean IgG antibody titres against OspA serotypes 1-6 after the first three vaccinations (range 6944-17,321) and booster (19,056-32,824) immunisations. The 30 μg adjuvanted formulation induced the highest antibody titres after the booster: range 26,143 (95% CI 18,906-36,151) to 42,381 (31,288-57,407)., Interpretation: The novel multivalent OspA vaccine could be an effective intervention for prevention of Lyme borreliosis in Europe and the USA, and possibly worldwide. Larger confirmatory formulation studies will need to be done that include individuals seropositive for Borrelia burgdorferi sensu lato before placebo-controlled phase 3 efficacy studies can begin., Funding: Baxter., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Two polymorphisms in the STAT4 and HLA-DQ loci were more recently reported to associate with chronic hepatitis B (CHB) induced hepatocellular carcinoma (HCC). We utilised an independent Vietnamese cohort of clinically classified HBV patients of chronic hepatitis B carriers (n=206), liver cirrhosis (n=222) and hepatocellular carcinoma (n=239) and assessed the influence of the reported variants. The STAT4 variant (rs7574865) was marginally associated with HCC susceptibility in CHB carriers in allelic and recessive genetic models (OR=0.84, 95%CI=0.7-0.99, P=0.048 and OR=0.7, 95%CI=0.5-0.99, P=0.047). No significant association between the studied variant with several clinical parameters such as liver enzymes (ALT, AST), total and direct bilirubin, AFP, HBV genotype and viral loads were observed. Our study highlights the reported variant to be a trivial factor and possibly other confounding factors may regulate STAT4 expression during HCC development., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The definition of artemisinin resistance is becoming one of a prolonged parasite clearance phenotype, although this variable is a complex function of both host and parasite characteristics. We discuss some of the limitations of this definition of artemisinin resistance, particularly because of its potential global impact. This opinion article reviews the mechanisms underlying parasite clearance after artemisinin treatment and how these might relate to in vitro methods to assay for resistance. It revisits criteria for defining artemisinin resistance that are not currently being applied and suggests the term 'treatment failure of artemisinin combination therapy' (TFACT) as a more accurate description of most cases of 'artemisinin resistance'., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Helminth infections are highly prevalent in the tropics and may have an effect on immune responses to vaccines due to their immunomodulatory effect. The prevalence of helminth infections in young children, the target group for malaria and most other vaccines, is high. Therefore we assessed the influence of helminth infection on vaccine-induced immune responses in a phase I clinical trial of the malaria vaccine candidate GMZ2., Methods: Twenty Gabonese preschool-age children were vaccinated with GMZ2, a blood stage malaria vaccine candidate. Humoral immune response against the vaccine antigens and parasitological status were assessed. Vaccine-specific antibody concentrations and memory B-cell numbers were compared in worm infected and non-infected participants., Results: Antibody response to GMZ2 was 3.4-fold (95% confidence interval: 1.6, 7.4) higher in Trichuris trichiura negative subjects compared to positive participants, whereas immunoglobulin subclass distribution was similar. Memory B-cell response was moderately increased in T. trichiura negative individuals, although the difference was not significant., Conclusions: Future malaria vaccine development programs need to account for worm-mediated hyporesponsiveness of immune reactions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Paediatric formulations of artemisinin combination therapies (ACTs) have recently been developed for the treatment of children with falciparum malaria. Compared with conventional tablet formulations, the new non-tablet preparations have shown equivalent efficacy, safety, and tolerability in individual trials. We aimed to investigate whether objective evidence supports the development and use of paediatric ACTs. A systematic review identified seven studies involving 2515 children that were eligible for meta-analysis. Similar efficacy and safety were seen in pooled analyses of paediatric and conventional formulations. 23 (2.0%) of 1154 patients in the paediatric formulation groups and 19 (1.7%) of 1137 in the tablet formulation groups were not cured (RR 1.27, 95% CI 0.66-2.44). Despite similar overall tolerability, the tolerability of drug administration was improved for paediatric formulations as shown by significantly fewer patients with drug-induced vomiting (93 of 1018 and 114 of 837 patients; risk ratio [RR] 0.78, 95% CI 0.61-0.99), and drug-related gastrointestinal disorders (8 of 545 and 15 of 358 patients; RR 0.36, 95% CI 0.15-0.85). These data provide, for the first time, evidence for improved management of children by use of paediatric formulations, and support the further development and use of paediatric ACTs., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The prevention and management of malaria is primarily based on the use of drugs. Clinical trials have however revealed that between individuals there is large variability in the pharmacokinetic profiles of many antimalarial drugs. The resulting variations in concentrations of the drug within plasma might lead to either suboptimum effectiveness or drug toxicity in some patients. The evidence is increasing that polymorphically expressed drug-metabolising enzymes, predominantly various cytochrome P450 isozymes but also drug transporters, might contribute to the variability in drug response (incomplete cure, relapse, or resistance) or toxicity experienced with antimalarial drugs. For example, there is a clear association between concentrations of proguanil within plasma and certain genetic polymorphisms of CYP2C19, and genetically established levels of CYP2C8 might have important clinical implications in the toxicity of amodiaquine. Variation in the expression of drug-metabolising enzymes and transport proteins affects the pharmacology of antimalarial drugs. Exploration of pharmacogenetics might help to optimise the use of antimalarial drugs.

Malaria is a major public health problem in Sub-Saharan Africa. In highly endemic regions infants, children and pregnant women are mostly affected. An effective malaria vaccine would complement existing malaria control strategies because it can be integrated in existing immunization programs easily. Here we present the results of the first phase Ia clinical trial of GMZ2 adjuvanted in aluminium hydroxide. GMZ2 is a malaria vaccine candidate, designed upon the rationale to induce immune responses against asexual blood stages of Plasmodium falciparum similar to those encountered in semi-immune individuals. Ten, 30 and 100 microg of GMZ2 were well tolerated in 30 healthy malaria-naïve German volunteers when given three times in monthly intervals. Antigen-specific antibodies as well as memory B-cells were induced and detectable throughout the one year follow-up of the study. We conclude that GMZ2 is a safe and immunogenic malaria vaccine candidate suitable for further clinical development.

The aim of this paper is to explore attitudes of mothers towards childhood vaccinations and reasons for non-attendance and non-adherence to mother-child clinics (MCCs). Forty in-depth interviews with mothers of children under 5 years of age revealed positive attitudes towards vaccination that seem at odds with the region's observed low vaccination coverage. Important reasons for MCC non-attendance included distance to the MCC, transport costs, negative experiences at MCCs (such as interactions with unfriendly staff) and mothers' feeling of shame provoked by different, often poverty-associated reasons such as attending the clinic with a dirty or poorly clothed child.

Protection to tetanus is often not optimal in developing countries due to incomplete vaccination schemes, or decreased efficacy of vaccination. In this study we investigated the immunological response to tetanus booster vaccination in school children living in a semi-urban or in a rural area of Gabon. Tetanus-specific total IgG as well as antibody subclasses of the IgG1, IgG2, IgG3 and IgG4 isotype and the avidity of the dominating IgG1 subclass were determined both before and 1 month after the booster vaccination. In addition, tetanus-specific cytokine responses were determined. We found a polarization towards a T helper 1 (Th1) profile in the semi-urban children, whereas the cytokine responses of the rural children showed a T helper 2 (Th2) skewed response. Furthermore, tetanus-specific antibodies of the different IgG subclasses were all increased upon a tetanus booster vaccination and levels of IgG1 and IgG3 were higher in the rural children. In conclusion, a tetanus booster vaccination induced a stronger Th2 over Th1 cytokine profile to tetanus toxoid (TT) in rural children who showed the highest levels of IgG1 and IgG3 anti-TT antibody responses.

Clindamycin is safe and effective for the treatment of Plasmodium falciparum malaria, but its use as monotherapy is limited by unacceptably slow initial clinical response rates. To investigate whether the protracted action is due to an accumulative, time of exposure-dependent or a delayed effect on parasite growth, we studied the in vivo and in vitro pharmacodynamic profiles of clindamycin against P. falciparum. In vivo, elimination of young, circulating asexual parasite stages during treatment with clindamycin displayed an unusual biphasic kinetic: a plateau phase was followed by a precipitated decline of asexual parasite densities to nearly undetectable levels after 72 and 60 h in adult patients and asymptomatic children, respectively, suggesting an uninhibited capacity to establish a second, but not third, infectious cycle. In vitro, continuous exposure of a laboratory-adapted P. falciparum strain to clindamycin with concentrations of up to 100 microM for two replication cycles (96 h) did not produce inhibitory effects of >50% compared with drug-free controls as measured by the production of P. falciparum histidine-rich protein II (PfHRP2). PfHRP2 production was completely arrested after the second cycle (96-144h) (>10,000-fold decrease of mean half-inhibitory concentrations measured at 96-144h compared to 48-96h). Furthermore, incubation with clindamycin during only the first (0-48h) versus three (0-144h) parasite replication cycles led to comparable inhibition of PfHRP2 production in the third infectious cycle (96-144h) (mean IC(99) of 27 and 22nM, respectively; P=0.2). When parasite cultures were exposed to different concentrations of clindamycin ranging from 50 to 1,000nM for 72h and followed up in an experiment designed to simulate a typical 3-day treatment regimen, parasitaemia was initially suppressed below the microscopic detection threshold. Nonetheless, parasites reappeared in a dose-dependent manner after removal of drug at 72h but not in continuously drug-exposed controls. The delayed, but potent, antimalarial effect of clindamycin appears to be of greatest potential benefit in new combinations of clindamycin with rapidly acting antimalarial combination partners.

Background/objectives: An ineffective cytokine response is thought to be one of the reasons for the failure to suppress hepatitis B virus (HBV) replication and to eliminate the virus. We investigated the serum levels of interleukin (IL)-6, IL-10, IL-12, and interferon (IFN)-gamma in HBV-infected Vietnamese patients to determine whether they were related to the outcome of HBV infection., Study Design: Samples from a total of 154 HBV-infected patients with well-characterised clinical profiles and 56 healthy controls were assessed., Results: Serum IL-6 levels, which were inversely correlated with transaminase levels, were highest in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) and lowest in those with either asymptomatic (ASYM), acute or chronic HBV, and thus, represented the best marker of HBV-related clinical progression. Compared with the healthy control group, serum IL-12 was uniformly elevated in all HBV-infected patients apart from those with ASYM infections, implying no impairment of production of this cytokine in HBV-infected individuals. Serum IL-10 and IFN-gamma levels, however, were uniformly low and showed no association with clinical presentation. Cytokine profiles were not influenced by the presence of hepatitis B e antigen (HbeAg)., Conclusions: Serum IL-6 and IL-12 but not IL-10 and IFN-gamma are associated with the clinical presentation in HBV-infected Vietnamese patients.

Plasmodium falciparum infection induces alterations in the transport properties of infected erythrocytes that have recently been defined using electrophysiological techniques. Mechanisms responsible for transport of substrates into intraerythrocytic parasites have also been clarified by studies of three substrate-specific (hexose, nucleoside and aquaglyceroporin) parasite plasma membrane transporters. These have been characterised functionally using the Xenopus laevis oocyte heterologous expression system. The same expression system is currently being used to define the function of parasite 'P' type ATPases responsible for intraparasitic [Ca(2+)] homeostasis. We review studies on these transport processes and examine their potential as novel drug targets.