bluuebunny/crossref_metadata_2025 huggingface dataset:
R&D TO TACKLE GLOBAL HEALTH CHALLENGES: ROLES AND RESPONSIBILITIES FOR EDCTP
Authors: Tanner Marcel
Published: February 2017

As well documented, the diseases of poverty and Neglected Tropical Diseases (NTDs) cost the lives of millions of people worldwide and threaten the health of millions more. More than 200 million health years of life are lost every single year due to mortality, morbidity and disability. This not only represents an unacceptable burden for the populations concerned, mainly the most impoverished segments of a population, but also impairs health development and all our efforts to reach the Sustainable Development Goals. NTDs and diseases of poverty are clearly part of the overall neglect of people and health and social systems.

The high burden of diseases of poverty and NTDs calls for new efforts in developing effective and efficient approaches to control or even eliminate these diseases. This in turn implies that we must aim at new discoveries and innovations and – at the same time – make most effective use of existing tools as well as of innovative partnerships between the public and the private sectors and between different countries; clearly the niche and responsibility of EDCTP.

The presentation will discuss needs and ongoing efforts in diagnosis, drug and vaccine development against diseases of poverty and NTDs and will also discuss (i) obstacles at the level of health and social systems that prevent access of the populations to new and existing efficacious tools as well as (ii) new approaches in R&D to overcome these obstacles and barriers. While there are great hopes and also substantial advances in drug, diagnostics and vaccine development, R&D does not and should not alone focus on developing new tools, but rather on combining existing and new tools for integrated approaches of diseases control and elimination that are tailored to a given endemic setting and are combined with effective capacity building. The outlook and discussion will emphasize the potential, chances and responsibilities of EDCTP to strengthen effective partnership, capacity building and national and global health development.
NEW POSSIBILITIES FOR THE DEVELOPMENT OF A COMBINED VACCINE AGAINST ETEC ANDSHIGELLA
Authors: Walker Richard
Published: February 2017

Background

Together, enterotoxigenicEscherichia coli(ETEC) andShigellacontribute greatly to the mortality and the morbidity due to diarrhoeal diseases, including a number of negative lifetime health impacts. Vaccines represent a reasonable option to reduce this burden.

Vaccine

candidates PATH has reviewed the landscape of vaccine candidates for these diseases and identified two candidates to be moved towards licensure in the near-term as a combined ETEC andShigellavaccine for use on an Expanded Programme on Immunisation (EPI) schedule.

ETVAX

One candidate is a formalin-inactivated ETEC vaccine (ETVAX) consisting of fourE. colipreparations, each engineered to hyper-produce the CFA/1, CS3, CS5, and CS6 antigens of ETEC. In addition, the vaccine contains a cholera B subunit modified to be more cross-reactive with the B subunit of ETEC. ETVAX is co-administered with a double-mutant of the ETEC heat-labile toxin (dmLT), which serves as a potent mucosal adjuvant.

TSWC

The other candidate includes formalin-killedS. flexneri2a and 3a andS. sonneiprepared as a trivalent vaccine, called TSWC. A prototype of TSWC,S. flexneri2a, was administered to North American volunteers and found to be safe and immunogenic; it is now currently in a challenge trial.

Looking

ahead Early 2017 in a phase I trial, we will test TSWC given alone and co-administered with ETVAX. ETVAX given alone exceeded expectations for immunogenicity in Swedish volunteers and is projected to be evaluated for safety and early efficacy in Finnish travellers to Benin in early 2017. ETVAX is also currently being tested in a descending-age trial in Bangladesh to determine the optimum safe dose of vaccine and adjuvant to be given to infants as young as 6 to 10 weeks of age. We also hope that the dmLT will have a dose-sparing effect on the vaccine given to this target population.
SAFETY AND IMMUNOGENICITY OF CO-ADMINISTERED HOOKWORM VACCINE CANDIDATES NA-GST-1 AND NA-APR-1 WITH ALHYDROGEL® AND GLUCOPYRANOSYL-LIPID A IN GABONESE ADULTS: INTERIM RESULTS
Authors: Adegnika Ayola , Vries Sophie De , Zinsou Frejus Jeannot , Honkpehedji J , Dejon Jean Claude , Loembe Marguerite Massinga , Bache Bache , Pakker Nadine , Leeuwen Remko Van , Hounkpatin Aurore Bouyoukou , Kremsner Peter , Yazdanbakhsh Maria , Lell Bertrand , Bethony Jeffrey , Hotez Peter , Diemert David , Grobusch Martin
Published: February 2017

Background

Hookworm disease is one of the most prevalent of the neglected tropical diseases. To date, the control of hookworm infection has been limited to mass-administration of anthelminthic drugs. Despite this, the global hookworm prevalence does not decrease, thus there is a need for a vaccine. We evaluated the Na-GST-1 and Na-APR-1 hookworm vaccine candidates simultaneously in a hookworm endemic Gabonese population.

Methods

Eligible healthy Gabonese adults aged 18–50 years were enrolled in a randomised, double blind, controlled phase I trial. The first cohort received 30 µg Na-GST-1 co-administered with 30 µg Na-APR-1. The second cohort received 100 µg Na-GST-1 and 100 µg Na-APR-1. All doses were administered after mixing with 5 µg of an aqueous formulation of glucopyranosyl Lipid A (GLA-AF), a Toll-like Receptor-4 agonist. Hepatitis B vaccination (HBV) was administered as a comparator. Study subjects were vaccinated on days 0, 28 and 180 by intramuscular injection. IgG antibody levels were measured by qualified ELISA. This study evaluated the safety, reactogenicity, and immunogenicity ofNa-GST-1/Alhydrogel® co-administered with Na-APR-1/Alhydrogel®.

Results

Thirty-two study participants were enrolled. No serious adverse events or significant changes in haematological, renal or liver function parameters were observed. Mild-to-moderate injection-site pain, headache and fever were common adverse events. Elevated Na-GST-1 and Na-APR-1 IgG antibody levels were detected on day 194. Significant differences in mean antibody levels were observed between dose groups for Na-APR-1 [30 µg: 18 (50–86.9)vs100 µg: 197 (131– 264); p< 0.0001] but not for Na-GST-1 [30 µg: 338 (213–463)vs100 µg: 402.54 (283.65–521); p=0.5].

Conclusions

Co-administration of the hookworm vaccine candidates (Na-GST-1 and Na-APR-1) was safe and well tolerated. In order to achieve optimal antibody levels, a series of three high doses needs to be administered. Additional investigations are necessary to consider this combination as a potential bivalent vaccine candidate.
ARTEMISININ-BASED COMBINATION TREATMENTS IN PREGNANT WOMEN IN ZAMBIA: EFFICACY, SAFETY AND RISK OF RECURRENT MALARIA
Authors: Nambozi Michael , Kabuya Jean-Bertin , Hachizovu Sebastian , Mwakazanga David , Kasongo Webster , Buyze Jozefien , Mulenga Modest , Geertruyden Jean-Pierre , D'Alessandro Umberto
Published: February 2017

Background

In Zambia, malaria is one of the leading causes of morbidity and mortality, especially among under five children and pregnant women. For the latter, WHO recommends the use of Artemisinin-based Combinations Treatments (ACTs) in the second and third trimester of pregnancy. In a context of limited information on ACTs, the safety and efficacy of three ACTs, namely artemether-lumefantrine (AL), mefloquine-artesunate (MQAS) and dihydroartemisinin-piperaquine (DHAPQ) were assessed in malaria-infected pregnant women.

Methods

Trial was carried out between July 2010 and August 2013 in Nchelenge district, Luapula Province, an area of high transmission, as part of multi-centre trial. Women in second or third trimester of pregnancy and with malaria were recruited and randomized to one of three study arms. Women were actively followed up for 63 days, and then at delivery and one year post-delivery.

Results

Nine hundred pregnant women were included, 300 per arm. PCR-adjusted treatment failure was 4.7% (12/258) (95%CI:2.7–8.0) for AL, 1.3% (3/235) (95%CI:0.4–3.7) for MQAS and 0.8% (2/236) (95%CI:0.2–3.0) for DHAPQ, with significant risk difference between AL and DHAPQ (p=0.01) and between AL and MQAS (p=0.03) treatments. New infections during follow up were more frequent in AL (Hazard Ratio (HR):4.70; 95%CI:3.18–6.94; p<0.01) and MQAS (HR:1.59; 95%CI:1.02–2.46; p=0.04) arms compared to DHAPQ arm. PCR-adjusted treatment failure was significantly associated with women under 20 years [HR5.35 (95%CI:1.07–26.73; p=0.04)] and higher malaria parasite density [3.23 (95%CI:1.03–10.10; p=0.04)], and still women under 20 years [1.78, (95%CI:1.26–2.52; p<0.01)] had a significantly higher risk of new infections. Unadjusted for treatment, low treatment dosage per kg body weight was significantly associated with the risk of new infections (HR:1.72; 95%CI:1.29–2.28; p<0.01). The three treatments were generally well tolerated. Dizziness, nausea, vomiting, headache and asthenia as Adverse Events (AEs) were more common in MQAS than in AL or DHAPQ (p<0.001). Birth outcomes were not significantly different between treatment arms.
RANDOMIZED TRIAL TO ASSESS EFFECT OF REPEATED TREATMENT OF DHA-PQ AND AL ON QTC INTERVAL IN PATIENTS PRESENTING WITH UNCOMPLICATED MALARIA IN BOBO-DIOULASSO, BURKINA FASO
Authors: Kabore Naomie , Barry Nouhoun , Kabre Zachari , Werme Karidia , Fofana Aminata , Compaore Daniel , Nikiema Frederic , Some Fabrice , Djimde Abdoulaye , Zongo Issaka , Ouedraogo Bosco
Published: February 2017

Background

Artemisinin combination therapies (ACTs) are widely used for the management of malaria and even tested for chemoprevention. In single episode efficacy studies, these drugs were clinically well tolerated but cardiac effects over repeated treatment are less investigated.

Methods

We conducted a prospective randomised controlled trial in Bobo-Dioulasso from August to October 2013 where patients aged 6 months and over were randomly allocated to receive either dihydroartemisinin-piperaquine (DHAPQ) or artemether-lumefantrine (AL) on first and subsequent episodes. Each participant was screened against inclusion criteria including the ECG which was repeated again 2 hours after the last dose. We considered that a QTc interval more than 30 ms compared to the baseline value is abnormal, but a prolonged QTc interval over 450 ms was reported as adverse event. QTc values were categorised into less or greater or equal to 450 ms. Drug tolerance was compared using Chi-square test, and p-value of less than 0.5 is significant.

Results

Patients were randomised to receive DHAPQ (n=224) or AL (n=236). During the 2 years follow-up we observed a total of 130 (in 1173 electrocardiogram performed on day 2 monitoring) prolonged QTc more than 450 ms (96/548 for DHAPQ and 34/625 for AL, p< 0.001). Irrespective of the drug, these proportions of prolonged QTc decreased over the subsequent episodes (50 QTc =450 in episode 1 to 0 in episode 8 up to episode 10).

Conclusions

The proportion of prolonged QTc was higher in DHAPQ group compared to the AL group but decreased along with the number of retreatments. Otherwise, DHAPQ and AL were well tolerated despite repeated treatment of malaria, which seemed to improve over consecutive episodes.
IMMUNOGENS DESIGNED FOR TARGETING NEUTRALIZING EPITOPES OF HIV-1 ENVELOPE GLYCOPROTEIN
Authors: Nchinda Godwin , Bopda Alain , Nji Nadesh , Ambada Georgia , Ngu Loveline , Tchadji Jules , Sake Carol , Magagoum Suzanne , Njambe Ghislain D. , Lisom Abel , Park Chae Gyu
Published: February 2017

Background

Due to its unique challenge of establishing lifelong reservoirs a successful HIV-1 vaccine must elicit protective antibodies responses at the portals of entry. Broadly neutralising antibodies (bnAb) have been demonstrated not only to be therapeutic through suppressing viraemia in HIV-1 infected people but also preventive in blocking HIV-1 infection in animal models. This implies that a desirable HIV-1 vaccine candidate should be able to induce HIV-1 specific bnAb with an extensive ability to neutralise a broad range of HIV-1 isolates. Although several bnAb are known to target conserved regions in the HIV-1 envelope glycoprotein, no vaccination strategy has successfully produced such antibodies. Thus, the ability to optimise and deliver HIV envelope immunogens that can induce bnAb has remained a formidable challenge.

Methods

To optimise immunogens for inducing bnAb, our group has pursued two main directions. In the first instance we developed B cell immunogens mimicking the native HIV-1 enveloped gp120 glycoprotein. Supernatants of stably transfected mutant lec1 CHO cells using a flag tag. We next assess antibodies isotypes specific to this immunogen in plasma obtained from antiretroviral naive participants. Secondly, through surface engineering of the evolutionary phage Qbeta we built in several epitopes of bnAbs for effective delivery to the immune system. We next assess in plasma from 648 seropositive participants the abundance of antibody isotypes specific to these B cell immunogens.

Results

The results obtained showed that all IgG isotypes were detected for both the manosylated and CHO wild-type expressed gp120. Although all IgG antibody isotypes including IgG1, IgG2, IgG3 and IgG4 were dictated, there was no significant difference between antibody titres directed to manosylated gp120 and wild-type gp120. Well over 87% of seropositive participants showed specific antibody responses to conserved B cell epitopes displayed on the surface of Qbeta phage.

Conclusions

These novel immunogens can be used as vaccine candidates.
PROGRESS IN THE DEVELOPMENT OF SAFE AND EFFECTIVE TUBERCULOSIS VACCINES
Authors: Tait Dereck
Published: February 2017

Background

Tuberculosis (TB) is the largest cause of mortality due to a single infectious agent. There were ∼9.6 million cases of TB and ∼1.5 million TB deaths in 2014, of which over 80% occurred in low- and middle income countries. In 1993, TB was declared a public health emergency by the World Health Organisation. Multidrug- and extensively drug-resistant TB is becoming increasingly common and adding significantly to the burden of disease. We will not meet the target of the WHO End TB Strategy of TB elimination by 2035 unless new interventions, drugs, diagnostics, and vaccines, become available. Modelling has demonstrated that elimination of TB is most likely to be achieved with new and effective TB vaccines. Effective and safe TB vaccines will also address the global crisis of drug resistant TB. The development of safe and effective TB vaccines is achievable as the human immune response does control TB in some circumstances – the highest risk of TB disease is within two years of skin test conversion, 90% of people with latent TB infection never develop TB disease, and BCG vaccine does provide partial protection. The probability of success is improved by significant progress in the field and the availability of new tools such as the robust use of improved animal models, increased diversity of mechanisms of action, combination vaccines, use of alternative routes of administration and stringent stage gates to concentrate resources of those vaccines most likely to succeed. New tools such as a controlled human infection model are in development, and novel clinical trial designs and use of special populations allow more streamlined studies and potentially earlier proof of concept. Globally, there are currently 13 TB vaccines in various stages of clinical development and efficacy data will be available from some of these candidates within one to three years.
COMMUNITY ENGAGEMENT IN TB VACCINE RESEARCH AND DEVELOPMENT IN ZAMBIA
Authors: Sibusiso Hlatjwako , Manda Olga , Croucher Kristin , Westhuizen Anja Van Der , Mshanga Isaac
Published: February 2017

Background

Community engagement (CE) is an essential component of clinical research. In 2000, the National Institute of General Medical Sciences recommended that researchers obtain community input into all phases of research, respect communities as partners, and establish appropriate community review procedures.

Method:

Aeras incorporated CE activities into all its studies and continues to seek input from communities into Aeras-conducted clinical trials.

Results

In Zambia, Aeras conducts TB vaccine clinical trials in collaboration with Zambia AIDS Related Tuberculosis (ZAMBART) Project and the Centre for Infectious Disease Research in Zambia (CIDRZ). Through an established CE program communities have received information on, and provided input to, the design and conduct of clinical trials. CE has provided a very useful avenue for communication between communities where clinical trials are being conducted and researchers.

Conclusions

The presentation will highlight CE activities related to TB vaccine clinical trials and their impact, and will promote discussion on the utility of CE activities in Zambia and elsewhere. The impact of funding shortfalls for CE will be discussed. As CE is an essential component of clinical trials continuous evaluation, it is important to ensure it remains effective and addresses changing knowledge and beliefs.
OCCURRENCE OF DAY 3 SUBMICROSCOPICPLASMODIUM FALCIPARUMPARASITAEMIA BEFORE AND AFTER IMPLEMENTATION OF ARTEMETHER-LUMEFANTRINE TREATMENT POLICY IN TANZANIA
Authors: Ngasala Billy , Jovel Irina , Malmberg Maja , Mmbando Bruno , Björkman Anders , Premji Zul , Mårtensson Andreas , Mwaiswelo Richard
Published: February 2017

Background

Emergence ofPlasmodium falciparumresistance against artemisinin in Southeast Asia raises a serious concern about the long-term efficacy of artemisinin-based combination therapy (ACT) globally. In Africa, ACT has remained highly efficacious with a microscopy determined asexual parasites clearance occurring within 48 hours post-treatment in most patients. However, submicroscopic parasitaemia has been reported on Day 3 after ACT treatment. We assessed the prevalence of patients with submicroscopic parasitaemia on Day 3 and its associated factors following treatment with artemether-lumefantrine (AL) from 2006 to 2014 in Bagamoyo district, Tanzania.

Methods

Cytochrome b-nested polymerase chain reaction (PCR) was used for screening of submicroscopic parasitaemia from blood samples collected on filter paper on Day 3 post-AL treatment for acute uncomplicatedP. falciparummalaria.

Primary outcome was proportion of patients with submicroscopic parasitaemia on Day 3 from 2006 to 2014. Secondary outcomes included proportional difference in submicroscopic parasitaemia across years, association of pre-treatment characteristics with submicroscopic parasitaemia, and association of submicroscopic parasitaemia with recurrent infection.

Results

Only 2/584 (0.34%) of the screened patients had microscopy determined parasitaemia on Day 3, whereas, 256/584 (43.8%) had submicroscopic parasitaemia. Submicroscopic parasitaemia prevalence increased from 28% (14/50) in 2006 to 74.2% (132/178) in 2007–8, and thereafter declined to 36% (50/139) in 2012–13 and 27.6% (60/217) in 2014, with the likelihood of being positive for submicroscopic parasitaemia decreasing by 14.7% (95% CI: 9.5–19.7%, p<0.001) for an increase in year by one. Pre-treatment parasitaemia >100,000/µL, haemoglobin <10 g/dL, fever, being aged <5 years and year of study 2007–8 and 2012–13 were associated with the presence of submicroscopic parasitaemia. There was no association between submicroscopic parasitaemia and recurrent infection.

Conclusions

Day 3 submicroscopic parasitaemia was common in patients treated with AL before and after implementation of the policy, and changed considerably across years from 2006 to 2014, however, its presence was associated with pre-treatment characteristics.
EVIDENCE OFPLASMODIUM FALCIPARUMRESISTANCE TO SULPHADOXINE-PYRIMETHAMINE (SP) IN PREGNANT WOMEN ALONG THE SLOPE OF MOUNT CAMEROON
Authors: Agbor Lenshina , Apinjoh Tobias
Published: February 2017

Background

Malaria in pregnancy (MiP) has debilitating effects for both mother and neonate, with intermittent preventive treatment in pregnancy (IPTp) central to successful malaria control and management in this vulnerable group. However, the effectiveness of IPTp with sulphadoxinepy-rimethamine (SP) is threatened by the emergence of drug resistantPlasmodium falciparumparasites vastly documented in some settings but not in south-western Cameroon. This study sought to ascertain the level of resistance of natural parasite populations to SP in this area.

Methods

A total of 358 parturients were enrolled through a cross-sectional survey from May to October 2015. Malaria parasitaemia was determined by light microscopy using Giemsa-stained thick and thin smears of the peripheral blood, while DNA was extracted from dried blood spots ofP. falciparum-positive samples by the Chelex-PBS method. SNPs inpfdhpsandpfdhfrwere then genotyped by nested polymerase chain reaction followed by allele-specific restriction analysis (ASRA).

Results

A total of 47 women (13.1%) had MiP, with a geometric mean parasitaemia density of 1064 parasites/µl of blood. The weight (p=0.038), gestational age (p=0.001), IPTp-SP usage (p< 0.001) and IPTp-SP dosage (p=0.001) of parturients were identified as risk factors of malaria parasitaemia. Overall, 76.5% (274/358) and 60.3% (216/358) of the women took IPTp-SP and two or more SP doses, respectively. Participants who had taken IPTp-SP (p=0.009) and two or more SP doses (p<0.001) had lower parasite loads compared to non-IPTp-SP users and those who had taken one dose or less, respectively. The Pfdhps K540E substitution was absent in the area, the prevalence of Pfdhfr S108N and Pfdhps A581G was 97.6% and 51.1%, respectively.

Conclusions

These results show the value of IPTp-SP usage and dosage in malaria parasitaemia control, in spite of the high prevalence ofP. falciparumresistance to SP in the area, with implications for the control of malaria in this vulnerable group.
EFFICACY AND SAFETY OF ARTEMISININ-BASED COMBINATION THERAPIES IN PEOPLE WITHPLASMODIUM FALCIPARUMMALARIA RECEIVING ANTIRETROVIRAL THERAPY IN ZAMBIA
Authors: Chaponda Mike
Published: February 2017

Background

The coverage of Artemisinin-based Combination Therapies (ACTs) for treatment of malaria and antiretroviral therapy (ART) is increasing rapidly in Sub-Saharan Africa. Because of the geographical overlap in areas of high malaria and HIV prevalence, HIV-infected people receiving ART may become malaria-infected and will need ACTs.

However, few studies have assessed the safety and efficacy of administering ACTs in people taking ART. The interactions might lead to high ACT drug levels which might cause toxicity or low drug levels which might adversely affect malaria parasite clearance, thereby fuelling resistance.

Methods

We conducted a phase IIIb single arm (non-comparative), open label clinical trial. We enrolled and followed up 155 patients at St. Paul's Hospital in Nchelenge district of Zambia. The patients were enrolled in the study after they consented to participate and met strict inclusion and exclusion criteria.

Results

Patient enrolment was completed in September 2015. The results of this study are currently being analysed.

Conclusions

Data on the safety and efficacy of ACTs in people taking different types of ART are lacking since previous regulatory trials have systematically excluded HIV-positive people, including those receiving ART. Thus, the results of our study will assist in the following ways: determine whether HIV-infected individuals receiving specific types of ART require a specific type of ACTs, inform clinical practitioners about what sort of adverse events they should expect and monitor in people taking different combinations of ACTs and ARTs, and provide evidence-based recommendations to the WHO and National Malaria Control Programmes on safe and effective ACTs that can be used in patients' EFV-based regimen. This study was part of a multicentre trial including centres in Malawi and Mozambique.
POLICY-DRIVEN INTERVENTIONS: TUBERCULOSIS
Authors: Walzl Gerhard , Chegou Novel , Malherbe Stephanus , Hatherill Mark , Scriba Thomas J. , Zak Daniel E. , Barry Clifton E. , Kaufmann Stefan H.E.
Published: February 2017

Annual tuberculosis (Tb) rates decline by 1.7%, which is inadequate to reach WHO targets. We describe three host-biomarker developments that are entering clinical testing and that could accelerate progress against TB.

Blood mRNA signatures with promising predictive ability for incident TB were recently described in African cohorts. Correlate of risk (COR) positive participants have 7 to 18 times increased risk for progression. A clinical trial is underway in South Africa under leadership of the South African Tuberculosis Vaccine Initiative to evaluate targeted chemoprophylaxis in COR positive people in an area with a very high prevalence of latent TB infection, where untargeted preventative treatment is not practical.

Historical data suggests that 85% of patients are cured after 4 months of TB treatment but attempts to shorten treatment without an unacceptable relapse rate have failed. Treatment shortening criteria based on PET/CT imaging and microbiological criteria were developed. An EDCTP/Bill & Melinda Gates Foundation/NIH co-funded study, led by the Tuberculosis Research Section of the NIH, will start in South Africa and in China in 2017 to evaluate biomarker-driven treatment shortening to 4 months.

To address diagnostic bottlenecks, a blood-based 7-host marker diagnostic signature was recently found with promising screening potential for active TB. An EDCTP-funded project with Africa and EU partners aims to develop a point-of-care, finger stick blood test that can simultaneously measure all 7 markers and rule out 75% of people with symptoms compatible of active TB in whom the diagnosis is subsequently ruled out. Such screening tests could speed up diagnostic work-up and save significant costs. Taken together, biomarker-driven interventions are now being actively tested and hold promise to provide important tools towards the eventual eradication of the TB scourge.
CXCL10 GENE PROMOTER POLYMORPHISM – 1447A>G IS ASSOCIATED WITH MALARIA IN GHANAIAN CHILDREN
Authors: Botchway Felix , Wilson Nana , Dickinson-Copeland Carmen M , Adjei Andrew A. , Wilson Michael , Stiles Jonathan K.
Published: February 2017

Background

Recent studies indicate that interferon gamma inducible chemokine, CXCL10, is a strong predictor of both human and experimental cerebral malaria. We hypothesised malaria infection is associated with variation in CXCL10 expression. We determined whether polymorphisms in the CXCL10 gene promoter region played a role in the clinical status of malaria patients and addressed the genetic basis of CXCL10 expression during malaria infection.

Methods

Basic demographics that may impact our assessments including age, gender, full blood count, sickle cell status and CXCL10 polymorphism were assessed. We assessed a single nucleotide polymorphism in the CXCL10 promoter (–1447A>G [rs4508917]) among 382 malaria and 117 non-malaria subjects using PCR-restriction fragment length polymorphism assay. Adjusted Odds Ratio (AOR) was used to find out if there was any association between CXC10 promoter polymorphism –1447 A>G and susceptibility to malaria.

Results

The median age for malaria patients was 4 years and that for non-malaria was14 years. There was significant difference with regards to haemoglobin levels and White cell counts between malaria patients and non-malaria subjects ( p<0.0001). Individuals with the 21447(A/G) genotype were susceptible to malaria (adjusted odds ratio [AOR]=2.60, 95% CI: 1.51–5.85, p=0.021). Additionally, individuals with the 21447(A/G) genotype had significantly higher plasma CXCL10 levels than individuals with the 21447(A/A) genotype. Stratifying patients according to gender, the observed association of malaria with over expression of CXCL10 were more pronounced in females than in male patients (AOR=5.47, 95% CI: 1.34–22.29, p=0.018).

Conclusions

Polymorphisms in the CXCL10 gene promoter sequence were associated with increased CXCL10 production, which is linked to severity of malaria. These results suggest that the 21447A>G polymorphism in CXCL10 gene promoter could be partly responsible for the reported variation underlying severity of malaria outcomes particularly in females.
GENE VARIATION AND SUSPECTEDPLASMODIUM FALCIPARUMHISTIDINE-RICH PROTEIN 2 GENE DELETION AND ITS IMPACT ON SENSITIVITY OF MALARIA RAPID DIAGNOSTIC TESTS IN SUDAN
Authors: Hamid Muzamil Abdel , Awad-Elgeid Mona , Nasr Awad
Published: February 2017

Background

Malaria rapid diagnostic tests (RDTs) play a significant role in malaria case management and case investigations. Variability or absence of antigens targeted by PfHRP2-based RDTs have been reported worldwide. However, little data is available concerning genetic variability within SudanesePlasmodium falciparumisolates while variable sensitivity of PfHRP2 based RDTs has been observed. The objective was to find out the possible effect of PfHRP2 gene variation and suspected deletion on the performance of PfHRP2-based RDTs.

Methods

Seventy-sevenP. falciparumisolates were selected from three geographical regions of Sudan. Malaria HRP2-RDTs and Giemsa-stained blood films data were included for analysis. Thepfhrp2exon 2 fragments were amplified to study genetic variation and suspected deletion. Chi-square test was used for testing significance of results.

Results

Forty percent (31/77) ofP. falciparumisolates showed amplification for PfHRP2 (which revealed five alleles of different sizes), whereas 60% of isolates were PfHRP2 PCR-negative. There is a concordance of positive and negative rates on PfHRP2 RDT and gene amplification results of (35%) and (33%) respectively. Eighty-seven percent (78%) of RDTs positive isolates were PfHRP2 negative (p-value=0.001), while 4 out of 31pfhrp2positive isolates gave false negative results in RDT detection. Twenty out of 47 RDTs positive isolates were PfHRP2 negative (p-value=0.001).Plasmodium falciparumHRP2-RDTs showed higher sensitivity than microscopy in malaria detection (p-value=0.007).

Conclusions

The study provided baseline data on genetic variation and suspected deletion in PfHRP2 and its potential effect on RDT performance.
RE-EVALUATION OF MALARIA DIAGNOSIS BY MOLECULAR METHODS REVEALS MUTATIONS IN HRP-2 AND DRUG RESISTANCE MARKERS IN CAMEROON
Authors: Netongo Palmer , Kamdem Séverin , Velavan Thirumalaisamy , Kremsner Peter
Published: February 2017

Background

As the decline in malaria cases becomes obvious in most sub-Saharan African countries, a new major concern is accurate diagnosis of low parasitaemia which can cause sub-patent infections and false-negative Rapid Diagnostic Test (RDT) results. We assessed the accuracy malaria diagnosis by RDT and microscopy are currently been conducted in Cameroon, by re-evaluating some samples from patients who sought medical care at three health centres in Yaounde. The study would provide information which can help the national malaria control program to reorient interventions strategies to enhance accurate diagnosis within the country.

Methods

We undertook a research project within a period of six months to re-evaluate malaria confirmed cases by microscopy and RDT test (HRP2: SD BIOLINE Malaria Ag P.f/Pan: Optimal screening test forP. falciparumand otherPlasmodium species). We used molecular methods such as nested PCR, in-house tailored loop amplified isothermal amplification (LAMP) and GenoType MalariaDR molecular assay to revalidate these samples. DNA was directly extracted from the RDT cassettes using qiagen spin columns.

Results

Results showed discrepancies in malaria diagnosis by microscopy, RDT, PCR, LAMP and GenoType MalariaDR. Most false negatives results (RDT negative but positive by microscopy and molecular methods) are linked to low parasite density usually<150 asexual parasites/μl. However, there were some cases where higher parasite density >5,00/μl could lead to false negative results (linked to a deletion of about 870 bp in the HRP-2 gene). GenoType MalariaDR revealed the presence of mutations onPfmdr1 and Pfcrtassociated with resistance to ART.

Conclusions

The study provided factual information on the detectedP. falciparumisolates,HRP-2mutations and the performance of RDTs andPfmdr1, PfcrtandARTresistance markers present in the population. The first-line of ACT in Cameroon is artesunate+amodiaquine, yet possible resistance isolates of amodiaquine and artesunate could be circulating in the country.
FOSMIDOMYCIN-PIPERAQUINE AS NON-ARTEMISININ-BASED COMBINATION FOR ACUTE UNCOMPLICATEDPLASMODIUM FALCIPARUMMALARIA
Authors: Mombo-Ngoma Ghyslain , Remppis Jonathan , Sievers Moritz , Manego Rella Zoleko , Endamne Lilian , Lell Bertrand , Hutchinson David , Kremsner Peter
Published: February 2017

Background

As investment in research related to artemisinin resistance is a key objective of the Global Plan for Artemisinin Resistance Containment (GPARC), fosmidomycin and piperaquine are being developed to address the delay in parasite clearance following treatment with Artemisinin-based Combination Therapy (ACT). Though artemisinin resistance occurs principally in the Greater Mekong Region, there are concerns that it will emerge in sub-Saharan Africa.

Methods

A proof-of-concept study has been conducted in Gabon to determine the efficacy, tolerance and safety of fosmidomycin and piperaquine when administered orally for three days. A total of 100 subjects, including 10 adults, 40 children aged 5–14 years and 50 children aged 1–5 years fulfilling the inclusion criteria of mono-infection withPlasmodium falciparumand initial parasite counts between 1,000 and 150,000/µL were enrolled and followed up for 63 days. The primary efficacy endpoint was per protocol, the PCR-corrected cure rate on Day 28. Safety endpoints included the incidence, severity, drug-relatedness and seriousness of adverse events and laboratory abnormalities. ClinicalTrials.gov Identifier:NCT02198807

Results

The PCR-corrected 28-day cure rate in the older children was 100% (n=31). It was also 100% (n=38) in the younger children, a group deemed to be more therapeutically challenging on account of their lower immune status. Tolerance was excellent and there were no drug-related safety issues. Full results will be presented.

Conclusions

Fulfilling the WHO criteria for combination therapy, fosmidomycin as a rapidly acting blood schizonticide and piperaquine with its prolonged post-treatment prophylactic effect have been shown to be highly efficacious for the treatment of acute uncomplicated falciparum malaria in an area of intense malaria transmission. Dose optimisation studies with the dual aim of achieving a reduction in the dose of fosmidomycin within a therapeutic regimen of once daily dosing are planned.
MALARIA
Authors: Noor Abdisalan
Published: February 2017

At the beginning of the Roll Back Malaria (RBM) initiative around 2000, sub-Saharan Africa was going through a major malaria epidemic, compounded by the failure of chloroquine and emerging resistance to sulphadoxine-pyremithamine, as the first-line treatments for uncomplicated malaria. The initial call for increased funding through the 2000 Abuja Declaration only began to materialise in 2002 when the Global Fund to Fight AIDS, Tuberculosis and Malaria was established. The scale-up of malaria interventions, especially for vector control, began in earnest in 2004 in sub-Saharan Africa but by 2007 only less than 20% of children in Africa had slept under an insecticide-treated net. In addition, it is only from 2006 that the widespread use of artemesinin combination therapy (ACT) started to occur on a wide scale. By 2015, however, substantial coverage with both vector and treatment interventions had been achieved. Consequently, the malaria burden has decreased across sub-Saharan Africa. Here I review the current malaria situation in sub-Saharan Africa and discuss opportunities and challenges. I discuss some of the analytical work, including mapping that contributed to our understanding of the epidemiology of malaria and progress during the RBM era. I present examples of how this research has led to changes in policy and practice globally and in sub-Saharan Africa. I discuss the current major research needs and policy gaps in the malaria elimination agenda and how these may be applicable to other diseases in the EDCTP remit. I conclude with suggestions on the potential role of EDCTP in supporting clinical trials and capacity strengthening towards malaria elimination.
LUMEFANTRINE DISPOSITION AFTER REPETITIVE TREATMENT OF UNCOMPLICATED MALARIA PATIENTS WITH ARTEMETHER-LUMEFANTRINE IN MALI
Authors: Tekete Mamadou , Burhenne Juergen , Fofana Bakary , Toure Sekou , Dama Souleymane , Dara Nianwalou , Traore Oumar , Sidibe Bouran , Djimde Abdoulaye , Haefeli Walter , Borrmann Steffen
Published: February 2017

Background

Since 2006 the national malaria control program in Mali recommended artemether-lumefantrine (AL) as the first-line treatment of uncomplicated malaria. The role of lumefantrine in this combination is to eliminate remaining parasites after the action of artemether and to protect the patient against a new blood infection. Some studies showed a correlation between lumefantrine's day 7 concentration and the efficacy of AL after treatment of a single episode of malaria. The objective of this work is to validate this observation after repetitive treatment of uncomplicated malaria patients with AL.

Methods

During a phase IIIb/IV comparative, randomised, multicentre, clinical study of artemisinin-based combination therapies, we collected plasma on Day 7 from patients treated with standard dose of AL in Sotuba, Bougoula Hameau, and Kolle (Mali). The age of the patients enrolled in this study was from 6 months old. The plasma samples were kept at – 80°C until lumefantrine analysis using high performance liquid chromatography was performed.

Results

We included 1076 subjects, of which 595 were females and a mean age of 12 years old in this analysis.

The median concentration was 66% higher (p<0.0001) in patients without recurrent parasite on day 28 compared to patients with recurrent parasitaemia: 509.1 ng/ml (inter quartile range: 329.6–723.2; n=919)vs372.5 (255.7–538.4; n=157). Day 7 concentrations increased with age; the difference between age group was statistically significant: 305.9 (207.3–491.5, n=140), 447 (290.7–622.9, n=399), 544.7 (383.9–738.5, n=254) and 571.1 (378.8–850.9), n=283) in patients under 5 years old, 5–9 years old, 10–14 years old and 15 years old and older, respectively. Girls under 5 years old had a lower lumefantrine concentration at day 7 compared to other age groups of 223.3 ng/ml (159.7–425.6, n=37).

Conclusions

We found a lower concentration of lumefantrine in patients with recurrent parasitaemia at day 28.
ONE MERCK FOR MALARIA PROGRAM: AN INTEGRATED R&D APPROACH TO FIGHT AGAINST MALARIA
Authors: Greco Beatrice , Spangenberg Thomas , Kourany-Lefoll Elly , Oeuvray Claude , Mulry Jim , Tyagarajan Kamala , Magsaam Bettina
Published: February 2017

Background

Integrated health care approaches are the most effective ways to tackle infectious diseases such as malaria. Within its Global Health activities focusing on health issues of vulnerable populations within developing environments, Merck has launched a program named ‘One Merck for Malaria’ integrating development of new antimalarials with new sensitive diagnostic approaches together with improving access to personal protection.

Methods

The first pillar of the program is based on drug discovery and development of new antimalarials. The second pillar focuses on development of diagnostics addressing the need for highly sensitive methods to identify low parasitaemia levels. The third pillar is to improve access to personal protection against malaria vectors.

Results

Merck is carrying out screens and early drug discovery with its partners, Medicines for Malaria Venture (MMV, Switzerland) and H3D (University of Cape Town, South Africa), to identify new compounds to address current gaps in existing antimalarials. Furthermore Merck is conducting regulatory preclinical activities to reach clinical phase 1 of a compound originated by Dundee University (UK). Based on its excellent efficacy and pharmaceutical profile shown in pre-clinical models, it is intended to be developed as a long-lasting single oral combination treatment for uncomplicatedP. falciparumandP. vivax. Other research activities focusing on target identification are conducted. The portable MUSE® cytofluorometer system is launched in African countries to measure the number and % of CD4 cells. An additional set ofP. falciparumandP. vivaxdetection kits are in development to detect type and parasitaemia levels in low blood quantities. Merck IR3535 is a widely used insect repellent being retested to assess the degree of its efficacy against variousAnophelescarryingP. falciparumin Africa.

Conclusions

Besides the drug and technology developments, the program covers also aspects of e-health, education, and local capacity building to complement the integrated approach being applied at Merck.
SPATIAL-TEMPORAL DYNAMICS IN HETEROGENEITY OF MALARIA INFECTION IN A SETTING WITH SEASONAL TRANSMISSION: A LONGITUDINAL STUDY IN THE GAMBIA
Authors: Mwesigwa Julia , Achan Jane , Jawara Musa , Ditanna Gian , Worwui Archibald , Affara Muna , Geertruyden Jean-Pierre , D'Alessandro Umberto
Published: February 2017

Background

The reduction in the malaria burden previously reported in The Gambia is largely due to the successful scaling up of control interventions. Understanding the current dynamics of malaria transmission in a context of high coverage of control interventions is critical to inform pre-elimination efforts.

Methods

A cohort study was conducted in 12 villages across the country during the 2013 transmission season. Enrolled residents aged over 6 months old had a blood sample collected monthly for molecular analysis (PCR) and microscopy. Clinical malaria cases were captured by passive detection. Mosquito abundance and species distribution were determined by collections with CDC light traps, human landing catches.

Results

A cohort of 4235 participants with a median age of 13 years (IQR 5, 28) was followed up. Long Lasting Insecticidal Nets coverage was 71.6% (2774/3876). The incidence rate ofPlasmodium falciparumparasitaemia infection was 1.1 episodes per person-year (95% CI: 0.8–1.2).P. falciparumtransmission was heterogeneous with low rates in the western region 0.47 episodes p-pyear (0.41–0.56) and highest in the eastern region 2.8 episodes per person-year (95% CI: 2.6–3.1). The peak mosquito densities were in September preceding peakP. falciparumincidence in December.Anopheles (An.) Gambiae Sform andAn. arabiensiswere the predominant species in all the regions except the central and lower river regions whereAn. gambiaeM form andAn. melaswere the predominant species. The risk of clinical malaria during the season was higher among individuals living with asymptomatic malaria at the start of the season; (Western region HR=3.9, 95% CI: 2.1–7.5) and eastern region (HR=1.5, 95% CI: 1.1–2.1).

Conclusions

In The Gambia, malaria transmission is seasonal and heterogeneous across the country, with clustering of infection and disease at household level, suggesting the need for targeted interventions.
GENETIC POLYMORPHISM OF MEROZOITE SURFACE PROTEIN-2 INPLASMODIUM FALCIPARUMISOLATES FROM DELIVERING WOMEN IN SOUTHERN BRAZZAVILLE, REPUBLIC OF CONGO
Authors: Koukouikila-Koussounda Félix , Kombo Michael , Vouvoungui Christevy , Ntoumi Francine
Published: February 2017

Background

In the Republic of Congo, the genetic diversity ofPlasmodium falciparumhas been extensively studied in isolates from children. However, limited data are available for isolates collected from delivering women. This study was conducted to determine the genetic polymorphism of merozoite surface protein-2 (msp-2) gene inPlasmodium falciparumisolates from asymptomatic delivering women in Brazzaville.

Methods

We used a total of 114 peripheral whole blood samples from delivering women collected from April 2014 to April 2015 at Madibou health centre in Southern Brazzaville and previously characterised asP. falciparum-positive by PCR technique targeting theSSUrRNAgene. After extraction of DNA using QIAamp DNA Blood Mini kit (Qiagen), the samples underwent nested PCR of themsp-2(block 3) and the allelic families, namely 3D7 and FC27, were determined.

Results

All the isolates were successfully genotyped. A total of 33msp-2alleles were detected, of which 17 belonged to the allelic family 3D7 and 16 to FC27 family. The 3D7 allelic family showed higher frequency (63.4%) compared to FC27 (36.6%) and 62 isolates (54.36%) harboured only 3D7 allele, while 22 (19%) harboured FC27 allele only and 30 (26%) showed both of these alleles. The mean multiplicity of infection (MOI) was 1.4 (95% CI: 1.33–4.01) and 35% of isolates had multiple genotypes. The MOI was lower in isolates from women who had not received any IPTp-SP (1.3) compared to those from women who had 3 doses of IPTp-SP (1.5) or in isolates from primiparous (1.3) compared to that of multiparous (1.5); however, the difference was not statistically significant (p >0.05).

Conclusions

This is the first report on genetic diversity offalciparumisolates from delivering women in the Republic of Congo. A noteworthy diversity was observed; the multiplicity of infection was neither influenced by IPTp-SP or parity.
FEASIBILITY OF IMPLEMENTING A CONTINUOUS HOUSEHOLD MALARIA INDICATOR SURVEY IN RARIEDA SUB-COUNTY, SIAYA COUNTY, WESTERN KENYA
Authors: Seda Brian , Kwambai Titus , Jangu Phelix , Samuels Aaron , Kuile Feike ter , Kariuki Simon
Published: February 2017

Background

Malaria transmission in Siaya County is high and perennial with peak transmission in May-July and October-November. The Kenya Medical Research Institute (KEMRI) and Centers for Disease Control and Prevention (CDC) have historically conducted malaria surveillance in western Kenya during peak malaria transmission season through annual population-based cross-sectional surveys. However, it may be important to characterise the seasonal spatial variation in malaria transmission for surveillance purposes, to monitor malaria interventions, and to inform decisions for changing and targeting malaria control strategies. We describe the feasibility of implementing a continuous malaria indicator survey (cMIS) for malaria surveillance in Rarieda sub-County, Kenya.

Methods

All households in the study area were GPS-mapped and household members enumerated. Community interviewers were trained and assessed in collecting blood for malaria rapid diagnostic tests (RDT), preparation of dried blood spots on Whatman 903 filter paper, preparing blood smears, and performing HemoCue® tests for haemoglobin determination. Community interviewers were also trained to provide appropriate treatment with antimalarials and haematinics based on test results. They visited a random subset of 5 houses in the study area each week and collected and transmitted data in real-time throughout the year.

Results

Four trained community interviewers visited a total of 1041 compounds, and consented and tested a total of 4714 participants for malaria by RDT in year one. Approximately 27% were positive for malaria by RDT and were offered treatment.

Conclusions

A large number of compounds were visited by few staff in year one. This suggests that cMIS may be a viable way to perform year-round surveillance, and to offer malaria testing and treatment in the community with minimal staff. Further analysis of results from cMIS and comparisons to existing surveillance platforms are warranted to determine if cMIS can provide accurate estimates of malaria case burdens throughout the year.