Malaria Centre Report - Virtual Open...

MalariaCentreReport

2014-16

Contents

Malaria Centre Report 2014-2016

Director’s message 4

Executive summary 5

Public engagement 6

Capacity strengthening 11

Malaria biology 16 Parasite biology 18 Immunology and host resistance 32Vector biology 39

Malaria prevention 44 Vector control 46 Chemoprevention 55Vaccine development 62

Treatment of malaria 66 Drug studies 68 Community-based case management 80

Malaria surveillance monitoring and evaluation 88

Publications 104

Abbreviations 122

Members 123

Obituary: Sylvia Meek 126

Executive summary 5


4 Director’s message

The World Health Organization’s latest

World Malaria Report from 2015 highlights

the tremendous advances that have

been made in reductions to both malaria

morbidity and mortality.

The report showed that 57 countries decreased their malaria burden by 75% and that the European region reported no indigenous malaria cases in the last three years. These advances are testament to the collective endeavours of governments, funders, industry, researchers and health workers across the globe. However, despite such improvements, malaria remains entrenched in several sub-Saharan African countries and the ominous spectre of insecticide resistance threatens our most effective interventions.This, coupled with consolidated reports on the emergence of parasite resistance to the first-line antimalarial drugs, requires increased attention and vigilance.

The LSHTM Malaria Centre remains at the forefront of addressing some of these pressing challenges. Having been established in 1988, it now has more than 300 members spanning all three faculties at the School. In addition, Centre members continue to collaborate with many partners in the UK and overseas in over 30 countries.

Please take the time to read this report which details the latest Malaria Centre activities. What is presented here highlights the breadth of research that is needed to ensure we continue to turn the tables on one of the world’s deadliest diseases.

The unprecedented reductions in malaria

morbidity and mortality in the last 15 years

give the global community huge cause for

optimism.

The challenge now is to, not only consolidate and sustain these reductions but, further decrease the level of malaria transmission, such that elimination becomes a realistic goal for all endemic countries. What is becoming clear is that malaria presents a unique challenge in the need to define and implement tailored solutions in each of the different settings in which it exists. This requires detailed understanding of both parasite and vector biology as well as relevant local social and ecological factors that shape disease transmission in specific settings.

As highlighted in this report, the School’s Malaria Centre is uniquely placed to address these complex challenges. The report is designed to emphasize both the diversity and the translational nature of our work.

Understanding the transmission of malaria has been a cornerstone of our activities for many years. This involves identifying new drug targets with transfected parasites and conducting field studies to identify who in the endemic community infects mosquitoes as well as the influence of specific human odours on this process. Similarly, fundamental immunology is being carried out to identify factors governing immune responses which affect potential malaria vaccines. Many Centre members were also involved in the largest clinical trial to date of a malaria vaccine. Evaluation of interventions in endemic settings represents a large part of the Centre’s output and demonstrates true interdisciplinary research with social science and economics allied to conventional trials of insecticides and drugs. Many of these studies are underpinned by new laboratory and statistical approaches to both describe the level of malaria transmission and measure any effects of interventions.

This report also highlights public engagement activities carried out by members which is a vital part of generating understanding about how our research can help fight malaria. The capacity strengthening activities detailed here demonstrate the strong emphasis we put on training students all over the world who will go on to lead future efforts to control malaria. Together, when combined with new and established skills that we have in parasitology, entomology, epidemiology and social science, these strengths allow the Malaria Centre to continue to be at the forefront of fighting one of the world’s major public health issues.

London School of Hygiene & Tropical Medicine

Peter PiotLondon School of Hygiene & Tropical

Medicine Director and Professor of Global Health

Chris DrakeleyMalaria Centre Director

and Professor ofInfection and Immunity

The School has a commitment to public

engagement with a promise to create a

rich programme of activities. As such,

it supports both staff and students to

translate their research for the mutual

benefit of the School and the public alike.

The Malaria Centre supports the School’s

vision and public engagement strategy.

Many of our members have been involved

in a variety of events during the period of

this report. Activities have included: our

World Mosquito Day commemorations;

a series of discussions, talks and

workshops at conferences seminars and

festivals; an arts-based project with school

children in Tanzania and a range of press

appearances.

Malaria Centre members employ a range of

techniques to reach as wide an audience as

possible. Here, we present a snap shot of

our members’ public engagement activities

and encourage you to find out more via the links provided as well as the Malaria Centre

web site.

Rebecca Tremain, Dalia Iskander, David Schellenberg, Ann Hardy and Jo Lines

Inspired by a photograph from the Ross Collection (held by the School’s Archives Service), World Mosquito Day celebrates the moment, on 20th August 1897, that Sir Ronald Ross identified that Anopheles mosquitoes transmit malaria.

Each year focuses on a different aspect of Ross’s life and work and employs different formats to bring a new, non-specialist audience into the Malaria Centre’s orbit. In 2014, to coincide with the centenary of the start of the First World War, the team dramatised highlights from Ross’s war work and examined the role played by the little known ‘lab girls’ – young girls employed in the School’s laboratories during this time when most able-bodied men of fighting age were on active service.

Songs from the period and other characters in the story (Lady Ross, Matron of the Ross Institute and Binkie the dog) brought the story to life. A vectors-themed pub quiz and best dressed guest competition encouraged audience participation.

Chris Whitty, Rebecca Tremain and The British Library, London

Professor Chris Whitty teamed up with The Mustard Club (MC member Rebecca Tremain and actress Penelope Dimond) in collaboration with the British Library’s Antonia Moon, Alex Hailey and Katie Howe to examine malaria treatment in India under British rule. Through a dramatisation of material held in the India Office Records, the group examined the historical understanding of the origins of malaria and contrasted interventions then and now.

The tea-time event was illustrated with maps and images from the digitised India Office Medical Archives project and recordings from the Endangered Archives Programme. The bulk of the audience worked outside academic or medical sectors and gave overwhelmingly positive feedback.

Lena Lorenz

The School’s ITD Small Grants Scheme was launched in 2015 to encourage early careers researchers to employ public engagement tools to reach beyond their research activities.

Malaria Centre member Lena Lorenz was one of the first recipients of the awards for a schools-based art project working in conjunction with two teachers from the Steven Tito Academy, Bagamoyo, Tanzania.

In her project, Lena asked children the question, “what makes you happy and healthy, what makes you sick?” and encouraged students to capture their answers using

digital photography and other art materials.

Malaria was one of the subjects that was most discussed by the class, especially during a visit to the school by scientists from The Ifakara Health Institute (IHI). The project ended with a school-based exhibition of the art work with captions by the children to which they invited their families and proudly showed off their learning. Further activities are now planned for other cohorts, including a visit to IHI to see the scientists at work.

http://blogs.lshtm.ac.uk/news/2015/11/13/students-show-off-their-science-projects-at-the-steven-tito-academy-tanzania/

6 Public engagement

Malaria Centre Report 2014-2016London School of Hygiene & Tropical Medicine

World Mosquito Day

Mosquitoes, Malaria & the Raj – Science

Unboxed

School-based arts in Tanzania

Public engagement 7

Public engagement 9


8 Public engagement

Deborah DiLiberto

In September 2014, Deborah DiLiberto addressed the All-Party Parliamentary Group on Malaria and Neglected Tropical Diseases (APPMG) in Westminster, UK.

Deborah presented results from the evaluation of PRIME, a complex health service intervention to improve quality of care for malaria at health centres in rural Uganda. Despite assertions that malaria interventions will lead to health system solutions, Deborah described how small improvements at health centres were insufficient to overcome health system challenges. Deborah recommended that attendees, including Members of Parliament, universities and non-governmental organisations, consider supporting government funding for innovations addressing wider political, economic and social challenges in order to strengthen health systems and improve quality of care.

Deborah’s presentation was acknowledged in the 2014 APPMG report (http://www.appmg-malaria.org.uk/) and was featured by the ACT Consortium, an international research collaboration answering key questions on malaria drug delivery in Africa and Asia, who funded the design and evaluation of the PRIME intervention.

http://www.actconsortium.org/news.php/83/there-are-more-medicines-and-diagnostic-tools-but-still-no-clean-water

Ailie Robinson

For the last two years, Malaria Centre member Ailie Robinson has been working as a STEM ambassador for STEMNET, a charity which promotes science, technology, engineering and maths (STEM) subjects by supporting school visits from people who work in those fields.

Along with other entomology STEM ambassadors, Ailie has taken live specimens, preserved parasites and slides to schools. She has discussed career pathways with students and given

‘lecture’ style presentations on topics ranging from vector borne diseases to Ebola. Ailie commented, ‘while juggling public engagement activities with my PhD can seem an unnecessary stress at times, it’s always a fantastic experience from which I learn something new every time. Working with STEM opened the door to public engagement for me, and in addition to doing something that I believe has real value for school children, I have definitely developed my skills as a presenter and communicator’.

David Baker

As part of the ‘Biology in Action’ day held at The UCL Institute of Education on 2nd March 2016, David Baker gave a talk on the global impact of malaria, symptoms of the disease and what control measures there are in place.

He used photos and moving images to illustrate the life cycle of the malaria parasite and the various

life forms that infect humans and mosquitoes. The talk then moved on to how molecular biology can be used to find out detailed information about the parasite and to identify essential biochemical pathways that might be targeted with new drugs.

With the urgent need to tackle antimalarial drug resistance and avoid a major public health disaster, David finished by pointing out that

a drug resistant parasite can be selected and spread through a population very quickly whereas it takes at least 10 years to get a new drug into the clinic.

The audience was made up of around 650 A-level students and the event was organised by The Training Partnership.

Matt Chico

With over 15.4 million sets in South Africa alone, radio plays a very important role in public engagement throughout Africa. With free call-in capacity via social media, lively phone-ins, health-related jingles and public health messaging, Channel Africa leads the way broadcasting daily to East, West and Central Africa and abroad.

On World Malaria Day 2015, Matthew Chico discussed the Global Call to Action to increase coverage of preventive treatment for malaria during pregnancy (Scale up of IPTp-SP) throughout sub-Saharan Africa on “Africa Today” – one of the flagship programmes on this popular station whose mission is “to produce and broadcast innovative and dynamic programming that informs, educates, entertains, and empowers African citizens”.

Matt spoke passionately about this “prevalent and entirely preventable disease” and the high burden of mortality and morbidity, especially in pregnant women who are often asymptomatic (symptom free) but have placentas that are compromised due to malaria infection. This deprives their unborn children of full nutrient and gas exchange and their babies are smaller than would otherwise be the case.

https://soundcloud.com/matthew-chico/matthew-chico-on-the-global-call-to-action

Jo Lines

In November 2015, the “Friends of the Global Fund” organised a side event within the “COP21” climate change conference in Paris to discuss the impact of climate and environmental changes on vector borne diseases.

Jo Lines was asked to speak on the threat to efforts to control malaria posed by the increase of insecticide resistance.

The event touched on a broad range of sustainable development and environmental issues, not just climate change and was attended by significant numbers of NGOs and members of the international press.

Malaria Centre students address the UK Parliament

STEM Ambassadors

Biology in Action

Channel Africa – ‘Voice of the African Resistance’

Guests speakers at conferences

Strengthening capacity for malaria

training and research is at the heart

of the Malaria Centre. Members work

in partnership with individuals and

organisations all over the world

to deliver high quality training

programmes, particularly in the UK

and Sub-Saharan Africa. Many of our

research programmes continue to have

capacity strengthening as a core aim.

World-wide teaching and training

The London School of Hygiene and Tropical Medicine is a world-leading centre for research and is renowned for its postgraduate education. The Centre currently supports over 40 PhD students whose research spans from basic science to social science research.

The study of malaria is present in several of the School’s Masters Degrees and short courses and is the chosen topic for many research degree students. Every year, staff of the Malaria Centre contribute to strengthening capacity amongst MSc students, with specialist malaria teaching forming an integral part of both London-based and distance-learning MSc courses.

Lectures and laboratory practicals, designed to foster a detailed understanding of the life history of malaria parasites and mosquito vectors, form a core component of teaching in the first term for several MSc courses.

In addition, all London-based MSc students have the option to take a 5-week module on the Epidemiology and Control of Malaria, which aims to give students a deeper view of malaria as a public health problem, and generate a comprehensive understanding of the environmental, biological, political and social roots of malaria, by building connections between a wide variety of aspects and viewpoints.

Strong emphasis is placed on providing up-to-date knowledge of the interventions that can be used to control malaria, as well as a critical understanding of current and future challenges to their effective use and application.

Students apply this knowledge to inform the design of either a control programme, intervention trial or elimination strategy according to the malaria epidemiology of a given setting (selected from a choice of 5-6 representative settings across the



10 Public engagement


ACT Consortium

Multidisciplinary teams of researchers from the ACT Consortium launched five resources to help guide communicators working in malaria endemic countries.

The free Starter Kit consists of training resources that were developed, piloted, delivered and evaluated to help convey the need for appropriate diagnosis and treatment amongst both health workers and patients. They can be used and adapted to other interventions and their contexts.

www.actconsortium.org/starterkit

Research and expert comment from School Malaria Centre experts have been making headlines around the world during 2014 and 2015, with more than 4,600 online articles plus TV and radio pieces. During this period, the press office received more than 470 calls and emails from journalists asking for information about our malaria research or requesting an interview with an expert.

High-profile stories from the School making headlines included: the final trials of the RTS,S malaria vaccine; research demonstrating the heritability of attractiveness to mosquitoes; the presence of fake and substandard anti-malarial drugs in Africa; and findings from the MONKEYBAR project looking at the links between deforestation and emerging zoonotic malaria in Southeast Asia.

Malaria Centre experts set the agenda with their comments on international news stories such as the World Malaria Report and international outbreaks of mosquito-borne diseases including the Zika virus in early 2016.

Coverage spanned international print, TV, radio and online outlets including BBC News, CNN, Reuters, TIME Magazine, Al Jazeera, South China Morning Post and Times of India.

Comment pieces written by experts from the Malaria Centre ran on news sites including the Guardian and Thomson Reuters Foundation.

Behind the scenes media visits to the insectaries led to pieces including a high-profile video by VICE Motherboard (128,000 YouTube views, 1.7 million Facebook shares); an NPR radio feature (broadcast across 800+ US stations); a popular feature on the Londonist website and a piece on BBC World Service’s World Update programme.

Malaria diagnosis and treatment starter kit

Malaria research makes the headlines

Katherine Theiss-Nyland

My PhD focuses on the integration of long lasting insecticide treated nets (LLINs) for continuous distribution within antenatal and immunization services in Africa.

Integrated programming is especially important during pregnancy and infancy to ensure that women and children receive a comprehensive package of preventative health interventions and care.

But implementing these services is difficult due to disease-specific funding streams and health departments, and limited staffing and time available for each client. Using a mixed-methods approach, I am evaluating policy, operational, and programmatic structures to identify features which either support or hinder integrated service delivery across countries.

This research will support improved policy development and implementation strategies for integrated health programming.

Having started my career in maternal and child health, the malaria centre has provided me with the opportunity to meet and connect with leaders in the field of malaria, as well as gain a broad understanding of malaria prevention and treatment strategies beyond programme implementation and evaluation.

Debora DiLiberto

My thesis explores the practices of designing and evaluating PRIME, a complex health service intervention to improve quality of care for malaria at health centres in rural Uganda.Multidimensional interventions to improve the quality of care provided in the public sector, including accurate diagnosis and prompt effective antimalarial treatment, are urgently needed. However, guidance on methodologies for demonstrating not only if these interventions work, but why, where, and for whom is limited. I am using a mixed-methods approach to assess the PRIME intervention’s outcomes and change processes. This thesis will inform best practices for designing complex interventions and evaluations considering how these practices influence interpretation and transferability of evidence. As a multidisciplinary researcher, I have benefited from working with different experts in the Malaria Centre including anthropologists, epidemiologists and statisticians. Likewise, being exposed to the Centre’s various research projects has motivated my future career interests in complex intervention design, implementation and evaluation.

PhD student profiles



Strengthening malaria research capacity in Africa

The Malaria Capacity Development Consortium (MCDC) is a partnership of five African and three European institutions, funded by the Wellcome Trust and the Bill & Melinda Gates Foundation. It works to strengthen the capacity of African scientists and institutions to conduct high quality research in malaria-endemic countries in East, West and Southern Africa.

The MCDC programme supports approximately fifty African scientists with doctoral and postdoctoral

research fellowships. It provides a formal postdoctoral programme for early-career researchers, which includes: (a) access to competitive postdoctoral research grants, (b) Personal Development Planning, (c) mentorship, (d) research dissemination and networking opportunities, and (e) leadership development.

In addition, the MCDC African partner institutions are supported with programmes to strengthen their research environments, research management and administration, and postgraduate and postdoctoral research programmes.

MCDC partners

LSHTM investigators:Brian GreenwoodDavid Schellenberg

External collaborators:Alister Craig (Liverpool School of Tropical Medicine, UK); Oumar Gaye (Université Cheikh Anta Diop de

Dakar, Senegal); Moses Kamya (Makerere University, Uganda); Gibson Kibiki (Kilimanjaro Christian Medical Centre, Tanzania); Thor Theander (Centre for Medical Parisitology, University of Copenhagen, Denmark); Pascal Magnussen (Faculty of Life Sciences, University of Copenhagen, Denmark); Victor Mwapasa (The College of Medicine, University of Malawi, Malawi); Harry Tagbor (Kwame Nkrumah University of Science and Technology, Ghana)

As the MCDC’s seven-year programme draws to a close, two key features have been put in place to help sustain this research capacity strengthening beyond the programme life time. Career Development Groups (CDGs) have been established within each of the African partner institutions, and an affiliated institution - the Centre for Biotechnology and Bioinformatics at the University of Nairobi - to embed institution-led programmes of career development support and training for researchers.

To encourage continued malaria research and the collaborations established during MCDC, “malaria centres” have been developed by the MCDC partner institutions – with the aim of facilitating collaborative interactions amongst malaria researchers, providing

links between researchers and policy-makers, and between senior researchers, students and junior faculty to identify research opportunities and to provide research supervision.

MCDC are also supporting the Malaria Research Capacity Development (MARCAD) programme, led by the Université Cheikh Anta Diop de Dakar, Senegal, and funded through the Wellcome Trust, DELTAS programme.

The aim of this programme is to establish a core group of internationally-competitive scientists, who will focus research on malaria control / elimination in West and Central Africa.

12 Capacity strengthening

globe). This is a highly popular module, attracting around 40 students each year, many of whom have gone on to play an active role either in malaria research and/or control in academia, NGOs, national control programmes, and international agencies.

Students come to the School from countries all over the world, creating a rich and diverse learning environment. In addition, there has been increased interest in the School’s Distance Learning IDM503 malaria module with 81 students registering for the module in 2014/15 and 75 in 2015/2016. Many members also help run or contribute to global training courses, particularly in malaria-endemic countries.

‘Having a tutor who is an expert in the topic you are writing on to guide you through the assessment is a great opportunity. Although the assignment initially seemed very challenging, my tutor was able to direct me towards relevant reading, offer advice and help to shape some of my ideas. The assignment helped me to gain a lot of skills in terms of designing a control programme and thinking critically and practically about the practical aspects of it.’

Student feedback from Epidemiology and Control of Malaria module.

‘This module definitely brings together a diverse group of specialists employing different strategies to better control the problem of malaria. It was a great module and I would highly recommend it to anyone having any interest in malaria.’

Student feedback from Epidemiology and Control of Malaria module.


Graduate Program Science for Development, Cape Verde

Since 2013 the PGCD Graduate Program Science for Development, has been running annually in Cidade da Praia, Cape Verde. This program is a pioneer advanced training scheme for Portuguese-speaking African and East Timorese students. The main objective is to give students the opportunity to learn advanced science and become scientists back in their original countries. Twelve new students are selected each year.

From the London School of Hygiene and Tropical Medicine, Professor Laura Rodrigues and Dr Nuno Sepúlveda have volunteered to organize and lecture on the Epidemiology and Statistics course each year.

Malaria genetics and epidemiology have been used as core examples for data analysis and study design. These annual visits to the country also brought new collaborative opportunities with local investigators from the National Institute for Public Health, namely, on a project measuring a quasi malaria elimination using a serological approach.



14 Capacity strengthening

MCDC Mentoring programme

Mentoring is an essential component of capacity strengthening. Its complementarity with Personal Development Planning (PDP) and researcher and staff development promotes the building of capacity and expertise within individuals and institutions.

The MCDC four-year mentoring programme supported mentors and mentees with their personal and career development - and in addition supported these individuals with developing and embedding mentoring programmes within their own institutions.

Collaborative workshops were held for mentors and mentees, transitioning mentees to mentors, and

with institutional stakeholders to scope, design and/or strengthen mentoring programmes to suit the context and needs of the institution. Each mentoring programme is designed for a specific target group within the institution – for example, mentoring early-career researchers through their postdoctoral transition phase, or mentoring junior faculty staff and researchers through their career progression and promotion.

To support sustainability, these institutions have invested in formalising and integrating their mentoring programmes within their institutional structures and processes.

Accreditation Project partners

LSHTM investigators: Alexandra Wright

External investigators:David Malone & Graham Small (IVCC- Innovative Vector Control Consortium, Liverpool UK)

Other capacity strengthening activities in Africa include the Accreditation Project which is taking place in Moshi, Tanzania.

The aim of the Accreditation Project is to successfully accredit the Pan African Malaria Vector Research Consortium (PAMVERC) Laboratories in Moshi, Tanzania by mid-2016. If successful, the PAMVERC Laboratory will be the first insecticide-testing laboratory

to reach accreditation . The site includes an insectary (for mosquito rearing), Insecticide-Testing Laboratory, animal house, suite of field site Experimental Huts, and a molecular laboratory.

The accreditation project initiative in Moshi, Tanzania was started by Innovative Vector Control Consortium (IVCC) in 2014 but the idea was born many years previously at IVCC’s inception. The variability and lack of traceability of data generated during certain IVCC projects that involved laboratory and field testing of novel vector control products highlighted the need for improvement in the data quality systems of collaborating institutions. Systems for assuring data quality tend to be common for contract research organizations while IVCC’s collaborators - which are predominantly based within academic institutions - lack such systems. As a result, IVCC has initiated activities with collaborators to encourage and assist in the development of Quality

Control systems. These activities have included field visits, a workshop and audits of the work and facilities of collaborating institutions in Africa and elsewhere.

There are several systems of accreditation that may be applicable to testing facilities conducting (mainly) bioassays using mosquitoes in the laboratory or semi-field systems. Good Laboratory Practice (GLP) was selected as the most appropriate system for PAMVERC Laboratories. If data being generated as part of an IVCC project is to be used for regulatory purposes, conducting the studies to GLP would be clearly beneficial. World Health Organization Pesticide Evaluation Scheme (WHOPES) have made statements publicly that data generated under accredited GLP could be submitted as an alternative to WHOPES sponsored studies. This could result in savings in both time and costs to those companies developing new vector control tools.

The project work has been challenging in many ways. The site needed physical construction to rebuild sections of the existing laboratories to comply with GLP. The staff also needed re-training, so various training workshops were held by experts in insectary, animal house, and molecular laboratory management; waste disposal; First aid and Fire Safety training; GLP Training; and Management training. Detailed day-to-day technical training for staff to perform duties according to GLP has been the most time consuming activity- behaviour change can be a challenge at all staff levels. If successful in the next 2 months, this project will roll out to other East and West African insecticide-testing laboratories in 2016-2018, and will collaborate with WHOPES to accredit sites in Asia over the next 2-3 years.


Insecticide-Testing Facility Test

Room• Before • After

Insectary- Adult Mosquito Room

• Before • AfterAn image of the Insectide-Testing Facility before accreditation project and after. The improved facility meets GLP standard by recording and monitoring temperature digitally, having clean work surfaces that are easily decontaminated, and refrigerator space for test materials that need to be kept at +4°C. The test island was developed by Matt Kirby, and contains dedicated drawers to keep consumables clean and organized- minimizing staff movement around the facility and risk of contamination.

An image of the Insectary- Adult Mosquito Room before and after accreditation project. The improved insectary has incorporated BugDorm cages that are easy to decontaminate, label and transport. The facility was also tiled floor to ceiling to make routine cleaning easier and all absorbent wooden cabinets, sinks and doors replaced with coated metal or aluminium, easy to decontaminate. The space is now cleaner, more efficient, and more comfortable for staff to work, lending to improved insectary output.

Malaria biology 17


SummaryThe laboratory-based research carried

out within the Malaria Centre comprises

a range of topics in the areas of parasite

biology, immunology and host resistance

and vector biology. The knowledge gained

from these studies will form a strong basis

for future intervention strategies.

Parasite population genetic studies focus on a variety of important topics in Africa but also in other parts of the world including Southeast Asia where artemisinin resistance is spreading. Several studies have examined, for example, the within host diversity and transmission dynamics in areas of contrasting transmission intensity. Whole genome sequencing is increasingly being utilised in these studies. Malaria transmission in the Gambia is highly seasonal and it is believed that the

parasite survives during the dry season at low levels in asymptomatic individuals. Genome analysis of parasites will help to understand selection during this bottleneck for the population. Another study has shown that these low density infections can transmit in a highly efficient manner. A genetic barcoding system based on sequence analysis of mitochondrial DNA has been used to determine the origin of isolates. Air travel allows the different types to be distributed between areas with implications for the dissemination of e.g drug resistance. Examples of studies in the area of cell biology include a transgenic approach to analysis of the adhesive proteins used by P. knowlesi to invade erythrocytes, investigation of the role of cyclic nucleotide signalling in regulating the parasite life cycle and studies on a family of cytoskeletal proteins, the alveolins.

Malaria Centre members focus on differentiating protective immune responses from those that drive pathology, on identifying targets of protective immunity and on understanding the nature of immune memory in order to better design effective vaccines. Highlights of our work over the past two years include work to

understand the genetic basis of susceptibility and resistance to malaria in endemic populations and the role of immune response genes in this process; mathematical modelling of longitudinal immunological data sets to derive estimates of the longevity of different components of the memory response to malaria; use of serological markers to better understand the changing transmission dynamics of malaria; development of new tools for researching malarial immunology including specific antigens for Plasmodium knowlesi and human monoclonal antibodies; and detailed exploration of malaria infections in animal models to better understand innate immunity and immunopathology.

The studies on vector biology and control presented in this section range from recently emerging vector / malarial parasite systems in the SE Asian region to fundamental questions about changes in attractiveness of vectors to the human host when infected with malaria parasites. On questions of control, studies are addressing the growing problem of insecticide resistance, developing new insecticides to replace the old, and piloting new strategies to target resources

more efficiently in those places where malaria is approaching elimination. Plasmodium knowlesi is the main cause of malaria in Malaysia, and Anopheles balabacensis is identified to be a highly competent vector with very early biting times (6-8pm) when people are unlikely to use long-lasting insecticidal nets (LLIN). In a multi-centre to assess the impact of insecticide resistance, the use of LLINs continues to provide an effective barrier to malaria infection. New types of LLIN incorporating insecticide chemistry new to public health show potential to improve on standard LLIN and circumvent pyrethroid resistance. Where malaria has become rare (S. Africa) of targeted IRS may provide a rational strategy of deploying scarce resources more economically to good effect. Mosquito movement between clusters may dilute intervention effect in cluster randomised trials, and new theoretical models indicate this can underestimate or confound the correct interpretation of results. This research on questions of fundamental and applied vector biology provide insight on how to solve emerging problems in malaria control.

16 Malaria biology


Malaria biology 19


Whole-genome sequencing of Malawi Plasmodium falciparum isolates reveals selection pressure on genes encoding drug-response proteins and candidate vaccine antigens.

LSHTM investigator: Taane Clark.

External collaborators: Harold Ocholla (Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Malawi and Liverpool School of Tropical Medicine, UK); Dominic Kwiatkowski (Wellcome Trust Sanger Institute, UK); Alister Craig & Jacqui Montgomery (Liverpool School of Tropical Medicine, Liverpool, UK).

Funding body: The Wellcome Trust and the Malaria Capacity Development Consortium.

Selection by host immunity and antimalarial drugs has driven extensive adaptive evolution in Plasmodium falciparum and continues to produce ever-changing landscapes of genetic variation. We performed whole-genome sequencing of 69 P. falciparum isolates from Malawi and used population genetics approaches to investigate genetic diversity and population structure and identify loci under selection. High genetic diversity (π = 2.4 × 10−4), moderately high multiplicity of infection (2.7), and low linkage disequilibrium (500-bp) were observed in Chikhwawa District, Malawi, an area of high malaria transmission. Allele frequency–

based tests provided evidence of recent population growth in Malawi and detected potential targets of host immunity and candidate vaccine antigens.

Comparison of the sequence variation between isolates from Malawi and those from 5 geographically dispersed countries (Kenya, Burkina Faso, Mali, Cambodia, and Thailand) detected population genetic differences between Africa and Asia, within Southeast Asia, and within Africa. Haplotype-based tests of selection to sequence data from all 6 populations identified signals of directional selection at known drug-resistance loci, including pfcrt, pfdhps, pfmdr1, and pfgch1. In conclusion, the sequence variations observed at drug-resistance loci reflect differences in each country’s historical use of antimalarial drugs and may be useful in formulating local malaria treatment guidelines.

Publication: Ocholla H et al. Whole-genome scans provide evidence of adaptive evolution in Malawian Plasmodium falciparum isolates. J Infect Dis. 2014 Dec 15;210(12):1991-2000.

Malaria parasite population structure on the edge of endemic distribution in west Africa.LSHTM investigators: Craig Duffy, Samuel Assefa, Freja Kirsebom & David Conway.

External collaborators: Hampate Ba, Yacine Deh, Mamadou Diallo & Abderahmane Tandia (INRSP, Nouakchott, Mauritania); Ambroise Ahouidi (Cheikh Anta Diop University, Senegal).

Funding body: The Medical Research Council & European Research Council.

Mauritania, on the interface between sub-Saharan West Africa and the Sahara desert, represents the most northern extreme of malaria transmission in the region. Molecular diagnosis of infections at

12 sites across the country identified widespread transmission of both P. falciparum and P. vivax with P. falciparum being most common in the south of the country.

We examined the impact of low transmission upon the P. falciparum population genetic structure through a combination of microsatellite typing and whole genome sequencing. Relative to the rest of West Africa we observed fewer multiple genotype infections and an increase in the overall genomic similarity between isolates. However, there was no evidence of population sub-structuring within the country, indicating that gene flow between sites was occurring in spite of the low transmission.

A comparative analysis of the Mauritanian data with populations from Mali, Senegal, The Gambia, Guinea and Ghana is separately being conducted in order to examine variations in selective pressures on parasite populations in different parts of West Africa.

18 Malaria biology


Parasite biology

Parasite biology research carried out by our members includes genomic analysis, population genetics, cell biology and the analysis of drug resistance.

Distribution of pairwise similarity among P. falciparum isolates from Mauritania (green), a region of low transmission in West Africa. Parasites from Mauritania share a higher proportion of alleles than those from Ghana (red), a region of high transmission.

Principal components analysis using single-nucleotide polymorphisms differentiates Plasmodium falciparum isolates by continent and within Southeast Asia (A) and between East and West Africa (B). The proportion of variation explained by the first 2 principal components is 13.4% (A) and 3.8% (B).

20 Malaria biology Malaria biology 21


Genomic characterisation of P. falciparum asymptomatic infections in The Gambia.

LSHTM investigators: Antoine Claessens, Dave Conway & Umberto D’Alessandro.

Funding body: The Medical Research Council through a joint LSHTM/MRC-Gambia West African Fellowship.

The dry season represents a major bottleneck for the total parasite population in The Gambia. Plasmodium falciparum is typically only found in asymptomatic individuals, with very low densities. Yet these individuals are the source from which the transmission restarts the following season.

This drastic environmental change likely selects parasites that are genetically better suited for one environment or the other. Here, by sequencing P. falciparum genomes, we want to identify what alleles are being selected for during the dry season. We have started collecting fingerprick samples from the same ~800 volunteers four times a year in The

Gambia. All samples are leuco-depleted and P. falciparum positive samples are sequenced at the Sanger Institute.

This work will provide important information for the possible elimination of malaria in The Gambia, as the last remaining parasites are likely to show a similar phenotype of infection to parasites in the dry season (low parasitaemia and asymptomatic, i.e. “the last parasite standing is the strongest” hypothesis).

Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites.

LSHTM investigator: Taane Clark.

External collaborators: Hanif Samad (Singapore General Hospital); Harold Ocholla (Malawi-Liverpool-Wellcome Trust Clinical Research Programme, Malawi and Liverpool School of Tropical Medicine, UK); Rick Fairhurst (National Institutes of Health, USA).

Funding body: The Medical Research Council.

Whole-genome sequencing technologies are being increasingly applied to Plasmodium falciparum clinical isolates to identify genetic determinants of malaria pathogenesis. However, genome-wide discovery methods, such as haplotype scans for signatures of natural selection, are hindered by missing genotypes in sequence data.

Poor correlation between single nucleotide polymorphisms (SNPs) in the P. falciparum genome complicates efforts to apply established missing-genotype imputation methods that leverage off patterns of linkage disequilibrium (LD).

The accuracy of state-of-the-art, LD-based imputation methods (IMPUTE, Beagle) was assessed by measuring allelic r2 for 459 P. falciparum samples from malaria patients in 4 countries: Thailand, Cambodia, Gambia, and Malawi. In restricting our analysis to 86k high-quality SNPs across the populations, we found that the complete-case analysis was restricted to 21k SNPs (24.5%), despite no single SNP having more than 10% missing genotypes.

The accuracy of Beagle in filling in missing genotypes was consistently high across all populations (allelic r2, 0.87-0.96), but the performance of IMPUTE was mixed (allelic r2, 0.34-0.99) depending on reference haplotypes and population. Positive selection analysis using Beagle-imputed haplotypes identified loci involved in resistance to chloroquine (crt) in Thailand, Cambodia, and Gambia, sulfadoxine-pyrimethamine (dhfr, dhps) in Cambodia, and artemisinin (kelch13) in Cambodia.

Tajima’s D-based analysis identified genes under balancing selection that encode well-characterized vaccine candidates: apical merozoite antigen 1 (ama1) and merozoite surface protein 1 (msp1). In contrast, the complete-case analysis failed to identify any well-validated drug resistance or candidate vaccine loci, except kelch13. In a setting of low LD and modest levels of missing genotypes, using Beagle to impute P. falciparum genotypes is

a viable strategy for conducting accurate large-scale population genetics and association analyses, and supporting global surveillance for drug resistance markers and candidate vaccine antigens.

Publication: Samad H, Coll F, Preston MD, Ocholla H, Fairhurst RM, Clark TG. Imputation-based population genetics analysis of Plasmodium falciparum malaria parasites. PLoS Genet. 2015; 11(4):e1005131.


Fingerprick samples collection in a village in the Upper River Region of The Gambia.

Fingerprick samples collection in a village in the Upper River Region of The Gambia.

The top positive selection Rsb hits for Thailand, Cambodia, and Gambia, using Malawi as the reference population. Dashed lines indicate the top 1% of Rsb values (median threshold across 3 populations) for Beagle-imputed (above zero) and complete-case (below zero) data.



A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains.

LSHTM investigators: Taane Clark, Cally Roper, Susana Campino, Ernest Diez Benavente & Colin Sutherland.

External collaborators: Rick Fairhurst (National Institutes of Health, USA).


A major obstacle to the successful elimination of malaria in any given area is the re-introduction of parasites via imported infections. Population mobility through international travel carries further risks of re-introducing parasites to elimination areas, as well as dispersing drug-resistant parasites to new regions.

A simple genetic marker that quickly and accurately identifies the geographic origin of malaria infections would be a valuable tool for locating the source of outbreaks. Here, we analysed the DNA of more than 700 P. falciparum malaria parasites.

These were taken from patients in 14 countries in west Africa, east Africa, south-east Asia, Oceania and South America. We identified short sequences in the DNA of the parasite’s mitochondria and apicoplasts which were distinct for parasites from certain geographic locations. This enabled us to design a genetic “barcode” which is highly accurate in predicting where a malaria parasite has come from, and is also stable to changes in the parasite’s genome over time. With this breakthrough in the genetic barcoding of P. falciparum we are currently refining the barcode to cover additional populations, such as India, Central America, southern Africa and the Caribbean, and plan to include genetic markers for other malaria species in the future.

Publication: Preston MD, Campino S et al. A barcode of organellar genome polymorphisms identifies the geographic origin of Plasmodium falciparum strains. Nat Commun. 2014 Jun 13;5:4052.

Dissecting the within-host diversity of Plasmodium falciparum infections.

LSHTM investigators: Lee Murray, Lindsay Stewart, Sarah Tarr, Craig Duffy & David Conway.

External collaborators: Alfred Amambua-Ngwa (Medical Research Laboratories, The Gambia); Ambroise Ahouidi (Universite Cheikh Anta Diop, Senegal); Mahmadou Diakite (University of Bamako, Mali); Gordon Awandare (University of Ghana); Marcel Loua (National Institute of Public Health, Guinea).

Funding body: BBSRC London Interdisciplinary Biosciences Doctoral Programme & GENINVADE Project European Research Council.

Clinical isolates of Plasmodium falciparum frequently consist of multiple genotypes, particularly within areas of high infection endemicity such as West Africa. Characteristics of the within-host evolutionary

ecology of clinical infections such as genotypic diversity have been proposed to impact on clinically important features such as gametocytogenesis and virulence in model Plasmodium species, but are yet to be confirmed within P. falciparum. In addition to genetic differences within and between infections, P. falciparum parasites can also exhibit transcriptional and phenotypic variation in important characteristics, even between highly related parasite genotypes.

This project has focused on characterising the genomic and transcriptomic diversity of clinical West African infections using sequencing based informatic approaches and novelly examined evidence of selection at the within-host scale for P. falciparum. In addition, lab based approaches have sensitively quantified the phenotypic variation in replication rates of clinical isolates, which remains challenging due to the generally poor growth seen in culture.

Furthermore, new in vitro tools are under development that will support the investigation of proposed interactions between parasites within multiple genotype infections.


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The nucleotide sequence landscape of the densely packed P. falciparum mitochondrion (mt) and apicoplast (apico) genomes. Protein-coding (green) and non-translated RNA (blue) regions in the ‘annotation’ ring are transcribed from either strand (inner, negative strand; outer, positive strand). The 20-fold difference in coverage between the genomes is visible. All mutations within mt (151 SNPs, 5,967-bp linear) and apico core (488 SNPs, 29,430-bp circular, excluding an inverted repeat) are shown relative to the P. falciparum 3D7 reference genome coordinates. SNPs are densely packed throughout, with more non-synonymous (NS) protein-coding changes (red) in apico than in mt. Synonymous, intronic, intra-genic (green) and RNA changes (blue) are also marked. The minor allele frequency (MAF), Fst and barcode SNPs are marked

in the outer three rings and are colour coded in the same way (the full catalogue is available online). The 23 barcoding SNPs (5 mt, 4 NS; 18 apico, 9 NS) are marked in the outer ring.

Sensitive profiling of newly cultured West African clinical isolates has revealed a diverse spectrum of replication rates during the culture adaptation process. The growth rates of clinical isolates are shown in blue bars, whilst the growth rates of four commonly cultured P. falciparum parasite genotypes are shown in red bars. Errors bars represent 95% confidence intervals.



Cryptic populations of infectious parasites: untangling the clonal composition of Plasmodium falciparum infections.

LSHTM investigators: Lynn Grignard, Bronner Goncalves, Sophie Jones & Chris Drakeley.

External collaborators: Teun Bousema (Radboud University Nijmegen Medical Centre, the Netherlands).

Funding body: The Bill and Melinda Gates Foundation.

The transmission dynamics of Plasmodium falciparum from the human host to the mosquito vector remain poorly understood. The contribution of low density parasitaemia to transmission and

to the reservoir of infection is still under debate. In addition, the detection of low density minority clones is hampered by the stochastic effects of PCR and the volume of human blood analysed in genotyping assays. We investigated data from MSP2 capillary electrophoresis genotyping in conjunction with direct membrane feeding assays in human (n=440) and mosquito samples (n=772) from 4 different surveys in West Africa.

We found that low density infections are very effective in transmitting from human to mosquito. Furthermore, mosquitoes are better at estimating the multiplicity of infection (MOI) than PCR on human blood samples and hence are important in determining the number of circulating, transmissible clones making up the reservoir of infection. The detection of minority clones in the human blood was further investigated by magnetic enrichment of gametocytes in field samples. PCR based next generation sequencing will be used to confirm our results.

Genomic variation in two gametocyte non-producing Plasmodium falciparum clonal lines.

LSHTM investigators: David Baker, Susana Campino & Taane Clark.

Funding body: The Medical Research Council and the Wellcome Trust.

Transmission of the malaria parasite Plasmodium falciparum from humans to the mosquito vector requires differentiation of a sub-population of asexual forms replicating within red blood cells into non-dividing male and female gametocytes. The nature of the molecular mechanism underlying this key differentiation event required for malaria transmission is not fully understood. We used whole genome sequencing to examine the genomic diversity of the gametocyte non-producing 3D7-derived lines F12 and A4. These lines were used in the recent detection of the PF3D7_1222600 locus (encoding PfAP2-G), which acts as a genetic master switch that triggers gametocyte development. We show the evolutionary changes from the 3D7 parental strain through its derivatives F12 (culture-passage derived cloned line) and A4 (transgenic cloned line). We highlight genetic mutation differences including the formation of chimeric var genes. We provide a genomics resource for the further study of gametocytogenesis or other phenotypes using these parasite lines.

Publications: Campino et al. Genomic variation in two gametocyte non-producing Plasmodium falciparum clonal lines. Submitted.

Kafsack BFC, et al. A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature. 2014 Feb 23. doi: 10.1038/nature12920.

http://blogs.lshtm.ac.uk/news/2014/02/28/mystery-solved-in-malaria-parasite-transmission/#sthash.s00rac7E.dpuf

Population genetic and genomic studies of Plasmodium knowlesi.

LSHTM investigators: Paul Divis, David Conway, Craig Duffy & Samuel Assefa.

External collaborators: Balbir Singh (Universiti Malaysia Sarawak, Malaysia).

Funding body: The European Research Council & Malaysia Ministry of Higher Education.

The zoonotic parasite Plasmodium knowlesi shows extraordinary population substructure.

Using a set of highly polymorphic microsatellite loci, we have genotyped 786 P. knowlesi infections (686 in humans and 100 in wild macaques) from Malaysian Borneo and Peninsular Malaysia. Highly divergent subpopulations were observed in the human clinical isolates, respectively associated

with the forest-dwelling long-tailed macaque and pig-tailed macaque reservoir hosts in Borneo. Furthermore, there is a significant geographical divergence between infections from Borneo and the mainland Peninsular Malaysia.

Genome-wide analysis of isolates shows subpopulation structures that match the analysis of microsatellite markers. Across the genome there was significant divergence between the two major subpopulations in Borneo, and the degree of this divergence varied across several chromosomes. Analysis of genome-wide single nucleotide polymorphisms on the largest subpopulation in clinical isolates (Cluster 1), showed signatures of balancing selection on particular genes.

Currently, genome-wide sequence data on the second subpopulation of clinical isolates from Borneo (associated with pig-tailed macaque host) is being analysed to test whether there are different signatures of selections.


For F12, we observe a 2-fold increased coverage for the second part of PF3D7_0421100 (green), and the first part of the adjacent gene, PF3D7_0421300 (dark blue) indicating a duplication-chimera formed by duplicating half of PF3D7_0421100 and the other half of PF3D7_0421300. For the A4 and 3D7A strains we see an increased coverage of the second half of PF3D7_0420700, the full genes PF3D7_0420900 and PF3D7_0421100 and first half of gene PF3D7_0421300. This indicates a duplication of the genes PF3D7_0420900 and PF3D7_0421100 and a chimeric gene formed by duplicating half of PF3D7_0420700 and half of PF3D7_0421300.

Subpopulation clusters of P. knowlesi isolates. Three subpopulation clusters observed by principal co-ordinate analysis using microsatellite data (Panel A) correspond with the analysis of genome-wide sequences shown on the neighbour-joining tree (Panel B). Cluster 1 and Cluster 2 subpopulations are human infections from Borneo, associated with long-tailed macaque and pig-tailed macaque hosts, respectively, while isolates in the Cluster 3 subpopulation are derived from Peninsular Malaysia.



Dissecting the red blood cell invasion pathways of the malaria parasite Plasmodium knowlesi.

LSHTM investigators: Robert Moon, Colin Sutherland & Franziska Mohring.

External collaborators: Simon Draper (Jenner Institute, UK); Helen Saibil (Birkbeck, UK); Mike Blackman & Tony Holder (Francis Crick Institute, UK); Arnab Pain (King Abdullah University of Science and Technology, Saudi Arabia); Jake Baum (Imperial College London, UK); Neil Almond (National Institute of Biological Standards and Control, UK).

Funding body: The Medical Research Council and the UK Department for International Development.

Malaria is caused by single-celled parasites called Plasmodium. Symptoms of malaria arise from the parasite destroying red blood cells (RBCs) by entering them, multiplying within and bursting out

again in a continuous cycle. The parasites produce a range of adhesive proteins enabling them to bind to the surface of RBCs and invade them. These parasite proteins can determine disease severity and which hosts are susceptible, as well as presenting important targets for vaccine design.

This MRC Career Development award Fellowship, jointly funded by the MRC and DFID, investigates the role of these adhesive proteins during RBC invasion using a malaria parasite known as Plasmodium knowlesi. This naturally infects macaques in SE Asia, and is now known to cause of severe and fatal human infections. Using techniques we recently developed to genetically modify these parasites, as well as cutting edge imaging technology we will determine which proteins the parasites need for invasion, what they bind to on host RBC and dissect their precise role during invasion. We will also develop new tools to allow us to use P. knowlesi to aid vaccine development for other important malaria parasites like P. vivax, which remain difficult to study within the lab.

Investigating expression of invasion genes in the malaria parasite, Plasmodium falciparum.

LSHTM investigators: Sarah Tarr, Lindsay Stewart, Lee Murray & David Conway.

Funding body: European Research Council.

Our research aims to improve our understanding of how malaria parasites invade their host red blood cells. Certain proteins expressed in the invasive form of blood-stage malaria parasites are targets of anti-malarial immunity. We wish to identify genes expressed at this stage, which may have potential as novel vaccine candidates. We have established fluorescence-activated cell sorting of live malaria parasites to specifically isolate red blood cells containing parasites of this invasive stage (figure 1, multi-nucleated cells), in order to determine their gene expression profiles. By extending these methods to clinical isolates of malaria that have been collected in the field, we are building on our

understanding of how these expression profiles differ between infections. We are also developing tools to study expression of these genes in single-cells, allowing an assessment of the diversity of expression patterns within a single infection.

Finally, we have developed fluorescent lines of P. falciparum that allow us to isolate and study the growth of specific strains within co-culture experiments (figure 2).


A long tailed macaque, the natural host for P. knowlesi in Malaysia.

Cluster of invasive P. knowlesi “merozoites”- Cell surface is labelled with red fluorescence and its nucleus is labelled with blue.

Figure 1: Fluorescence-based identification and isolation of early-stage (singly-nucleated) and late-stage (multi-nucleated) Plasmodium-infected red blood cells using a DNA stain.

Figure 2: Gating strategy for fluorescence-based cell sorting of co-cultured, differentially labelled P. falciparum lines. GFP- and mKOk-labelled parasites are easily distinguished from each other and from uninfected red blood cells.



Sequencing of Plasmodium ovale wallikeri from patient isolates.

LSHTM investigators: Mary Oguike, Ernest Diez Bienevente, Susana Campino, Taane Clark, Ozan Gundogdu & Colin Sutherland.


Recent evidence suggests that Plasmodium ovale curtisi and Plasmodium ovale wallikeri are very closely related malaria parasites yet genetically distinct. There is also a clear phenotypic difference between them related to the duration of pre-erythrocytic latency, and as such represents an ideal system in which to identify candidate genes linked to hypnozoisis. We hypothesized that if genome data were available for both ovale parasite species, new insights into the species barrier between them could

be gained using a comparative genomic approach. We attempted the first genome sequence of a P. ovale wallikeri isolate, derived from an imported case of ovale malaria in the UK, using an Illumina Miseq platform in-house at LSHTM. We generated the first ever partial genome sequence for P. ovale wallikeri, which we compared with partial published data for P. ovale curtisi.

The multicopy extra-chromosomal genomes of the apicoplast and mitochondrion were particularly well represented. These were compared against genome sequence data from other Plasmodium species, including P. falciparum, P. knowlesi and P. vivax. The full-length mitochondrial genome was found to be very similar to those of the latter two species.

These data will be used for exploration of the phylogenetic history of the two closely-related ovale malaria parasite species.

Manipulation of artemisinin and partner drug susceptibility in African malaria parasites by genome editing.

LSHTM investigators: Ryan Henrici, Don van Schalkwyk & Colin Sutherland.

Funding body: British Society for Antimicrobial Chemotherapy.

The objective of this study is to explore the contributions of individual mutations in the malaria parasite genome to antimalarial resistance using the novel CRISPR-Cas9 system. Previous work by members of our laboratory established geospatial and temporal trends in the prevalence and

persistence of molecular markers of drug resistance throughout Sub-Saharan Africa. In particular, this work identified and tracked several new candidate mutations linked with decreased ACT efficacy in patients in Kenya including polymorphisms in pfap2mu and pfubp1.

Our present work aimed to validate our surveillance of these polymorphisms and confirm their role in drug resistance in vivo by engineering the mutations into P. falciparum with the Cas9 system and observing their impacts on parasite growth, fitness, and drug sensitivity. Preliminary work suggests that pfap2mu may a role in decreased sensitivity to chloroquine and artemisinins, validating our belief that pfap2mu polymorphisms should be more widely tracked, though future work is planned to further study these observations.

High heterogeneity of malaria transmission and a large sub-patent and diverse reservoir of infection in Wusab As Safil district, Republic of Yemen.

LSHTM investigators: Jackie Cook, Lynn Grignard, Chris Drakeley & Immo Kleinschmidt.

External collaborators: Samira El-Eryani (University of Yemen, Yemen); Caroline Barwa (WHO, Egypt).

Funding body: Global Environmental Facility.

Multiple measures of malaria transmission intensity can give a more accurate assessment of the presence of malaria. This study utilised parasitological (microscopy and RDT measures), serological (presence of antibodies to P. falciparum antigens) and molecular measures (PCR prevalence, Multiplicity of Infection (MOI), heterozygosity

and allelic richness) of transmission intensity to investigate transmission patterns in a mountainous area in Southern Yemen.

P. falciparum infection prevalence was 12.4, 11.1 and 19.6% by RDT, microscopy and polymerase chain reaction (PCR) respectively, indicating the higher sensitivity of the molecular PCR method. RDT and microscopy were unable to detect 45% of infections present, suggesting many infections were low-density. Infection prevalence and seroprevalence was highly heterogeneous between clusters. The mean multiplicity of infection (MOI) was 2.3 and high heterozygosity and allelic richness was detected.

The heterogeneity of infection and exposure to infection over small distances was unexpected and highlights the importance of identifying areas experiencing a higher burden of transmission. In addition, the highly diverse parasite population suggests a high degree of transmissibility and coupled with the high proportion of low-density infections, may pose challenges for malaria control and elimination efforts.


Plasmodium ovale wallikeri short-read data mapped to the apicoplast genome of P. knowlesi shows several species-specific substitutions (arrows).

Malaria biology 31


Functional analysis of the cGMP signalling pathway in malaria parasites: a master regulator of life cycle progression.LSHTM investigators: Christian Flueck, Eloise Thompson & David Baker.

External collaborators: Mike Blackman (National Institute for Medical Research, UK).

Funding body: the Wellcome Trust through a joint Senior Investigator Award (to Baker and Blackman).

Plasmodium falciparum causes the most serious form of malaria and leads to around half a million deaths each year. The number of malaria deaths has decreased in recent years due to implementation of more effective vector control strategies and the use

of highly effective artemisinin based drug treatments. However, artemisinin resistance is now spreading through parts of Southeast Asia and there is an urgent need to develop new drugs against novel malarial targets.

The aim of this research programme is to deliver a detailed understanding of the molecular machinery used by the malaria parasite to control its complex life cycle. Our work will focus on a functional dissection of the cyclic GMP signalling pathway, which regulates the progression of the malaria parasite life cycle through its various developmental stages in both the human host and mosquito vector.

Importantly, the cyclic GMP signalling system in malaria parasites operates very differently to that in humans, so we envisage that the fundamental knowledge of parasite biology we gain will help the development of a new generation of effective drugs to treat malaria and prevent its transmission by mosquitoes.

30 Malaria biology

Molecular studies of Plasmodium alveolins.

LSHTM investigators: Johannes Dessens, Annie Tremp & Fatimah Al-Khattaf.

Funding body: The Wellcome Trust.

The invasive and motile life stages of malaria parasites (merozoite, ookinete and sporozoite) possess a unique cortical cytoskeletal structure termed the subpellicular network (SPN).

The SPN consists of intermediate filaments, whose major constituents include a family of proteins called alveolins. We have identified 13 family members characterised by conserved ‘alveolin’ domains that fall into two types/clades (Figure 1).

A major finding is our discovery that both types of alveolin domain contain tandem repeats with a consensus 12 amino acid periodicity (Figure 2). We are now working toward determining the atomic structure of the alveolins and their evolutionary relationship with other intermediate filament proteins.


Figure 1: Repertoire and domain structure of Plasmodium alveolins. A: Phylogeny of conserved domains within the alveolin family members PbIMC1a to PbIMC1m (a-m). Numbers give amino acid coordinates of the conserved domains in the corresponding PbIMC1 protein. Type 1 (red) and type 2 (green) domains separate into distinct clades. B: Schematic diagram depicting the 13 alveolin family members (a-m), showing relative positions of the type 1 (red) and type 2 (green) domains.

This fluorescence micrograph shows two P. falciparum schizonts. The green pattern shows the cellular distribution of a phosphodiesterase enzyme; a key regulator of cyclic GMP signalling. Image by Dr. Laura Drought.

Figure 2: Tandem repeat identification in alveolins by the program HHrepID. A: IMC1e. B: IMC1b.

Malaria biology 33


levels to four clinical grade malarial antigens (AMA1, MSP1, MSP2, and (NANP)4) plus total IgE were measured by ELISA. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. Sickle cell trait likely indirectly reduces antibody levels (by reducing the frequency or density of parasitaemia). The study provides a framework for combining data from sites with heterogeneous malaria transmission levels with which to explore genetic effects on anti-malarial immunity.

Publication: Shelton, J.M.G., Corran, P., Risley, P., Silva, N., Hubbart, C., Jeffreys, A., Rowlands,

K., Craik, R., Cornelius, V., Hensmann, M., Molloy, S., Sepuveda, N., Clark, T.G., Band, G., Clarke, G.M., Spencer, C. C. A., Kerasidou, A., Campino, S., Auburn, S., Tall, A., Mercereau-Puijalon, O., Sakuntabhai, A., Djimde, A., Maiga, B., Doumbo, O., Dolo, A., Troye-Blomberg, M., Mangano, V.D., Verra, F., Modiano, D., Bougouma, E., Sirima, S.B., Ibrahim, M., Hussain, A., Elzein, A., Williams, T.N., Ndila, C., Marsh, K., Manjurano, A., Reyburn, H., Lemnge, M.M., Ishengoma, D., Carter, R., Karunweera, N., Fernando, D., Dewasurendra, R., Drakeley, C.J., Riley, E.M., Kwiatkowski, D.P. and Rockett, K.A., in collaboration with the MalariaGEN Consortium. (2015) Genetic determinants of anti-malarial acquired immunity in a large multi-centre study. Malaria J., 14: 333.

Dynamics of the antibody response to Plasmodium falciparum infection in African children.

LSHTM investigators: Onome Akpogheneta, David Conway, Eleanor Riley.

External collaborators: Michael White, Jamie Griffin & Azra Ghani (Imperial College London, UK) Kojo Koram (Noguchi Institute, Ghana).

Funding body: The Medical Research Council, the Wellcome Trust & the Bill & Melinda Gates Foundation.

Acquired immune responses to malaria have widely been perceived to be short-lived, with previously immune individuals suffering a loss of immunity when they move from malaria-endemic areas. However long-lived P. falciparum specific antibody responses lasting for an individual’s lifetime are frequently observed. We have fitted mathematical models of the dynamics of antibody titres to Plasmodium falciparum antigens from longitudinal cohort studies of African children to estimate the half-lives of circulating Immunoglobulin G (IgG) antibodies and IgG antibody secreting cells (ASC). We found that antibody responses in African children can be described by a model including both short-lived ASCs (half-life in the range 2-10 days) responsible for boosting antibody titres following infection, and long-lived

ASCs (half-life in the range 3-9 years) responsible for maintaining sustained humoral responses. Comparison of antibody responses in the younger Ghanaian cohort and the older Gambian cohort suggests that young children are less able to generate the long-lived ASCs necessary to maintain the circulating antibodies that may provide protection against reinfection.

The rapid decay of antibodies following exposure to malaria and the maintenance of sustained antibody responses can be explained in terms of populations of short-lived and long-lived ASCs.

Publication: White, M.T., Griffin, J.T., Akpogheneta, O., Conway, D.J., Koram, K., Riley, E.M., and Ghani, A. (2014) Dynamics of the antibody response to Plasmodium falciparum infection in African children. J. Infectious Diseases, 210: 1115-22.

Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

LSHTM investigators: Nuno Sepulveda, Taane Clark, Chris Drakeley, Hugh Reyburn & Eleanor Riley.

External collaborators: Jennifer Shelton, Christina Hubbart, Anna Jeffreys, Kate Rowlands, Rachel Craik, Victoria Cornelius, Meike Hensmann, Sile Molloy, Gavin Band, Geraldine Clarke, Chris Spencer, Angeliki Kerasidou, Dominic Kwiatkowski & Kirk Rockett (University of Oxford, UK); Patrick Corran, Paul Risley & Nilupa Silva (NIBSC, UK); Susana Campino (Sanger Institute, UK); Sarah Auburn (Menzies School of Public Health, Australia); Adama Tall, Alioune, Badara Ly, Odile Mercereau-Puijalon & Anavaj Sakuntabha (Pasteur Institute, France); Abdoulaye Djimdé, Boubacar Maiga, Ousmane Touré, Ogobara K. Doumbo & Amagana Dolo (Malaria Research and Training Center, Bamako, Mali); Marita Troye-Blomberg (Stockholm University, Sweden); Valentina Mangano, Frederica Verra & David Modiano (Sapienza University of Rome, Italy); Edith Bougouma & Sodiomon Sirima (Centre de Recherche et de la Formation au Paludisme, Burkina Faso); Muntaser Ibrahim, Ayman Hussain, Nahid Eid, Abier Elzein, Hiba Mohamed, Ahmed Elhassan & Ibrahim Elhassan (Institute for Endemic Diseases, Sudan); Tom Williams (Imperial College London, UK); Carolyne Ndila, Alexander Macharia & Kevin Marsh (Kilifi, Kenya); Alphaxard Manjurano, Martha Lemnge & Deus Ishengoma (Joint Malaria Programme, Tanzania); Richard Carter (University of Edinburgh);

Nadira Karunaweera, Deepika Fernando & Rajika Dewasurendra (University of Colombo, Sri Lanka).

Funding body: The Wellcome Trust and the Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative. Additional funding from the Wellcome Trust & the Medical Research Council

This multisite analysis across Africa and Asia, used standardized methods to search for reproducible and consistent associations between host genotype and anti-malarial antibody levels. Sera, DNA and clinical data were collected from 13,299 individuals. DNA was typed for 202 Single Nucleotide Polymorphisms (SNPs) with reported associations to malaria or antibody production, and antibody

32 Malaria biology


Immunology and host resistance

Malaria Centre members focus on identifying protective rather than immunopathological responses and on understanding the nature of immune memory in order to better design effective vaccines.

Figure 3: Mean logged antibody titre for the five antibodies measured, shown for

each age group at each site. Each colour represents a different antibody whilst shape of

point represents the antibody type: (∆) for anti-merozoite, (□) for anti-sporozoite, and (○)

for total IgE.

Biological models of antibody boosting and decay

Biological models of antibody boosting and decay.

Figure 3: Mean logged antibody titre for the five antibodies measured, shown each age group at each site. Each colour represents a different antibody whilst shape of point represents the antibody type: ( ) for anti-merozoite, ( ) for anti-sporozoite, and ( ) for total lgE.



Serology describes a profile of declining malaria transmission in Farafenni, the Gambia.

LSHTM investigators: Lotus van den Hoogen, Jackie Cook, Nuno Sepúlveda, Patrick Corran, David Conway, Paul Milligan, Geoff Targett, Umberto D’Alessandro, Brain Greenwood, Eleanor Riley & Chris Drakeley.

External collaborators: Jamie Griffin (Queen Mary University of London, UK); Muna Affara & Serign Ceesay (MRC, the Gambia) Stephen Allen (LSTM, UK); Carla Proietti (QIMR Berghofer Medical Research Institute, Australia).

Funding body: The 1988 survey was funded by the World Health Organization/TDR and UK Medical Research Council. CD and NS are funded by the Wellcome Trust Grant Number 091924. NS also acknowledges partial funding from Fundação para a Ciência e Tecnologia (Portugal) through the project Pest-OE/MAT/UI0006/2011.

Malaria morbidity and mortality has declined in recent years in a number of settings. The ability to describe changes in malaria transmission

associated with these declines is important in terms of assessing the potential effects of control interventions, and for monitoring and evaluation purposes.

We compared data from five cross-sectional surveys conducted in Farafenni and surrounding villages on the north bank of River Gambia between 1988 and 2011. Antibody responses to the 19 kDA fragment of P. falciparum merozoite surface protein 1 (MSP-119) were measured in samples from all surveys, and expressed as seroprevalence and seroconversion rates (SCR; i.e., the rate at which the population becomes seropositive). The data described very similar decreases over the time period in parasite prevalence (from 62% to 2% - 97% decrease) and seroprevalence (from 19% to 1% - 95% decrease) in one to five year old children. The SCR across all ages dropped from 0.069 year−1 (0.059–0.080) to 0.022 year−1 (0.017–0.028; p=0.004). These results show an accurate reconstruction of historical malaria transmission patterns in the Farafenni area using anti-malarial antibody responses.

The congruence between serological measures, and conventional clinical and parasitological measures suggests broader utility for serology in monitoring changes in malaria transmission.

Immunity to Plasmodium falciparum merozoite surface proteins.

LSHTM investigators: Harvey Aspeling-Jones & David Conway.

External collaborators: Gordon Awandare (Univeristy of Ghana, Ghana); Seth Owusu-Agyei (Kintampo Health Research Centre).


Plasmodium falciparum malaria causes the deaths of hundreds of thousands of infants and pregnant women. Despite decades in development, the most advanced P. falciparum vaccine candidate, based on a sporozoite antigen, offers only moderate protection.

This project aims to assess the potential efficacy of vaccines incorporating P. falciparum merozoite antigens. Individual memory B-cells, isolated from healthy adults living in a region with year-round malaria transmission, that express B-cell receptors recognising a specific merozoite antigen will be isolated. The mRNA encoding the variable regions of the B-cell receptor expressed by these cells can then be amplified and cloned to allow expression of mono-clonal antibodies that are effectors of immunological memory against P. falciparum.

Functional characterisation of these antibodies can determine if they are likely to contribute to controlling parasite replication in vivo, shedding light on mechanisms of parasite immune evasion and providing evidence for the selection of antigens for future malaria vaccines.


Predicted age-seroprevalence curves for MSP-119 between 1988 and 2011 in Farafenni, The Gambia.

Isolation of antigen specific memory B-cells for production of mono-clonal antibodies. a) Recombinantly expressed merozoite antigens are biotinylated and combined with fluorescently labelled streptavidin, which binds the biotin on the antigen forming a fluorescent antigen tetramer. b) This tetramer is added to memory B-cells isolated from clinically immune individuals. If the B-cell receptor recognises the merozoite antigen, this leads to the fluorescent labelling of the cell, which allows the memory B-cell to be isolated by cell sorting. c) RNA is extracted from the cell and (d) reverse transcribed into complementary DNA. e) Primer mixes designed to bind either side of the variable region of the immunoglobulin genes are then used in a nested polymerase chain reaction to amplify the variable regions of the immunoglobulin genes that encode specificity for the merozoite antigen. f) These variable regions are then cloned into a vector for the expression of immunoglobulin G which is transfected (g) into a human cell line. h) These cells will then express naturally derived, mono-clonal antibodies specific for the merozoite antigen used to isolate the memory B-cells.



IL-27R signalling regulates memory CD4+ T cell populations and suppresses rapid inflammatory responses during secondary malaria infection.

LSHTM investigators: Emily Gwyer Findlay, Ana Villegas Mendez, Noelle O’Regan, Eleanor Riley & Kevin Couper.

External collaborators: Brian De Souza (University College London, UK); Chris Saris (Amgen, USA).

Funding body: European Union (EviMalaR).

IL-27 controls primary CD4+ T cell responses but its role in regulating memory CD4+ T responses had not been investigated. We examined the functional importance of IL-27R signalling in regulating the formation and maintenance of memory CD4+ T cells following malaria infection and in controlling their subsequent reactivation during secondary parasite challenge. We found that although the primary

effector/memory CD4+ T cell response was greater in IL-27R deficient (WSX-1-/-) mice following P. berghei NK65 infection compared with wild type mice, there were no significant differences in the size of the maintained memory CD4+ T population after infection. However, the composition of the memory CD4+ T cell pool differed in WSX-1-/- mice, with higher numbers of late effector memory CD4+ T cells in the spleen and liver and increased production of IL-2 in the spleen. Crucially, WSX-1-/- mice were significantly more able to control their parasite infections compared with wild type mice and this was associated with rapid proliferation of antigen-experienced T cells in the liver. These data are the first to demonstrate that IL-27R signalling plays a role in regulating the magnitude and quality of secondary immune responses during infection.

Publication: Gwyer Findlay, E., Villegas Mendez, A., O’Regan, N., de Souza, J.B., Grady, L-M., Saris, C.J., Riley, E.M. and Couper, K.N. (2014) IL-27R signaling regulates memory CD4+ T cell populations and suppresses rapid inflammatory responses during secondary malaria infection. Infection and Immunity, 82:10-20.

Identification and validation of novel antigenic markers of exposure to Plasmodium knowlesi for development as serological tools.

LSHTM investigators: Lou Herman, Kimberly Fornace, Rob Moon, Mike Blackman, Chris Drakeley & Kevin Tetteh.

External collaborators: Matt Grigg & Nick Anstey (Menzies School of Health Research and Charles Darwin University, Australia Infectious Diseases Society & Sabah-Menzies School of Health Research); Tim William (Menzies School of Health Research, Australia).

Funding body: The Wellcome Trust & MonkeyBar.

Plasmodium knowlesi (Pk) is the most common cause of malaria in Malaysian Borneo. Infections follow a rapid 24 hour cycle, quickly reaching high parasitemias, which can lead to severe disease in humans. Information to date largely relates to clinical cases, giving little information as to the extent of transmission within the affected communities.

There are no large scale epidemiological studies due to the lack of Pk-specific reagents. To address this, we identified 18 novel Pk-specific targets for expression as recombinant antigens. IgG antibody prevalence to Pf and Pv blood stage antigens (AMA1 and MSP1-19) was assessed by ELISA for a subset of 60 serum spot samples from a hospital clinical case control study to determine baseline reactivity. A further 2000 bloodspot samples from a cross-sectional study in Kudat, Malaysian Sabah, the Pf and Pv prevalence to which was at 16% (AMA1) and 10% (MSP1-19), respectively. Pooled clinical case control samples were screened against 9 of the 18 Pk candidates by western blot, showing clear specific serum reactivity. Preliminary data demonstrates a strong serum reactivity profile for the recombinant Pk SERA3 antigen in field samples. Suggesting the possibility of this reagent being a good marker for measuring exposure to Pk infections.

Further validation of these reagents is in progress across multiple serological platforms (protein microarray and Luminex) to assess the specificity of these tools compared to other plasmodia.


IL-27R signalling regulates memory CD4+ T

cell populations

Wild type (WT) and IL-27 receptor deficient

(WSX-1-/) mice were infected with 104 P.

berghei NK65 parasitized RBC (pRBC) on day 0

and treated with chloroquine on days 8-12. At 20

weeks post infection, mice were re-infected with

105 pRBC. The figure shows representative flow

cytometry plots (gated on CD4+ T cells)

demonstrating the expression of IFN-γ (following

PMA and ionomycin stimulation) vs. CD44

expression by CD4+ T cells from the spleen and

liver of WT and WSX-1-/- mice 20 weeks after

primary infection (20w 1o) and 3 (3d 2o) and 7

(7d 2o) days after secondary infection.

IL-27R signalling regulates memory CD4+ T cell populations Wild type (WT) and IL-27 receptor deficient (WSX-1-/) mice were infected with 104 P. berghei NK65 parasitized RBC (pRBC) on day 0 and treated with chloroquine on days 8-12. At 20 weeks post infection, mice were re-infected with 105 pRBC. The figure shows representative flow cytometry plots (gated on CD4+ T cells) demonstrating the expression of IFN-γ (following PMA and ionomycin stimulation) vs. CD44 expression by CD4+ T cells from the spleen and liver of WT and WSX-1-/- mice 20 weeks after primary infection (20w 1o) and 3 (3d 2o) and 7 (7d 2o) days after secondary infection.

Fluorescent dual-labelled Western blot showing serum-specific reactivity to pooled Pk-positive clinical case control sera to novel recombinant targets.



IL-18-induced expression of high affinity IL-2R on murine NK cells is essential for NK cell IFN-γ production during murine Plasmodium yoelii infection.

LSHTM investigators: Kerstin Stegmann & Eleanor Riley.

External collaborators: Brian De Souza (University College London, UK).

Funding body: European Union (EviMalaR).

Early production of pro-inflammatory cytokines, including IFN-γ, is essential for control of blood-stage malaria infections. We have shown that IFN-γ production can be induced among human natural killer (NK) cells by co-culture with P. falciparum-infected erythrocytes, but the importance of this response is unclear.

To further explore the role of NK cells during malaria infection we have characterised the NK-cell response of C57BL/6 mice during lethal (PyYM) or non-lethal (Py17XNL) P. yoelii infection. Ex vivo flow cytometry revealed that NK cells are activated within 24 hours of Py17XNL blood-stage infection, expressing CD25 and producing IFN-γ; this response was blunted and delayed during PyYM infection.

CD25 expression and IFN-γ production were highly correlated, suggesting a causal relationship between the two responses. Subsequent in vitro experiments revealed that IL-18 signalling is essential for induction of CD25 and synergises with IL-12 to enhance CD25 expression on splenic NK cells.

In accordance with this, Py17XNL-infected erythrocytes induced NK-cell CD25 expression and IFN-γ production in a manner that is completely IL-18- and partially IL-12-dependent, and IFN-γ production is enhanced by IL-2. These data suggest that IL-2 signalling via CD25 amplifies IL-18- and IL-12-mediated NK-cell activation during malaria infection.


Natural killer cells

From malaria control to sustainable elimination: Cluster randomised trial comparing targeted versus generalised vector control in South Africa.

LSHTM investigator: Immo Kleinschmidt, Jackie Cook & Chris Drakeley.

External collaborators: Maureen Coetzee, John Govere (Wits University); Jaishree Raman (National Institute for Communicable Diseases, South Africa); Philip Kruger (Malaria Control Manager, Limpopo Province); Aaron Mabuza (Malaria Control Manager, Mpumalanga); Natashia Morris (South African Medical Research Council).

Funding body: The Medical Research Council, the Wellcome Trust & the UK Department for International Development: Joint Global Health Trials.

An area comprising about 500,000 persons in the municipalities of Phalaborwa and Bushbuckridge in South Africa has been divided into 62 clusters which have been allocated by constrained randomisation to receiving either standard of care generalised IRS or receiving reactive IRS in response to two linked malaria cases. Malaria incidence in this area has averaged about 2 cases per 1000 per annum over the five years preceding the trial.

The trial will test the hypothesis that targeted spraying is as effective as generalised spraying as a protective measure against malaria, leads to

higher quality of IRS application because it can be better supervised; that it is more acceptable to householders and as such, will lead to better co-operation with access to premises and therefore higher spray coverage; and that householders will exercise better compliance with not repainting, washing or re-plastering of walls after spraying.

The study will compare malaria case incidence, householder acceptability and compliance, spray coverage and quality, and economic costs of the interventions as outcome indicators. The study will also assess whether passively reported incident cases arise from stable ‘hotspots’ of transmission by testing bloodspots taken from residents of case households and neighbouring households for malarial antibodies.

A pre-trial baseline survey in study clusters revealed that spray coverage in the 12 months preceding the survey was only 40% on average, and in some clusters no spraying had been carried out. Analysis of blood spots collected from a random sample of residents in this low transmission setting showed that sero-prevalence of antibodies to malarial antigens was about 8%, and that seropositives appear to be spatially clustered. The challenges of finite resources at a time of escalating insecticide costs and difficulties in accessing households during spray campaigns pose severe limitations for malaria control programs to provide high coverage blanket vector control, particularly in semi-urban settings of low malaria transmission. This study will evaluate a surveillance based alternative to generalised IRS to make vector control more sustainable during the pre-elimination period.

Vector Biology

Research to identify and assess innovative anti-mosquito vector interventions involves discovery of mechanisms in the laboratory, coupled with experimental-hut semi-field studies and controlled evaluation of effectiveness in malaria endemic communities.

Natural killer cells.



Modelling the effect of mosquito movement on village-scale indicators of malaria transmission.

LSHTM investigators: Jo Lines & John Bradley.

External collaborators: Jess Floyd (University of Southampton UK).

Conventional cluster-randomised trials of vector control interventions assume that contamination due to mosquito movement between villages is negligible.

To test this, we modelled age-structured mosquito populations in a landscape containing a mosaic of villages of two kinds, A and B, Figure 3. The effect of between-village movement on the observed effectiveness of vector control in simulated village-scale trials. The model assumes two types of village A and B, which are the same except that B villages have an intervention that reduces vector survival and longevity. The percentage of mosquitoes moving between A and B villages in each feeding cycle is assumed to be zero (black lines) or 10% (red lines) or 20% (purple lines).

The x axis is time, the y axis represents the apparent effectiveness of the invention, measured as the ratio between the infective biting rate (EIR) in control A villages compared to that in B intervention villages. The lighter lines represent the results of individual Monte Carlo simulations; the solid lines represent the median of 100 runs of vectors surviving through each gonotrophic cycle, but have the same level of human infectiousness (= the proportion of vector females becoming infected with Plasmodium in each gonotrophic cycle). In each cycle, there is a fixed probability that a female will transfer from an ‘A’ to a ‘B’ village and vice versa (as expected if some breeding sites are “shared” between villages).

Monte carlo simulations showed a consistent negative association between vector density (abundance) and sporozoite rate (proportion infective), challenging conventional methods of EIR estimation that assume overall independence of these two parameters. The simulated effects of vector control (i.e. contrasts between study arms in EIR and sporozoite rate), were very sensitive to, and greatly reduced by, even small amounts of mosquito movement (e.g. 10% per cycle). This suggests that contamination between study arms can be a major source of bias in vector control trials if the clusters are too small.

Interceptor G2, a novel insecticide mixture LLIN for controlling malaria transmitted by pyrethroid resistant mosquitoes.

LSHTM investigators: Mark Rowland, Raphael N’Guessan, Matt Kirby, Richard Oxborough & Corine Ngufor.

External collaborators: Frank Mosha (Kilimanjaro Christian Medical College, Tanzania); Martin Akogbeto (CREC Benin); William Kisinza & Patrick Tungu (NIMR Muheza Tanzania); David Malone (IVCC, UK); Egon Weinmuller & Susanne Stutz (BASF Chemicals, Germany).

Funding body: the Bill & Melinda Gates Foundation through the IVCC Consortium.

LSHTM staff have been at the forefront of the development of chlorfenapyr from the moment in 2003 that BASF was alerted to the potential vector control properties of this unusual insecticide.

In a programme of incremental and iterative development that spanned the Gates Malaria Partnership and IVCC the point was reached in 2015-16 when a mixture LLIN demonstrated full control of mosquito populations of the vectors Anopheles gambiae, An. arabiensis and An. funestus in experimental hut trials in which standard pyrethroid LLIN failed completely.

Because of its unusual mode of action on cellular respiration, chlorfenapyr behaves very differently in laboratory bioassay compared to neurotoxic insecticides and this has led to dissention and controversy from some quarters and to protracted development and evaluation of the LLIN.

However, in experimental hut trials its effectiveness is consistent across a variety of species in a variety of countries of West and East Africa. The latest formulation demonstrates wash resistant over 20 washes. It is predicted to become an important new generation LLIN in the continuing arms race against the vector and continuing battle to control malaria.


The effect of between-village movement on the observed effectiveness of vector control in simulated village-scale trials. The model assumes two types of village A and B, which are the same except that B villages have an intervention that reduces vector survival and longevity. The percentage of mosquitoes moving between A and B villages in each feeding cycle is assumed to be zero (black lines) or 10% (red lines) or 20% (purple lines). The x axis is time, the y axis represents the apparent effectiveness of the invention, measured as the ratio between the infective biting rate (EIR) in control A villages compared to that in B intervention villages.The lighter lines represent the results of individual Monte Carlo simulations; the solid lines represent the median of 100 runs.



The impact of insecticide resistance on the effectiveness of malaria vector control interventions, and combining indoor residual spraying and long-lasting insecticidal nets.

LSHTM investigators: Immo Kleinschmidt, John Bradley, Phillipa West & Jackie Cook.

External collaborators: Hmooda Kafy, Bashir Ismail & Mohamed Ahmed Abass (MoH, Sudan); Abraham Mnzava (WHO-GMP); Martin Donnelly (LSTM, UK); Martin Akogbeto (Benin); Carles Mbogo (Kenya); Etienne Fondjo (Cameroon); Kamaraju Raghavendra (National Institute of Malaria Research, India).

Funding body: The Bill and Melinda Gates Foundation via WHO.

In Sudan, a cluster RCT comparing universal coverage of LLINs with combined use of LLINs and IRS was implemented in areas with varying levels of insecticide resistance. Baseline levels of insecticide resistance of the main malaria vector (An. arabiensis) were balanced between the two study arms. In each cluster, resistance to insecticides was

monitored, and malaria incidence was estimated from cohorts of children followed over the duration of the study. This study will provide (1) an estimate of the effect of the combined intervention (LLIN plus IRS) relative to LLINs alone, adjusted for the presence of insecticide resistance, and (2) an estimate of the effect of insecticide resistance on vector control effectiveness.

In the other four countries, clusters have been established and malaria vector mosquitoes in each cluster assessed for resistance to the insecticide used. Cohorts of children are being followed-up to estimate malaria incidence. Resistance impact will be assessed from (1) the ratio of incidence rates in clusters with high compared to those with low resistance, and (2) ratio of protective effectiveness provided by LLINs in clusters of high compared to those of low resistance. Resistance mechanisms were determined in subsets of study clusters.

In the presence of insecticide resistance, the use of LLINs still provides protection against malaria. There is no clear evidence that the protective effectiveness of LLINs is diminished when mosquitoes are not fully susceptible to the insecticide on the nets. IRS loses its protective effect when vectors are no longer susceptible to the insecticide used. Insecticide resistance is growing and widespread.

Seasonal and spatial dynamics of the primary vector of Plasmodium knowlesi in Sabah, Malaysia.

LSHTM investigators: Kimberly Fornace & Chris Drakeley.

External collaborators: Meng Wong, Cherng Leong, Loke Khaw, Wan-Yusoff Wan-Sulaiman & Indra Vythilingam (University of Malaya, Malaysia); Tock Hing Chua (Universiti Malaysia Sabah, Malaysia); Timothy William (Jesselton Medical Centre, Malaysia); Heather Ferguson (Glasgow University, United Kingdom).

Funding body: UK Research Councils: BBSRC, ESRC, MRC and NERC.

The simian malaria Plasmodium knowlesi is an emerging public health problem in Malaysian Borneo. A one year longitudinal study of P. knowlesi

vectors was conducted within an endemic area in Sabah, Malaysia. Mosquitoes were caught using human landing catches and all mosquitoes were dissected to determine oocyst, sporozoite and parasite rates. Anopheles balabacensis was confirmed as the primary vector of P. knowlesi, mainly biting people outdoors in early evening (6-8pm). Vector densities were higher and more seasonally variable in village areas than in agricultural or forested areas. Average parous rates of this vector were over 55% in all sites. A total of 3% of An. balabacensis were positive for Plasmodium species, the majority of which had multiple species. The high parity, survival and sporozoite rates found in this mosquito species indicates that it is a highly competent vector.

Publication: Wong ML, Chua TH, Leong CS, Khaw LT, Fornace K, Wan-Sulaiman WY, et al. Seasonal and Spatial Dynamics of the Primary Vector of Plasmodium knowlesi within a Major Transmission Focus in Sabah, Malaysia. PLoS neglected tropical diseases. 2015 Oct;9(10):e0004135.

Does malaria infection influence the human odour profile and therefore attractiveness to mosquitoes?

LSHTM investigators: Ailie Robinson, Khalid Beshir, Teun Bousema, Colin Sutherland & James Logan.

External collaborators: Jetske De Boer & Willem Takken (University of Wageningen, Netherlands); Annette Busula, & Geoffrey Omondi (International Centre of Insect Physiology and Ecology, Kenya); John Caulfield, Stephen Powers, Mike Birkett & John A Pickett (Rothamsted Research, London).

Funding body: ZonMW, The Netherlands.

We have used air entrainment techniques and analytical chemistry to measure volatiles that are produced by the skin. We have conducted multivariate analyses to determine qualitative and

quantitative differences in the volatiles produced by Plasmodium-infected and -uninfected individuals in an experimental setting, with measurements taken over the duration of the study (i.e. before, during and after infection). These infections were cured at an early stage and as such were acute phase infections (with ‘during’ infection measurement at days 6 and 8 PI), additionally, these individuals had no prior exposure to malaria.

Our second dataset comprises odour samples from naturally malaria-infected children from Western Kenya (Mbita Point). This analysis requires a detailed examination of the infection status of these children, encompassing a variety of techniques including both field-based (RDT and film) and laboratory-based (qPCR and QT-NASBA) diagnostics. This information will be used to inform groupings in the dataset, allowing allocation of odour profile samples to groups with similar infection status. Following the multivariate analysis, the samples from both experimentally-infected and naturally-infected individuals will be measured for entomological response using electrophysiology.


Collection of odour and blood samples.

SummaryConsiderable progress has been made

in malaria control during the past decade

but this progress is threatened by drug

and insecticide resistance. Thus, novel

approaches to the prevention of malaria

are needed, including new insecticides,

alternative methods of vector control,

chemoprevention and vaccination. Staff

of LSHTM are contributing to research in

each of these fields as indicated in the contributions to this section of the Malaria

Centre report.

Evaluation of chlofenapyr for indoor residual spraying (IRS), development of a new device to provide even distribution of insecticide on walls and a trial of an insecticide treated wall lining are reported. Pyrethroid resistance, which is spreading across Africa, can be overcome to some extent by the synergist PBO and an important trial which is comparing nets incorporating PBO with conventional nets and IRS is being conducted in Tanzania. The results of this trial will have an important impact on whether these nets are used more widely as, unlike other studies, it has a parasitological as well as an entomological end-point.

Intermittent preventive treatment with sulphadoxine-pyrimethamine in pregnancy (IPTp-SP) is effective in preventing low birth weight and maternal anaemia but its efficacy is being threatened by increasing resistance to SP. Alternative drugs to SP for IPTp have been evaluated and promising results obtained with dihydro-artemisinin/piperaquine. However, there are some concerns over the safety of this drug combination in pregnancy and this is being investigated in Tanzania.

44 Malaria prevention


Malaria prevention 45


Screening and treatment of pregnant women (ISTp) is an alternative approach to IPTp which has been evaluated in a multicentre trial in West Africa. ISTp was non-inferior to IPTp in preventing low birth weight, maternal anaemia and placental malaria but was less effective at preventing malaria attacks in the mother. A detailed economic analysis showed that it was less cost effective.

Seasonal malaria chemoprevention (SMC) is now recommended policy for children under five years of age in countries of the Sahel and sub-Sahel. However, as malaria incidence declines, the peak age incidence of malaria moves into older children. Thus, it is reassuring that the results of a study conducted in approximately 600,000 children in Senegal showed that SMC is effective in this older age group and that it also had a modest impact on malaria transmission. In areas where SMC is recommended, respiratory and gastrointestinal infections are also prominent during the period when SMC is given and a large trial being conducted in Burkina Faso and Mali is investigating whether the

incidence of these infections can be reduced by giving azithromycin in addition to SMC. Extension of chemoprevention to school age children provides another potentially valuable use of this approach. This has been investigated in randomised controlled trials studies in Uganda, and in Mali where it has been combined with nutritional supplementation.

In July 2015, the European Medicines Agency (EMA) provided a positive opinion on the use of the malaria vaccine RTS,S/AS01, the first malaria vaccine to be recognised in this way, based on the results of a large phase3 trial of this vaccine to which several members of the staff of LSHTM contributed in various ways. A number of safety signals were identified during the course of the phase 3 trial and WHO has requested the conduct of three to five large scale implementation studies before the vaccine is recommended for routine use.



Vector Control

Malaria Centre members are conducting vector control research mainly across Africa. We work with multilateral agencies to evaluate the reach and usage of long-lasting insecticidal treated nets (LLINs) in universal coverage campaigns, the potential impact of combining indoor residual spraying campaigns with LLINs, and the potential of and constraints to less established form of vector control such as insecticide treated durable wall lining, larval source management, and topical and spatial repellents.

Revolutionizing vector control for malaria elimination.LSHTM investigator: Lucy Tusting.

External collaborators: Yasmin Williams, Allison Tatarsky & Roly Gosling (Global Health Group, University of California, San Francisco); Gerry Killeen (Liverpool School of Tropical Medicine and Ifakara Health Institute); Tricia Graves (James Cook University).

Funding body: Parker Foundation.

This project aims to identify malaria vector control interventions beyond LLINs and IRS, with existing or future potential to target key vector life stages and adult vector behaviours to reduce malaria transmission.

A systematic review is underway to evaluate the availability of evidence for a range of vector control interventions that already exist, are under development, or could be adapted for Anopheles control, and their technological and operational readiness. Interventions of interest include improved housing, aerial larvicide spraying and other forms of larval source management, endectocide-treated humans and livestock, attractive toxic sugar baits and novel interventions in the pipeline.

The overall goal is to develop a shortlist of anti-Anopheles interventions for countries working towards elimination and to highlight gaps in the evidence to inform future research into novel vector control for malaria elimination.

Controlling malaria using livestock-based interventions: a one health approach.

LSHTM investigators: Ana Franco, Mark Rowland, Paul Coleman & Clive Davies.

External collaborators: M. Gabriela. & M. Gomes (Instituto Gulbenkian de Ciência, Portugal).

Funding body: Ana Franco was funded by the Portuguese Fundação para a Ciência e Tecnologia (FCT - SFRH/BD/9605/2002), co-financed by the Programa Operacional Ciência e Inovação 2010 (POCI 2010) and Fundo Social Europeu (FSE), and by EPIWORK - European Commission (Grant Agreement 231807). The publication fees were paid by LSHTM.

This project explored the different effects that untreated and insecticide-treated livestock (ITL) can have on human malaria in regions where the disease is transmitted by mosquitoes that also blood-feed on animals, to assess when livestock-based

Conducting interviews in a Konso village in Ethiopia: A field assistant is concentrated filling the study questionnaire to collect data. (Photo by Ana Franco).



interventions could help malaria control. This was achieved by developing a mathematical model combined with data from Pakistan, where malaria vectors are highly zoophilic and a community trial of ITL halved malaria cases, and to data from Africa (Ethiopia), where vectors are more anthropophilic and the impact of ITL on malaria has not yet been tested formally.

The model characterizes situations where livestock by itself could decrease or increase malaria transmission to humans, and it indicates when treating livestock with insecticide could be a complementary tool to control malaria in sub-Saharan Africa: high treatment coverage of livestock population, with a stronger or longer lasting insecticidal than in the Pakistan trial, and with small repellency effect, or if increasing the attractiveness of treated livestock to malaria vectors. We hope this study may lead to a community-based trial of ITL in an African region where moderately zoophilic vectors predominate (namely Anopheles arabiensis), and where this intervention could contribute to integrated control of human malaria and livestock diseases.

Predicted impact of Insecticide Treatment of Livestock on malaria prevalence with repellency or attractancy (PR: prevalence ratio = prevalence with ITL divided by baseline prevalence) (Source: Franco et al. PLoS ONE 2014; 9(7): e101699).



The evidence for improving housing to control malaria.

LSHTM investigators: Lucy Tusting, Immo Kleinschmidt & Barbara Willey.

External collaborators: Grant Dorsey, Roly Gosling & Matthew Ippolito (University of California, San Francisco); Steve Lindsay (Durham University).

Funding body: Leverhulme Centre for Integrative Research in Agriculture and Health; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, US Department of Homeland Security, the Fogarty International Center (US National Institutes of Health); the Bill & Melinda Gates Foundation; Novartis Foundation for Sustainable Development; Medical Research Council and UK Department for International Development.

A systematic review and meta-analysis was conducted to assess whether modern housing (with closed eaves, ceilings, screened doors and windows) is associated with a lower risk of malaria

than traditional housing (with mud, stone, bamboo or wood walls; thatched, mud or wood roofs; earth or wood floors), across all age groups and malaria-endemic settings.

Of 15,526 studies screened, 53 were included in a meta-analysis. Residents of modern houses had a 47% lower risk of malaria infection and a 45–65% lower risk of clinical malaria, compared to traditional houses. Residents of modern houses had 47% lower odds of malaria infection compared to traditional houses (adjusted odds ratio (OR) 0.53, 95% confidence intervals (CI) 0.42–0.67, p<0.001) and a 45–65% lower odds or rate of clinical malaria (case–control studies: adjusted OR 0.35, 95%CI 0.20–0.62, p<0.001; cohort studies: adjusted rate ratio 0.55, 95%CI 0.36–0.84, p=0.005). Evidence of a high risk of bias was found within studies.

Despite low quality evidence, the direction and consistency of effects indicate that house quality is an important risk factor for malaria. Future research will evaluate the protective effect of specific house features and the impact of incremental housing improvements associated with socioeconomic development.

Community Sensitization Meetings and Installation of PermaNet® Insecticide-Treated Wall Lining. Insecticide-treated durable wall lining in Tanzanian house.

The effectiveness of non-pyrethroid insecticide-treated durable wall lining to control malaria in rural Tanzania: cluster randomized trial.

LSHTM investigators: Louisa Messenger, Sophie Weston, Mark Rowland, Immo Kleinschmidt & Jackie Cook.

External collaborators: William Kisinza, George Mtove, Joseph Mugasa and Robert Malima (National Institute for Medical Research, Tanzania); Frank Mosha (Kilimanjaro Christian Medical College, Tanzania).

Funding body: US Agency for International Development.

A two-armed, cluster randomized controlled trial is currently underway in rural Tanzania to assess whether non-pyrethroid insecticide-treated wall lining (ITWL) and universal coverage of long-lasting insecticidal nets (LLINs) provide added protection against malaria infection in children, compared to LLINs alone.

Study children, aged 6 months to 11 years old, have been enrolled from 44 village clusters (22 ITWL+LLINs and 22 LLINs only) and are followed monthly to estimate cumulative incidence of malaria infection, time to first malaria episode and prevalence of anaemia before and after the intervention.

Entomological inoculation rate is being estimated using indoor light traps and outdoor tent traps and insecticide resistance levels monitored using CDC bottle bioassays. Social and cultural

factors influencing community and household ITWL acceptability are also being explored through focus-group discussions and in-depth interviews.

Cost-effectiveness per malaria case averted by the combination of ITWL and LLINs compared to LLINs alone is also being estimated. If ITWL is proven both effective and durable under field conditions, it may warrant consideration for programmatic implementation, particularly in areas where pyrethroid-resistant vectors predominate.

Trial findings will provide crucial information for policy makers in Tanzania and other malaria-endemic countries to guide resource allocations for future control efforts.



Development and evaluation of a Chlorfenapyr Long-lasting Indoor Residual Spray formulation.

LSHTM investigators: Matt Kirby, Raphael N’Guessan, Corine Ngufor & Mark Rowland.

External collaborators: Franklin Mosha & Jovin Kitau (Kilimanjaro Christian Medical University College, Tanzania); Martin Akogbeta (Centre de recherché entomologique de Cotonou, Benin); Susanne Stutz & Egon Weinmuller (BASF, Germany); Dave Malone (IVCC, UK).

Funding body: Bill & Melinda Gates Foundation through the Innovative Vector Control Consortium (IVCC).

Several formulations of the pyrrole insecticide chlorfenapyr (CFP) have been screened for their efficacy and duration of effective action against both pyrethroid-resistant, and pyrethroid-susceptible mosquito strains in the PAMVERC labs in Benin and Tanzania. CFP (in combination with alphacypermethrin) on bed nets has already been shown to be effective in late-stage trials, so there is confidence that CFP can also work as an IRS. There is no evidence of cross-resistance, and it is likely that CFP will be an important component of

the IRS arsenal in future years, used in rotation with existing IRS insecticides. The IRS formulations being screened are undergoing further tests using a novel assay technique developed by LSHTM staff (the IRS simulator, or ‘cube’ assay), with the intention to

test the most promising candidates in semi-field conditions (experimental hut studies) against wild free-flying mosquitoes.

As part of the same study, experiments are also on-going testing a polymer applied to mud substrates as a ‘primer’ layer that is then over-sprayed with CFP, as a potential solution to improving the duration of insecticidal activity. Typically insecticides do not last as long on mud versus concrete or



Calibration, optimisation and evaluation of a mechanised track sprayer for spraying IRS in experimental hut trials.

LSHTM investigators: Janneke Snetselaar, Matt Kirby & Mark Rowland.

External collaborators: John Clayton (Micron, UK); John Lucas (Sumitomo chemicals, Japan); David Malone (Innovative Vector Control Consortium, UK); Franklin Mosha (Kilimanjaro Christian Medical Centre, Tanzania).

Funding body: Bill and Melinda Gates Foundation through the Innovative Vector Control Consortium (IVCC).

The Micron track sprayer has been developed for the controlled application of Indoor Residual Spray (IRS) treatments. Early prototypes of the track sprayer have been tested and optimized by LSHTM staff in an experimental hut study at the PAMVERC Harusini field site in Tanzania.

Instead of spraying manually, the track sprayer provides a mechanical way of applying Insecticide Residual Sprays.

It consists of a carriage mounted spray nozzle that moves on a vertically oriented track positioned in front of the wall, distributing a controlled amount of insecticide on the wall. The speed of the

carriage can be varied and the run length of the track sprayer can be adjusted according to the dimensions of the experimental huts. Quantitative comparisons of the amount of insecticide applied during manual spraying and during spraying with the Micron track sprayer are currently ongoing. Sprayed filter papers are compared between spraying method, treatments with different compounds and filter paper mounting on the wall.

A controlled and standardized way of applying insecticides would be a major improvement for IRS evaluation.

Blocks sprayed with insecticide being evaluated in the IRS simulator.



Schematic overview of the Micron track sprayer (courtesy Micron Sprayers Ltd. 2015).

Mud and concrete blocks stored between assays.



wooden surfaces, but many rural houses in sub-Saharan Africa still have mud brick walls.

The useful life of mosquito nets for malaria control in Tanzania: Attrition, Bioefficacy, Chemistry, Degradation and insecticide Resistance (ABCDR study).LSHTM investigators: Lena Lorenz, Jason Moore, John Bradley & Zawadi Mageni.

External collaborators: Hans J Overgaard (Norwegian University of Life Sciences, Norway); Sarah Moore (Ifakara Health Institute, Tanzania & Swiss Tropical and Public Health Institute, Switzerland); William Kisinza (National Institute for Medical Research, Tanzania); Renata Mandike (National Malaria Control Programme, Tanzania).

Funding body: Research Council of Norway (RCN) – GLOBVAC (Global Health and Vaccination Research).

The ABCDR study investigates use and durability of Long-Lasting Insecticidal Nets (LLINs) in eight districts in Tanzania over three years following WHO guidelines to provide data to the Government for net procurement decisions.

In 2013, 10,598 new LLINs were distributed to 3,398 households. After 10 months, 77% were still in households whereas 23% were no longer present. Net attrition, defined as discarding nets or using them for alternative purposes, was 3.2%. The other nets no longer in the study households had mainly been given away to other family members “who needed the nets more”.

Of the 2,248 (30%) nets not in use, a third were saved for future use or visitors. Only 2% of nets had not been used because they were too old or torn. Non-net use varied geographically. In Mbozi district, more than 50% of the general population and children under five years old did not use a net the night before the survey, whereas in Bagamoyo district, non-net use in both groups was below 20%.

A metal frame was used to count holes in nets still present within households. Of 6,175 nets, 32% had no holes at all but 10% had too many holes to be deemed useful against malaria transmission following WHO guidelines. An open fire, presence of rats and tucking net underneath a mat/mattress were risk factors for the presence of holes. Damage to nets mainly came from holes located on the bottom quarter of the net.

The study is continuing to monitor net use, attrition and durability with final results expected early 2017.



Evaluation of a novel LLIN and IRS product, separately and together, against malaria transmitted by pyrethroid resistant mosquitoes In North-West Tanzania: a cluster randomized controlled trial.

LSHTM investigators: Natacha Protopopoff, Mark Rowland, Jacques Derek Charlwood, Alexandra Wright, Immo Kleinshmidt & Andreia Santos.

External collaborators: Franklin Mosha (Kilimanjaro Christian Medical University College, Moshi, Tanzania); William Kisinza (National Institute of Medical Research, Tanzania); Jacklin Mosha (National Institute of Medical Research, Tanzania).

Funding body: Medical Research Council, Wellcome Trust and UK Department for International Development.

This randomised controlled trial is evaluating the relative effectiveness of four vector control interventions for reducing malaria transmission and controlling vector populations in an area where Anopheles gambiae, the main vector, is pyrethroid resistant.

We allocated 48 village clusters to 4 arms using a factorial design: 1/ Standard long lasting insecticidal net (LLIN), 2/ Novel LLIN incorporating the synergist PBO, 3/ Long lasting indoor residual spray (IRS) formulation (pirimiphos methyl CS) combined with standard LLIN and 4/a long lasting IRS formulation with the novel LLIN.

Plasmodium infection prevalence was assessed in children aged 0.5 to 14 years through cross sectional surveys. Indoor and outdoor Anopheles densities were monitored using CDC light trap and adapted furvela tent trap. Entomological inoculation rate was compared between study arms.

At baseline, malaria infection prevalence (+ 95% CI) was 64.7% (63.2-66.2) in the study area. Mean vector density (+ 95% CI) per collection per night was 24.5 (19.4-29.6) indoor and 12.7 (8.7-16.7) outdoor and a daily EIR of 0.34 (0.20-0.49). IRS and the distribution of the two types of LLIN were conducted in February 2015. 93.6% of the houses were sprayed and LLIN ownership and usage reached 98.5% and 77.3% respectively.

Two post intervention cross sectional studies have been completed in June and December 2015 and analysis is ongoing. This important trial involving the best available vector control tools should determine to what extent resistance is undermining control and whether the new tools can overcome the problem.

Field interviewer counting holes in mosquito net (Geita district; October 2014). Outdoor insectary.


Evaluating the effectiveness and feasibility of reactive targeted parasite elimination vs. reactive case detection as a community level intervention in response to passively identified index cases in Zambezi region, Namibia.

LSHTM investigator: Immo Kleinschmidt.

External collaborators: Davis Mumbengegwi (University of Namibia); Lizette Koekemoer & John Govere (University of Witwatersrand, South Africa); Roly Goslimg, Hugh Sturrock & Jennifer Smith (University of California, USA); Michelle Hsiang (University of Texas Southwestern Medical Center, USA).

Funding body: the Bill & Melinda Gates Foundation & the Novartis Foundation.

Reactive case detection in the form of active surveillance in communities around passively

detected cases, is a recommended elimination strategy to identify secondary cases, but it is labour, time, and cost intensive, and misses many cases because RDTs have limited sensitivity to detect low parasite density and non-falciparum infections.

Targeted Parasite Elimination (TPE) consists of presumptive treatment, without first being tested, of all individuals in the immediate neighbourhood of a passively detected case, thereby targeting individuals at highest risk for malaria. Reactive targeted vector control (RAVC) consists of targeted Indoor Residual Spraying (IRS), treating all houses in the immediate neighbourhood of a passively detected case. In this study, the two interventions, TPE and RAVC will be evaluated using a cluster-randomised trial with a factorial design.

TPE will consist of presumptive treatment using artesunate lumefantrine (Coartem®). RAVC will consist of IRS using Actellic 300 CS. The interventions will be compared, separately and in combination, against current practice, which is reactive case detection. The primary outcome of the study will be incidence of malaria cases by passive case detection.




Chemoprevention

We are currently seeking to generate knowledge on the health impact, cost, feasibility and acceptability of chemoprevention and screening and treatment strategies in a number of target populations including children, school children and pregnant women.

A non-inferiority, individually randomized trial of intermittent screening and treatment versus intermittent preventive treatment in the control of malaria in pregnancy.

LSHTM investigators: Daniel Chandramohan, Matt Cairns, Brian Greenwood, Paul Milligan, Harry Tagbor & Arouna Woukeu.

External collaborators: Kalifa Bojang, Ismaela Abubakar, Francis Akor, Khalifa Mohammed & Fanta Njie (MRC Unit, The Gambia); Sheick Oumar Coulibaly, Richard Bationo, Edgar-Dabira, & Alamissa Soulama (Faculty of Health Sciences, University of Ouagadougou, Burkina Faso); Kassoum Kayentao, Moussa Djimdé, Etienne Guiro & Ogobara Doumbo (Malaria Research and Training Centre, Mali); John Williams, Timothy Awine, Stephen Quaye, Abraham Hodgson & Abraham Oduro (Navrongo Health Research Centre, Navrongo, Ghana); Jaume Ordi (Barcelona Centre for International Health Research (CRESIB), Barcelona, Spain); Steve Meshnick (University of North Carolina, USA); Steve Taylor (Duke University Medical Center, USA); Pascal Magnussen (University of Copenhagen, Denmark); & Feiko ter Kuile (Liverpool School of Tropical Medicine, UK).

Funding body: European Developing Country Clinical Trials Partnership and the Bill and Melinda Gates Foundation through the Malaria in Pregnancy Consortium.

WHO recommends administration of sulphadoxine pyrimethamine (IPTp-SP) at each antenatal clinic visit after the first trimester to prevent malaria in

pregnancy. However, this intervention is threatened by emerging resistance to SP and alternative approaches to prevention of malaria in pregnancy need to be explored. One of these is screening of women with a rapid diagnostic test at each antenatal clinic visit and treating those who are positive (ISTp). To investigate the efficacy of the latter approach, a trial was undertaken in 5,354 primigravidae and secundigravidae in four West African countries.

ISTp was non-inferior to IPTp-SP in preventing low birth weight (prevalence 15.6% and 15.1% respectively) and in preventing anaemia (haemoglobin concentration at the last clinic attendance before delivery 10.94 and 10.97 g/dL respectively). Active malaria infection of the placenta was found in 24.2% of women in the ISTp group and in 24.5% of those in the IPT-SP group. More women in the ISTp group experienced a clinical attack of malaria during pregnancy than did women in the IPT-SP group (182 versus 310 episodes).

Based on the findings from this study and from trials in East Africa, WHO recommends continuing use of IPTp-SP in areas of moderate or high malaria transmission, even in the presence of moderate levels of resistance to SP.

Maintaining mosquitoes after exposure to insecticide, Tanzania. Pregnant women waiting to be tested for malaria.


Economic analysis and evaluations for the Malaria in Pregnancy (MiP) Consortium.

LSHTM investigators: Kara Hanson, Silke Fernandes & Jayne Webster.

External collaborators: Elisa Sicuri (Barcelona Institute for Global health (ISGobal); Azra Ghani & Patrick Walker (Imperial College, UK); Feiko ter Kuile & Jenny Hill (Liverpool School of Tropical Medicine, UK); James Akazili (Navrongo Health Research Centre, Ghana); Kassoum Kayentao & Halimatou Diawara (Malaria Research and Training Centre Bamako, Mali); Mwayi Madanitsa (College of Medicine, Blantyre, Malawi); Vincent Were (KEMRI/CDC Kisumu, Kenya); Suparat Phuanukoonnon (Papua New Guinean Institute of Medical Research).

Funding body: Bill & Melinda Gates Foundation though the Malaria in Pregnancy Consortium.

Sitting within the Public Health Impact activity of the Malaria in Pregnancy Consortium (MiPc), the objectives of the economics contributions are: a) to assess the cost and cost-effectiveness of new prevention and case management interventions; b) to estimate the cost of scaling up new MiP

interventions and c) to estimate the economic burden of MiP.

Fieldwork was conducted in 8 countries over the course of 5 years ending in 2015. Data were collected using a variety of methods, including cross-sectional household and facility surveys, exit surveys and observational studies. A cost-effectiveness analysis building on a meta-analysis of clinical trials found that intermittent preventive treatment (IPTp) with 3 or more doses of Sulfadoxine-Pyrimethamine (SP) was highly cost-effective compared with two doses of SP. For a WHO Evidence Review Group meeting in July 2015, we conducted a cost-effectiveness analysis of a non-inferiority trial in West Africa comparing Intermittent Screening and Treatment for malaria in pregnancy (ISTp) with IPTp.

We found ISTp not to be cost-effective at current levels of SP resistance in West Africa. However we explored in a model the level of SP efficacy (which is anticipated to decrease in Africa due to spread of SP resistance) at which ISTp would become cost effective, providing insight for policy makers from settings with a high SP resistance. We are currently conducting a cost effectiveness analysis comparing IPTp with Dihydroartemisinin-Piperaquine (3 doses given monthly) versus IPTp-SP (3 doses) using trial data from Kenya and Uganda.


Discrete choice experiments (DCEs) to elicit preferences of combination therapy against malaria and curable sexually transmitted and reproductive tract infections (STIs/RTIs) among pregnant women and health-care providers in Tanzania.LSHTM investigators: Matthew Chico, Daniel Chandramohan & Jayne Webster.

External collaborators: Antonieta Medina-Lara (Exeter University, UK); Joyce Wamoyi, Soori Nnko, Catherine Bunga & John Changalucha (National Institute of Medical Research, Tanzania).

Funding body: Medicines for Malaria Venture.

The underlying premise of DCEs is that people make trade-offs, conscious or not, in the process of

decision-making. Understanding these trade-offs can help policymakers and programme managers to forecast the demand for new health interventions. The DCEs we conducted were designed to measure the most influencial barriers to the scale-up of intermittent preventive treatment of malaria in pregnancy (IPTp).

The current treatment given to women for IPTp is sulphadoxine-pyrimethamine which provides a sub-optimal protective effect against the adverse consequences of malaria in pregnancy in some situations. Azithromycin has modest antimalarial activity, but is curative against many STIs/RTIs that are prevalent in sub-Saharan Africa. Thus, azithromycin combined with a more efficacious antimalarial drug may offer superior protction against adverse birth outcomes. This study investigated the acceptability of such combination therapy relative to malaria-only chemoprevention. IPTp coverage has plateaued around 25% in sub-Saharan Africa and in some areas has decreased in recent years. Strong preference among providers and pregnant women for combination therapy may help to increase the coverage of IPTp if adopted as a replacement for sulphadoxine-pyrimethamine.



Cardio-safety of dihydroartemisinin-piperaquine and pharmacokinetics of piperaquine amongst pregnant women in Tanzania.LSHTM investigators: Matthew Chico, Daniel Chandramohan & Brian Greenwood.

External collaborators: Franklin Mosha (Kilimanjaro Christian Medical University College, Tanzania); Jacklin Mosha (National Institute of Medical Research, Tanzania); Alphaxard Manjurano (National Institute of Medical Research, Tanzania).

Funding body: Medicines for Malaria Venture.

Many antimalarial drugs induce transient prolongation of the corrected QT interval (QTc) without causing clinical effects. Malarial infection

itself can lengthen the QTc interval independent of treatment. Dihydroartemisinin-piperaquine (DP) has also been shown to prolong the QTc interval, the effect resolving within a week without any clinical consequences.

DP is the leading candidate to replace sulphadoxine-pyrimethamine in the intermittent preventive treatment of malaria in pregnancy. However, because all prior QTc studies have systematically excluded pregnant women, the effect of DP on the QTc interval in this population is unknown.

Pregnancy is known to alter the pharmacokinetics of many compounds, potentially increasing or decreasing rates and quantities that are absorbed, distributed, metabolized, and eliminated. Thus, knowing the effect of DP on the QTc interval amongst pregnant women is important and a study to determine this will start in Tanzania in 2016.

Seasonal Malaria Chemoprevention (SMC) in Senegal.

LSHTM investigator: Paul Milligan.

External collaborators: Jean Louis NDiaye & Oumar Gaye (Universite Cheikh Anta Diop, Senegal); Maddy Ba & Medoune Ndiop (Programme National de Lutte contre le Paludisme, Senegal).

Funding body: Wellcome Trust & President’s Malaria Initiative.

In Senegal, the decision was taken to provide SMC for children up to 10 years of age in view of the high malaria burden in older children.

Despite progress in controlling malaria in Senegal, the southern regions of the country continue to have a high burden.

SMC was introduced in the last two months of 2013 as a pilot in 60,000 children, and extended to four regions from September to November in 2014, covering a population of approximately 600,000 children. Door-to-door campaigns resulted in high coverage.

We monitored the impact on inpatient malaria cases by collecting data from 2012 onwards from hospitals serving the four regions, and on outpatient cases from a sample of outpatient clinics selected with probability proportional to catchment. This allowed

us to estimate the total number of cases each year with a more detailed breakdown by age than is possible from national data.

The data for older age groups that did not receive SMC allowed adjustment for year to year fluctuations. During the months when SMC was administered, there was a 66% (95%CI:57%,73%) reduction in outpatient malaria cases in the targeted age group and a 57%(50%,64%) reduction in cases of severe malaria. This is likely to indicate the true direct impact of SMC during these months, as no other malaria interventions targeting this age group were implemented during the same timeframe.

The overall impact could be increased by providing SMC for 4 months as the main period of malaria risk starts at the end of July. When older children are included in SMC programmes, an effect on transmission may be expected.

Measurement of these indirect effects relies on comparing incidence in older groups in SMC and non-SMC areas, which is prone to confounding. The reduction in incidence in older age groups in SMC areas in 2014 is consistent with a modest transmission-reduction effect, as elsewhere in Senegal there was no reduction in incidence in 2014.

It is important that longer-term monitoring is maintained to assess these effects, to determine the importance of any rebound malaria caused by reduced acquisition of immunity, to detect changes in drug efficacy, and to monitor safety.


Only two cases of severe adverse drug reactions have been reported, both severe skin reactions in girls aged 8 and 10 years. Countries that are implementing SMC in children under 5 years old children, and which have a high incidence of malaria

in older age groups, may consider extending their programmes to include older children. The Senegalese experience indicates this could have a substantial impact.

A trial of seasonal malaria chemoprevention plus azithromycin in African children.

LSHTM investigators: Daniel Chandramohan, Irene Kuepfer, Matt Cairns, Paul Milligan & Brian Greenwood.

External collaborators: Alassane Dicko, Issaka Sagara & Ogobara Doumbo (Malaria Research & Training Center, Bamako, Mali); Jean Bosco Ouedraogo, Tinto Halidou & Issaka Zongo (Institut de Recherche en Sciences de la Santé, Bobo-Dioulasso, Burkina Faso).

Funding body: Medical Research Council, Wellcome Trust and UK Department for International Development.

The primary objective of this double blind, randomised, placebo controlled trial is to determine whether adding azithromycin (AZ) to Seasonal Malaria Chemoprevention (SMC) using sulphadoxine/pyrimethamine (SP) +amodiaquine (AQ) would provide additional reduction in deaths and severe illness in young children. Secondary objectives include an assessment of the safety and cost-effectiveness of the addition of AZ to SMC with SP+AQ.

Children aged 3 - 59 months are randomised to receive four cycles of either SP+AQ+AZ or SP+AQ+ placebo at monthly intervals during the peak malaria transmission season..

Primary endpoint: Incidence of the combination of death or hospital admission for at least 24 hours, not due to trauma or elective surgery during the intervention period.




The secondary endpoints include: attendance at a study health centre with a non-malarial febrile illness and/or malaria, the prevalence of anaemia and malnutrition at the end of each malaria transmission season, prevalence of nasopharyngeal carriage with pneumococci and macrolide resistant pneumococci before and at the end of each malaria transmissions

season, and the prevalence of resistance markers to SP at the end of the study. The sample size is19,200 children (9600 in each country). The delivery of interventions and the follow up of children will be completed in December 2016 and the results will be disseminated in 2017.

Seasonal malaria chemoprevention in an area of extended seasonal transmission in Ashanti, Ghana: an individually-randomised clinical trial.LSHTM investigators: Matthew Cairns, Daniel Chandramohan & Harry Tagbor.

External collaborators: Princess Ruhama Acheampong, Gifty Dufie Antwi & Harry Tagbor (Kwame Nkrumah University of Science and Technology (KNUST), Ghana); Constance Bart Plange (National Malaria Control Programme, Ghana Health Service, Ghana).

Funding body: COMDIS-HSD (University of Leeds, UK), Sir Halley Stewart Trust.

The aims of this study were to investigate the effectiveness of seasonal malaria chemoprevention (SMC) and community case-management with long-acting artemisinin-based combination therapies

(ACTs) in an area of extended seasonal malaria transmission in Ghana.

An individually-randomised, placebo-controlled trial was conducted in Ejisu-Juaben, Ashanti Region, Ghana. 2400 children aged between 3-59 months received either: 1) a short-acting ACT for case management of malaria (artemether-lumefantrine, AL) plus placebo SMC, 2) a long-acting ACT (dihydroartemisinin-piperaquine, DP) for case management plus placebo SMC or 3) AL for case management plus active SMC with sulphadoxine-pyrimethamine and amodiaquine. SMC or placebo was delivered on five occasions during the rainy season.

The incidence of malaria was 38% (95% confidence interval 7%, 59%) lower in children given SMC during the rainy season. There were no major differences between groups given different ACTs for case-management.

In conclusion, SMC may have an important public health impact in areas with a longer transmission season, but further optimisation of SMC is needed to maximise its impact in such settings.

Number of cases of malaria during the months September to December in four regions of Senegal (Tambacounda, Kedougou, Kolda and Sedhiou) before and after introduction of SMC in children under 10 years of age.

Blood spots drying on filter paper before analysis.


School-based treatment with ACT to reduce transmission of malaria’ - (START-IPT): Evaluation of the community-level impact of intermittent preventive treatment for malaria in Ugandan children.

LSHTM investigators: Sarah Staedke, Chris Drakeley, Clare Chandler & Andrea Rehman.

External collaborators: Grant Dorsey & Francesca Aweeka (University of California, USA); Moses Kamya, Joaniter Nankabirwa & Yeka Adoke (Makerere University, Uganda); Steve Lindsay (Durham University, UK); Lucy Okell & Jamie Griffin (Imperial College London, UK).

Funding body: Joint Global Health Trials Scheme; Medical Research Council, UK Department for International Development, Wellcome Trust.

Intermittent preventive treatment (IPT) for malaria in schoolchildren benefits individual children, and may decrease transmission within the community. This cluster-randomised trial assessed the impact of IPT

for malaria in schoolchildren with dihydroartemisinin-piperaquine (DP) on community-level clinical outcomes and malaria transmission in Jinja, Uganda. A total of 84 clusters were randomised equally between intervention and control, and 10,746 children were enrolled in the intervention. From June-Dec 2014, up to 6 rounds of DP were delivered to participants. The impact of the intervention was measured by comparing parasitological outcomes in community and school surveys pre- and post-intervention, and through continuous entomological surveillance.

Preliminary results suggest that the IPT intervention had a substantial impact on individual schoolchildren, and a smaller but detectable effect at the community level. Parasite prevalence by microscopy was significantly lower in the intervention clusters than in the control, in both the final school survey (9.2% vs 44.1%, respectively, aRR 0.22, 95% CI 0.16-0.30, p<0.001) and in the final community survey (19.0% vs 23.1%, respectively, aRR 0.83, 95% CI 0.70-0.98, p=0.03).

IPT for malaria in schoolchildren is a promising malaria control intervention for school-aged children and the population as a whole. Further research is needed to inform policy.




Seasonal malaria chemoprevention combined with micronutrient supplementation delivered through community preschools in Mali.

LSHTM investigators: Siân Clarke & Hans Verhoef.

External collaborators: Natalie Roschnik & Lauren Pisani (Save the Children, USA); Yahia Dicko, Niélé Hawa Diarra, Philippe Thera, Modibo Bamadio & Seybou Diarra (Save the Children, Mali); Moussa Sacko & Renion Saye (Institut National de Recherche en Santé Publique Mali); Yvonne Griffiths (UCL Institute of Education, UK & University of Leeds, UK); Rebecca Jones (University College London, UK); Josselin Thuilliez (Centre d’Economie de Sorbonne, France); Bore Saran Diakité, Diahara Toure, Moctar Coulibaly & Fatoumata Dougnon (Ministry of Health, Mali); Alassane Dicko & Hamidou Niangaly (University of Bamako, Mali); Bonaventure Maiga & Maria Sangaré (Ministry of Education, Mali).

Funding body: UBS Optimus Foundation and World Bank Strategic Impact Evaluation Fund.

This project aims to evaluate the combined impact of two newly–recommended interventions in early childhood: seasonal malaria chemoprevention and home fortification with micronutrient powders.

Although each intervention has been shown to improve malaria morbidity, anemia and/or physical growth, the benefits for cognitive and linguistic development are not known.

The impact evaluation utilises a randomised trial design, in which 60 rural communities with pre-schools in southern Mali were randomised to the intervention or control arm in 2013. Children aged 0-5 years in the 30 intervention communities receive seasonal malaria chemoprevention in September-December each year, followed by daily supplementation of micronutrients for four months from January-April.

Malaria infection, nutritional status and cognitive performance at age 3 and 5 years is being compared between children in intervention and control communities. Preliminary results show coverage and compliance with both interventions is high.

After the first 12 months of implementation, malaria infection was significantly lower in intervention compared to control communities (3 years old children: 21% vs 45%; 5years old children: 32% vs 55%, both p<0.001).

No difference was observed in haemoglobin concentration, nutritional indices or cognitive function. Seasonal malaria chemoprevention has now been extended to control communities, and a final evaluation will be carried out in 2016 to assess the additional impact of the micronutrient intervention after three consecutive years of implementation.

START-IPT staff. START-IPT participants.



Vaccine development

Several of our staff have participated in the design, execution and evaluation of RTS,S candidate vaccine trials as well as a trial of a prime boost vaccine candidate in Senegal.

Immunogenicity of the RTS,S/AS01 malaria vaccine over time and implications for duration of vaccine efficacy: analysis of data from a phase 3 randomised controlled trial

LSHTM investigators: Brian Greenwood, Chris Drakeley & Eleanor Riley.

External collaborators: Michael White, Robert Verity, Jamie Griffin & Azra Ghani (Imperial College London, UK); Kwaku Poku Asante (Kintampo Health Research Centre, Ghana); Seth Owusu-Agyei (Kintampo Health Research Centre, Ghana & London School of Hygiene and Tropical Medicine); Samwel Gesase (Tanzania National Institute for Medical Research (NIMR), Tanzania) John Lusingu (NIMR, Tanzania & University of Copenhagen, Denmark); Daniel Ansong & Tsiri Agbenyega (Kwame Nkrumah University of Science and Technology, Ghana); Samuel Adjei (Agogo Presbyterian Hospital, Ghana); Bernhards Ogutu, Lucas Otieno & Walter Otieno (KEMRI-Walter Reed Project, Kombewa, Kenya); Selidji T Agnandji, Bertrand Lell & Peter Kremsner (Centre de Recherches Médicales de Lambaréné, Gabon, Institut für Tropenmedizin, Universitätsklinikum Tübingen, Germany & German Center for Infection Research); Irving Hoffman (University of North Carolina, USA); Francis Martinson & Portia Kamthunzu (University of North Carolina (UNC) Project-Malawi, Malawi); Halidou Tinto, Innocent Valea & Hermann Sorgho (Institut de Recherche en Sciences de la Sante, Burkina Faso); Martina Oneko & Kephas Otieno (KEMRI/CDC Public Health and Research Collaboration, Kenya); Mary Hamel (US Centers for Disease Control and Prevention, USA); Nahya Salim, Ali Mtoro & Salim Abdulla (Bagamoyo Research and Training Centre, Ifakara Health Institute, Tanzania); Pedro Aide (Centro de Investigação em Saúde de Manhiça (CISM), Mozambique); Jahit Sacarlal (CISM, Mozambique & Faculdade de Medicina, Universidade Eduardo Mondlane, Mozambique); John Aponte (CISM, Mozambique & Universitat de Barcelona, Spain);

Patricia Njuguna (KEMRI Wellcome Trust Research Programe, Kenya); Kevin Marsh (University of Oxford, UK & African Academy of Sciences); Philip Bejon (KEMRI Wellcome Trust Research Programe, Kenya & University of Oxford, UK).

Funding body: This analysis was funded by an MRC fellowship to MTW. The trial was funded by GlaxoSmithKline Biologicals SA and the PATH Malaria Vaccine Initiative.

The RTS,S/AS01 malaria vaccine targets the circumsporozoite (CS) protein inducing antibodies associated with the prevention of Plasmodium falciparum infection. We studied the association between anti-CS antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial conducted between 2009 and 2014 using a model of anti-CS antibody dynamics and the natural acquisition of protective immunity over time. Anti-CS titres waned according to a bi-phasic exponential distribution, with half lives of 45 and 591 days for short-lived and long-lived antibodies, respectively in children who were 5-17 months old at vaccination.

We estimated that approx 12% of the antibody response was long-lived after the primary vaccination, rising to 30% following a booster dose. An anti-CS antibody titre of 121 EU/mL (95% CrI: 98, 153) was estimated to prevent 50% of infections. Waning anti-CS antibody titres over time predicted the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy waned more rapidly at higher transmission intensity.

We conclude that anti-CS antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered.

Publication: White, M.T., et al. (2015) Immunogenicity of the RTS,S/AS01 malaria vaccine over time and implications for duration of vaccine efficacy: analysis of data from a phase 3 randomised controlled trial. Lancet Infectious Diseases, 15:1450-8.



Anti-circumsporozoite antibody dynamics and association with efficacy against infection (A–D) Anti-circumsporozoite antibody dynamics after a primary schedule of RTS,S/AS01 with or without booster.

The black bars denote the median and 95% ranges (2·5–97·5 percentile).

The solid and dashed curves denote the median of the model predicted antibody titres.

The dark and light shaded regions represent 50% and 95% of the model predicted variation in antibody titres.

(E) Estimated dose–response relationship for the association between anti-CS antibody titre and efficacy against infection.

(F) Estimated vaccine efficacy profile for infection based on waning antibody titres. CS=circumsporozoite.

R3C=three doses of RTS,S/AS01 and a booster with a comparator vaccine.

R3R=three doses of RTS,S/AS01 and a booster with RTS,S/AS01.


A phase, individually randomised, controlled trial of the RTS,S/AS01 malaria vaccine in African infants and children, including an evaluation of the efficacy of a booster dose.

LSHTM investigators: Daniel Chandramohan, Chris Drakeley, Brian Greenwood, Seth Owusu-Agyei & David Schellenberg.

External collaborators: RTS,S/AS01 Clinical Trials Partnership.

Funding body: Glaxo SmithKline & PATH.

A phase 3 trial of the malaria vaccine RTS,S/AS01 has been conducted in 15,459 children in seven African countries. Children were immunised with three doses of vaccine at the ages of 6-12 weeks or 5-17 months; some children received a further dose 18 months later. Follow-up continued for three to four years.

Efficacy against both uncomplicated and severe malaria was seen in both age groups but it was higher in children vaccinated at 5-17 months than in those vaccinated at an earlier age. Efficacy waned over time but was partially restored by a further dose. Efficacy during the four–year follow-up period in older children who received the additional dose was 36% [95% CI 31.8; 40.5] against uncomplicated malaria and 32.2% [95% CI 13.7, 46.9] against severe malaria. The vaccine caused febrile convulsions in a small proportion of older children and an unexplained increase in meningitis was observed in the older age group.

RTSS/AS01 has been reviewed by the European Medicines Agency and, having considered benefits and risk, the agency gave it a positive opinion in October 2015. WHO has subsequently recommended that several, large scale pilot implementation projects go ahead before the vaccine is used more widely, with a focus on whether a fourth dose can be delivered, safety and on the impact of the vaccine on mortality.




First child in Kintampo Health Research Research Centre, Ghana to receive the malaria vaccine RTS,S/AS01. News coverage in the Independent about RTS,S/AS01 malaria vaccine. April 2015.

Treatment of malaria 67


SummaryClinical studies within the malaria centre

cover the full range of research activities

from identification of novel compounds to implications of current drug delivery

strategies for treatment efficiency.

Studies with industry partners have identified a series of protein kinase inhibitors which have considerable potential as antimalarial compounds. However, work has also focused on addressing some surprising knowledge gaps with one of the oldest anti-malarial

compounds primaquine. Primaquine has a unique action against gametocytes and is thus potentially potent tool for transmission reduction and elimination. The Malaria Centre, together with the Malaria Elimination Initiative at University of California, San Francisco, has coordinated several meetings on the use of primaquine in Africa. Field studies have shown that the low dose of primaquine advocated by the World Health Organization can block parasite transmission and is safe in G6PD deficient individuals.

Knowing what parasites are present in populations is vital to develop appropriate treatment and control strategies. In north Sumatera Indonesia, work describes the distribution of infections of four different malaria species including the zoonotic malaria P.knowlesi.

The Malaria Centre remains a key player in evaluating and optimising Seasonal Malaria Chemoprevention (SMC) with latest data highlighting the influence of duration of season and intensity of transmission on drug choice for SMC.

As highlighted in previous reports a flagship programme for the Malaria Centre has been the ACT Consortium. Multiple studies have been conducted to investigate how best to deliver the right treatment in a variety of settings and interfaces where infected individuals seek treatment. Implicit in this is that the drugs are of good quality with work showing that up to a third of drugs are substandard in some African countries with the downstream impacts on health and economic costs the subject of ongoing modelling studies.

In some countries, the private sector is a major source of antimalarials and studies conducted under the ACT Consortium umbrella have examined the capacity of the private sector to provide more targeted treatment.

Studies in Uganda have shown that the introduction of Rapid Diagnostic Tests to shops that sold drug was both acceptable to patients and vastly improved the number of correctly treated infections. Further analysis suggested that this is cost-effective compared to presumptive treatment though there are concerns about the costs to individual households.

66 Treatment of malaria


68 Treatment of malaria Treatment of malaria 69


Drug Studies

Malaria centre members carry out a range of research related to malaria diagnosis and treatment from target drug identification, drug quality assessments and optimal targeting of drugs with diagnostics.

ACT Consortium: Answering key questions on malaria drug delivery.

LSHTM investigators: Evelyn Ansah, Katia Bruxwoort, Matthew Cairns, Clare Chandler, Daniel Chandramohan, Sian Clarke, Bonnie Cundill, Catherine Goodman, Baptiste Leurent, Philippa West, HELEN Burchett, Heidi Hopkins, Kristian Hansen, Harparkash Kaur, Sham Lal, Toby Leslie, Seth Owusu-Agyei, Hugh Reyburn, Mark Rowland, David Schellenberg, Sarah Staedke , Rebecca Thomson, Jayne Webster, Christopher Whitty, Virginia Wiseman, Shunmay Yeung, Deborah DiLiberto & David Bath.

External collaborators: US Centers for Disease Control and Prevention, USA; College of Medicine, University of Malawi, Malawi; College of Medicine, University of Nigeria, Nigeria; Ghana Health Service, Ghana; Georgia Institute of Technology, USA; Health Protection and Research Organisation, Afghanistan; Healthnet, Afghanistan; Ifakara Health Institute, Tanzania; Karolinska Institutet, Sweden; Likimanjaro Christian Medical Centre, Tanzania; Kintampo Health Research Centre, Ghana; Liverpool School of Hygiene & Tropical Medicine, United Kingdom; Makerere University, Uganda; Merlin, Afghanistan; National Malaria Control Programme, Cambodia; National Institute for Medical Research, Tanzania; National Malaria Control Programme, Tanzania; Ministry of Health, Kampala, Uganda; University of California, San Francisco, USA; University of Cape Town, South Africa; University of Copenhagen, Denmark; University of Yaoundé, Cameroon; Zanzibar Malaria Control Proramme, Zanzibar.

Funding body: The Bill & Melinda Gates Foundation.

The ACT Consortium is an international research collaboration aiming to answer key questions on the access, targeting, safety and quality of artemisinin-based combination therapy (ACT), the recommended treatment for P. falciparum malaria.

With 25 projects in 10 countries, the multidisciplinary team conducted formative research, cluster randomised trials, cohort and descriptive studies, impact evaluations, and economic and anthropological assessments.

They found that health providers don’t always prescribe treatment according to rapid diagnostic test (RDT) results. Practices vary across settings and should be considered when designing implementation and training programmes.

In order to improve the management of patients with fever in the public and private health sectors, and in community health worker programmes, accurate diagnosis is key, and context matters.

By using RDTs, fewer patients without malaria receive ACTs, reducing the wastage of these valuable drugs.

The use of RDTs also increases the number of patient referrals for further care, and the number of antibiotic prescriptions – which are not needed by most patients. Data from more than 3,000 patients showed no new safety concerns relating to ACTs.

The investigators also analysed more than 10,000 ACT samples and found that falsified antimalarials are not as common as previously reported, but substandard medicines are common and dangerous: not only they leave patients untreated, but they may also contribute to the development of drug resistance.

Download a short booklet summarising research findings from the ACT Consortium at www.actconsortium.org/findings

Learn more about each of the ACT Consortium studies at www.actconsortium.org/projects

Screening and identification of inhibitors of the Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) as novel antimalarial drugs.

LSHTM investigators: David Baker & Maria Penzo.

External collaborators: Elena Fernandez-Alvaro & Maria Jesus Vazquez (GSK, Tres Cantos, Spain).

Funding body: co-funded by the European Union and the Tres Cantos Open Lab Foundation.

The spread of resistance to current antimalarials dictates the need for new antimalarial compounds with novel modes of action. Previous reports described prototype drugs that target the chicken parasite Eimeria tenella, through the of inhibition of

the cGMP-dependent protein kinase (PKG). These compounds also inhibit the malaria parasite PKG, which is essential in blood, liver and mosquito stages. PKG inhibitors therefore have the potential to both treat malaria pathology and prevent infection. A recent partnership between LSHTM MRC Technology produced some highly promising inhibitors that provided proof of concept that PKG is a valid antimalarial drug target.

This new project will perform a new screen in partnership with the GSK Open Lab to identify additional PKG inhibitors. Compound libraries will be screened using high throughput platforms available in Tres Cantos Screening Centre. Promising compounds will be tested in a range of in vitro parasite-based phenotypic assays and in vivo.

The aim of the project is to generate a pre-clinical candidate for future development as a component of a new antimalarial combination treatment.

A graph showing the results of a P. falciparum growth inhibition assay with three different PKG inhibitors. Data generated by Dr. Paul Bowyer.



Finding the lowest efficacious dose of primaquine to prevent the transmission of Plasmodium falciparum malaria after dihydroartemisinin-piperaquine treatment in Mali.

LSHTM investigators: Teun Bousema.

External collaborators: Kjerstin Lanke & Helmi Pett (Radboud University Medical Centre, Netherlands); Alassane Dicko, Halimatou Diawara, Ibrahima Baber, Almahamoudou Mahamar, Harouna M Soumare, Koualy Sanogo, Fanta Koita, Sekouba Keita & Sekou F Traore (Malaria Research and Training Centre, Bamako, Mali); Joelle Brown, Ingrid Chen, Charles McCulloch, Eugenie Poirot & Roly Gosling (University of California, San Francisco, US); Jimee Hwang (Centers for Disease Control and Prevention, Atlanta, US); Mikko Niemi (University of Helsinki, Helsinki, Finland); François Nosten (University of Oxford, Oxford, UK).

Funding body: The Bill & Melinda Gates Foundation.

Low dose (0.25 mg/kg) primaquine is recommended in combination with artemisinin-based combination therapies to reduce falciparum malaria transmission.

However, the lowest efficacious dose of primaquine to prevent malaria transmission has never been determined. We determined the efficacy and safety of four low doses of primaquine combined with dihydroartemisinin-piperaquine (DP).

Eighty-one microscopy positive gametocyte carriers were treated with DP and 0.5, 0.25, 0.125, 0.0625 or 0 mg/kg (control) of primaquine. The primary efficacy outcome

was the average within-person percentage change in mosquito infectivity in membrane feeding assays, 2 days following primaquine. Among participants who infected mosquitoes pre-treatment, primaquine doses of 0.125, 0.25 and 0.5 mg/kg resulted in large and significant reductions in infectivity compared to the control group of 95% (95%CI 87 - 100%, P=0.04), 99% (95%CI 98 - 100%, P=0.008) and 88% (95% CI 60 - 100%, P=0.03), respectively (figure 1). Gametocyte density by Pfs25 quantitative-reverse transcriptase PCR was strongly associated with mosquito infection rates before but not after treatment.

Primaquine at the recommended dose of 0.25 mg/kg, given in conjunction with DP, appears to be safe and efficacious for the prevention of P. falciparum malaria transmission in G6PD non-deficient populations.

Single Low Dose Primaquine to Reduce Plasmodium falciparum Transmission after Artemether-Lumefantrine.

LSHTM investigators: Teun Bousema, Chris Drakeley & Bronner Gonçalves.

External collaborators: Alfred Tiono (CNRFP, Burkina Faso) & Sodiomon Sirima (CNRFP, Burkina Faso).

Funding body: The Bill & Melinda Gates Foundation (as part of the AFIRM research programme).

A single 0.25 mg/kg primaquine dose is recommended as a gametocytocide in combination with artemisinin-based combination therapies for Plasmodium falciparum but its effect on post-treatment gametocyte circulation and infectiousness has not been quantified.

In this randomised, double-blind, placebo-controlled trial, 360 asymptomatic parasitaemic children were assigned to receive: artemether-lumefantrine (AL) and a dose of placebo; AL and a 0.25 mg/kg primaquine dose; or AL and a 0.40 mg/kg primaquine dose. On days 0 (day of AL initiation), 2 (day of placebo or primaquine administration), 3, 7, 10 and 14, gametocytes were quantified by microscopy, Pfs25 mRNA QT-NASBA, and qRT-PCR. For a subset of participants, pre- and post-treatment infectiousness was assessed by mosquito feeding assays.

Both primaquine arms had lower gametocyte prevalences after day 3 compared to the placebo arm, regardless of detection method. We observed similar gametocyte clearance rates

after 0.25 and 0.40 mg/kg primaquine doses and both regimens were associated with significantly shorter post-treatment gametocyte circulation compared to AL alone.

Infectivity to mosquitoes after AL was very low and absent in primaquine arms: while 38.0% (30/79) of gametocytemic individuals were infectious before treatment, only 1/251 participant, from the AL-placebo group, infected mosquitoes after treatment.


0

25

50

75

100

Gam

eto

cyte

pre

vale

nce

(%)

AL only 0.25 mg/kg 0.40 mg/kg0.01

0.1

1

10

100

1000

Gam

eto

cyte

sp

er

L

AL only 0.25 mg/kg 0.40 mg/kg

day 0day 2

day 3day 7

day 10day 14

A B

0

25

50

75

100

Gam

eto

cyte

pre

vale

nce

(%)

AL only 0.25 mg/kg 0.40 mg/kg0.01

0.1

1

10

100

1000

Gam

eto

cyte

sp

er

L

AL only 0.25 mg/kg 0.40 mg/kg

day 0day 2

day 3day 7

day 10day 14

A B

Proportion (95% Confidence Interval) of individuals who infected ≥1 mosquito, by visit and treatment group (1A). Proportion (median, interquartile range) of mosquitoes infected among participants who infected ≥1 mosquito (1B).

Gametocyte prevalences (A) and densities (B) measured by qRT-PCR in children with patent gametocytes on day 0 (enrollment).



Single low dose primaquine leads to limited haemolysis in G6PD deficient males with falciparum infection.

LSHTM investigators: Chris Drakeley, Teun Bousema & Bronner Gonçalves.

External collaborators: Guido Bastiaens (Radboud University Medical Centre, Netherlands); Alfred Tiono (CNRFP, Burkina Faso); Sodiomon Sirima (CNRFP, Burkina Faso).

Funding body: The Bill & Melinda Gates Foundation (as part of the AFIRM research programme).

Low dose (0.25 mg/kg) primaquine is recommended in combination with artemisinin-based combination therapies to reduce falciparum malaria transmission. However, the haemolytic changes related to this

regimen in G6PD deficient individuals have not been described.

In this safety trial, 70 asymptomatically infected male adults (50 G6PD-deficient; 20 G6PD-sufficient) were assigned to receive: artemether-lumefantrine (AL) and a dose of placebo (N=10); AL and a 0.25 mg/kg primaquine dose (N=30); or AL and a 0.40 mg/kg primaquine dose (N=30). On days 0 (initiation of AL and single dose of primaquine), 1, 2, 3, 7, 10, 14 and 28, haemoglobin concentrations were assessed by self-calibrating HemoCue 201+ photometers. The mean change as well as the mean maximum decrease in haemoglobin concentrations during follow-up did not differ significantly between treatment groups (P = 0.48 and P = 0.34).

All reported adverse events (AEs) were graded as mild or moderate. We recorded no severe adverse events and no severe haemolysis. Our data suggest that low dose primaquine can be administered to G6PD-deficient individuals safely.

Epidemiology of four human Plasmodium malaria species in North Sumatera, Indonesia.

LSHTM investigators: Inke Lubis & Colin Sutherland.

External collaborators: Hendri Wijaya, Munar Lubis, & Chairuddin P. Lubis (University of Sumatera Utara, Indonesia).

Funding body: University of Sumatera Utara, Indonesia; Directorate General of Higher Education, Indonesia.

We performed a cross-sectional survey as part of a drug efficacy study for P. falciparum infection to determine the epidemiological profile of Plasmodium infections in North Sumatera, Indonesia. Active and passive case screening were conducted in Batubara regency, Langkat regency and South Nias regency between January and June 2015.

A total of 3635 clinical and asymptomatic participants were screened using thick and thin blood smears

and rapid diagnostic tests at local health facilities. Giemsa-stained blood smears were examined by trained microscopists for Plasmodium speciation and parasite density determination. Blood-spotted filter papers were collected and transferred to LSHTM for molecular analysis. We performed a nested PCR assay to screen Plasmodium infection targeting the gene encoding Plasmodium SSU ribosomal RNA.

Additional screening for P. knowlesi infection was also performed using a novel PCR assay targeting the multi-copy gene family encoding the P. knowlesi-specific variant antigen, SICAvar.

Our study shows a substantial number of submicroscopic Plasmodium infections in North Sumatera province. Molecular tests have identified the presence of P. malariae and P. knowlesi infections among exposed population, both were previously misdiagnosed as the more common P. vivax or P. falciparum using conventional microscopy. We developed a novel P. knowlesi PCR assay which has detected a high cross-sectional prevalence of human P. knowlesi infection, demonstrating the hidden burden of asymptomatic P. knowlesi infections in the population.


Screening for malaria in North Sumatera.Woman waits outside hospital in Uganda.



Pro-active case detection and community participation for malaria elimination study (PACES).

LSHTM investigators: Shunmay Yeung, Clare Flach, Rebecca Thomson & Nicola James.

External collaborators: Huy Rekol, Po Ly, Chea Huch & Lek Soley (National Malaria Centre (CNM), Cambodia); Top Samphornarann (World Health Organisation (WHO), Cambodia); Didier Ménard (Institut Pasteur du Cambodge (IPC), Cambodia); Koen Peeters (Institute of Tropical Medicine (ITM), Belgium); Iveth Gonzalez (Foundation for Innovative New Diagnostics (FIND), Geneva); Soy Ti Kheang (Health and Social Development (HSD), Cambodia).

Funding body: Department for International Development through the Tracking Resistance to Artemisinins Collaboration.

The potential spread of artemisinin-resistant malaria from the border areas of South East Asia to Africa poses a huge threat to global health. In response, the Cambodian government has declared a goal to eliminate malaria by 2025.

Key strategies include surveillance; the targeting of prevention and control interventions at the forest-going mobile and migrant populations (MMPs); and community engagement.

This study, centres around a 3-arm cluster-randomised control trial in 130 malaria-endemic villages in Oddor Meanchey district, where the failure rates to the first-line Artemisinin Combination Therapy exceeds 30%.

It aims to develop, implement and evaluate proactive case detection focusing on MMPs and community participation strategies, in close collaboration with the National Malaria Control Programme and other academic and implementing partners.

In November 2015, we completed a baseline survey in 130 villages across Oddar Meachey province, in a total of 908 households.

Moving forward, we plan to build on the current community-level surveillance system, designing and implementing a proactive case detection strategy that includes both “reactive” case detection and more pro-active screening of co-travellers and high-risk populations.

Quantitative and qualitative outcome measures will assess whether it is feasible, effective and cost-effective to screen and treat asymptomatic infections in these high risk populations.

Seasonality in malaria transmission: implications for case-management with long-acting artemisinin combination therapy in sub-Saharan Africa.

LSHTM investigators: Matthew Cairns, Daniel Chandramohan, Brian Greenwood & Paul Milligan.

External collaborators: Kwaku Poku Asante & Seth Owusu-Agyei (Kintampo Health Research Centre, Kintampo, Ghana); Badara Cisse (Universite Cheikh Anta Diop, Dakar, Senegal); Diadier Diallo (PATH Malaria Vaccine Initiative, Dakar, Senegal); Alassane Dicko (Malaria Research and Training Centre, Bamako, Mali); Tini Garske, Jamie Griffin, Lucy Okell & Patrick Walker (Imperial College London, United Kingdom).

Funding body: UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement, which is part of the EDCTP2 programme supported by the European Union.

The aims of this study were to understand the epidemiological situations and geographical areas where long-acting artemisinin-based combination therapy (LACT) would be most beneficial.

The relationship between seasonality, transmission intensity and the interval between malaria episodes was explored using data from six cohort studies in West Africa and an individual-based malaria transmission model.

In high transmission settings, and particularly in high transmission settings with highly seasonal transmission, repeat malaria attacks soon after previous illness make up an important percentage of the total burden. Up to 30% of malaria cases in children are estimated to be due to repeat episodes within six weeks of a previous attack.

Countries with highly seasonal transmission and a high malaria burden may particularly benefit from using long-acting ACTs for malaria case management. The degree of seasonality, in addition to the overall intensity of transmission, should be considered by policy makers when deciding between different ACTs.

A surveillance system and drug forensic network to monitor the quality and authenticity of artemisinin-based combination treatments in Africa.LSHTM investigators: Harparkash Kaur.

External collaborators: Facundo Fernandez (Georgia Institute of Technology, Atlanta, USA); Michael D Green (Centres for Disease Control and Prevention, Atlanta, USA).

Funding body: The Bill & Melinda Gates Foundation as part of an award to the ACT Consortium at the London School of Hygiene and Tropical Medicine.

Poor-quality medicines contribute to the rise of drug resistance, can kill patients by leaving them untreated for their illness, and increase citizens’ mistrust in health systems. They are divided into three main classes: falsified, substandard or degraded. Falsified (fake) medicines do not contain the active pharmaceutical ingredient (API) stated in the package, and may carry a false representation of their source of identity. Substandard drugs result from poor manufacturing practices and contents or dissolution times that are outside accepted limits.


Blood taking during the baseline survey.

Degraded samples.Mapping of study villages with the local collaborating partners.

Blood samples collected during the baseline survey.



Degraded formulations may result from exposure of good-quality medicines to light, heat and humidity.

The ACT Consortium drug quality programme purchased over 10,000 artemisinin-based combination therapy (ACTs) samples from six malaria endemic countries, using representative sampling approaches, and assessed their quality.

Laboratory analyses of these samples showed that falsified ACTs were found in just two of the countries, whilst substandard ACTs were present in all six

countries, some of which may have been degraded. Artemisinin-based monotherapy tablets are still available in some places (see Table 1).

Guidelines are lacking on how to distinguish between substandard and degraded drugs. Re-analyses of all substandard ACTs from Enugu Metropolis (Nigeria) revealed that insufficient SAPIs together with detection (using liquid chromatography-mass spectrometry) of degradation products can be used to classify drugs as degraded (see Table 2).

Poor-quality medicines in the Mekong; lessons from the fight against falsified and substandard antimalarial drugs.

LSHTM investigators: Marie Lamy.

Funding body: London School of Hygiene and Tropical Medicine & Fondation Marcel Bleustein-Blanchet pour la Vocation.

The Mekong region has been a hub for falsified and substandard antimalarial medicines that contribute to the rise of antimicrobial resistance. Despite notable national efforts to fight this illicit trade, the problem of poor quality medicines remains. Falsified and substandard medicines are a cross-border public health challenge that requires national, regional and global policy attention.

This study is anchored in social sciences research and relies on a three-part qualitative research methodology including, an institutional and stakeholder map, document analysis, and a series of semi-structured interviews with international experts and locally-based stakeholders in access to medicines.

The first objective of this study is to understand the drivers of the illicit trade in falsified and substandard

medicines in the Mekong region of Southeast Asia. Subsequently, this study investigates the existing legal and policy mechanisms for improving access to quality antimalarial treatments in the region.

Key initiatives to improve access to quality antimalarial treatments in Cambodia for example have proved successful and may serve as a good example for future regulatory action in neighbouring countries. However, the general landscape of regulatory mechanisms for antimalarial drug safety and security in the region appears largely fragmented. Regulatory gaps and low enforcement capacity mean that most developing countries in the region are ill equipped to tackle this problem alone. Actions against poor-quality medicines are largely donor-driven and current drug-specific initiatives lack sustainability and applicability to other therapeutic drug categories. This study argues that regional institutions have a role to play by harnessing political commitment and facilitating the harmonization of efforts towards guaranteeing access to quality essential medicines.

The findings of this study may thereafter serve to inform the development of adequate regional regulatory and governance mechanisms to tackle the issue of falsified drugs for other therapeutic categories. Moreover, the analytical framework that emerged from the data may serve to conduct further research to understand and explain the drivers of the illicit trade in fake drugs in different regional settings.


Table 1: Numbers of samples analysed and quality of ACTs found per country

Country (date of sampling)Number of

Samples

Number of

Brands

Percent quality

assured

Percent

falsified

Percent

Substandard

Artemisininmonotherapy

tablets

Rwanda (2008) 97 1 93.8 Not found 6.2 Not found

Cambodia (2010) 291 21 68.7 Not found 31.3 Found

Ghana-Kintampo (2011) 257 31 63.0 Not found 37.0 Not found

Tanzania (2010) 1737 37 88.0 Not found 12.0 Found


Nigeria-Enugu Metropolis (2013) 3024 131 92.2 1.2 6.6 Found

Nigeria-Ilorin city (2013) 1450 77 91.5 0.8 7.7 Found

Equatorial Guinea-Bioko Island (2014) 677 142 91.0 7.4 1.6 Found

Table 2: Proportion of degraded samples in relation to brands of ACTs purchased inEnugu, Nigeria

Brand Stated manufacturer SAPIsNumber ofsamples

PercentAcceptable

Quality

PercentSubstandard

PercentDegraded

Amatem Forte®

Micro Labs Limited, India AM/LUM 43 97.7 0 2.3

Amatem Tab® 20/120

Micro Labs Limited, India AM/LUM 31§ 71.0 12.9 16.1

Arcofan 20/120 Naxpar Lab Pvt Ltd, India AM/LUM 15§ 0 0 100.0

Artemetrin® 80/480

A.C. Drugs Ltd, Nigeria AM/LUM 5§ 20.0 0 80.0

Artrin® Medreich Limited, India AM/LUM 15 73.3 0 26.7

Fynale Naxpar Lab Pvt Ltd, India AM/LUM 1 0 0 100.0

OgamalVapi Care Pharma Pvt Ltd, India

AM/LUM 1§ 0 0 100.0

Ogamal QSVapi Care Pharma Pvt LtdIndia

AM/LUM 35 91.4 2.9 5.7

MaltarkaVapi Care Pharma Pvt Ltd, India

AS/S/P* 5 0 33.3 66.7

Droa-Quine® Hubei Meibao, Pharmaceutical, China

DHA/PIP 1 0 0 100.0

Total 152 (100%) 71.1 3. 9 25.0

AM = artemether, APIs = active pharmaceutical ingredients, AS = artesunate, DHA = dihydroartemisinin, LUM = lumefantrine, PIP = piperaquine, S = sulfadoxine, P = pyrimethamine

Note: All manufacturers listed in Table 2 were found to be non-WHO prequalified * Not co-formulated, i.e. AS in one tablet with S/P in a second tablet§ When purchased all tablets except for the one package of Ogamal had not reached their expirydate, however another 3 packages of tablets (Amartem Forte®, Arcofan 20/120, Artemerin® 80/480)had exceeded their expiry date at the time of laboratory analysis. All the other tablets remained withindate.

Table 1: Numbers of samples analysed and quality of ACTs found per country

Country (date of sampling)Number of

Samples

Number of

Brands

Percent quality

assured

Percent

falsified

Percent

Substandard

Artemisininmonotherapy

tablets

Rwanda (2008) 97 1 93.8 Not found 6.2 Not found

Cambodia (2010) 291 21 68.7 Not found 31.3 Found

Ghana-Kintampo (2011) 257 31 63.0 Not found 37.0 Not found



Nigeria-Enugu Metropolis (2013) 3024 131 92.2 1.2 6.6 Found

Nigeria-Ilorin city (2013) 1450 77 91.5 0.8 7.7 Found

Equatorial Guinea-Bioko Island (2014) 677 142 91.0 7.4 1.6 Found

Table 2: Proportion of degraded samples in relation to brands of ACTs purchased inEnugu, Nigeria

Brand Stated manufacturer SAPIsNumber ofsamples

PercentAcceptable

Quality

PercentSubstandard

PercentDegraded

Amatem Forte®

Micro Labs Limited, India AM/LUM 43 97.7 0 2.3

Amatem Tab® 20/120

Micro Labs Limited, India AM/LUM 31§ 71.0 12.9 16.1

Arcofan 20/120 Naxpar Lab Pvt Ltd, India AM/LUM 15§ 0 0 100.0

Artemetrin® 80/480

A.C. Drugs Ltd, Nigeria AM/LUM 5§ 20.0 0 80.0

Artrin® Medreich Limited, India AM/LUM 15 73.3 0 26.7

Fynale Naxpar Lab Pvt Ltd, India AM/LUM 1 0 0 100.0

OgamalVapi Care Pharma Pvt Ltd, India

AM/LUM 1§ 0 0 100.0

Ogamal QSVapi Care Pharma Pvt LtdIndia

AM/LUM 35 91.4 2.9 5.7

MaltarkaVapi Care Pharma Pvt Ltd, India

AS/S/P* 5 0 33.3 66.7

Droa-Quine® Hubei Meibao, Pharmaceutical, China

DHA/PIP 1 0 0 100.0

Total 152 (100%) 71.1 3. 9 25.0

AM = artemether, APIs = active pharmaceutical ingredients, AS = artesunate, DHA = dihydroartemisinin, LUM = lumefantrine, PIP = piperaquine, S = sulfadoxine, P = pyrimethamine

Note: All manufacturers listed in Table 2 were found to be non-WHO prequalified * Not co-formulated, i.e. AS in one tablet with S/P in a second tablet§ When purchased all tablets except for the one package of Ogamal had not reached their expirydate, however another 3 packages of tablets (Amartem Forte®, Arcofan 20/120, Artemerin® 80/480)had exceeded their expiry date at the time of laboratory analysis. All the other tablets remained withindate.

Table 1: Numbers of samples analysed and quality of ACTs found per country.

Pharmacy outlet in Southeast Asia (picture by Brian Evans, flickr creative commons).

Table 2: Proportion of degraded samples in relation to brands of ACTs purchased in Enugu, Nigeria.

AM = artemether, APIs = active pharmaceutical ingredients, AS = artesunate, DHA = dihydroartemisinin, LUM = lumefantrine, PIP = piperaquine, S = sulfadoxine, P = pyrimethamine Note: All manufacturers listed in Table 2 were found to be non-WHO prequalified * Not co-formulated, i.e. AS in one tablet with S/P in a second tablet§ When purchased all tablets except for the one package of Ogamal had not reached their expiry date, however another 3 packages of tablets (Amartem Forte®, Arcofan 20/120, Artemerin® 80/480) had exceeded their expiry date at the time of laboratory analysis. All the other tablets remained within date.



Health and economic cost of poor quality and falsified antimalarial drugs.

LSHTM investigators: David Bath, Catherine Goodman & Shunmay Yeung.

Funding body: World Health Organization; the Bill & Melinda Gates Foundation through the ACT Consortium.

We developed a cost-effectiveness decision tree model that follows the treatment pathway of patients with non-differentiated fever from the point of a decision to seek treatment to their final health outcome. (See the ‘Community Case Management’ section of this report.)

We are adapting the model to examine the health and economic cost of substandard, spurious, falsely-labelled, falsified, and counterfeit (SSFFC) drugs for first-line treatment of uncomplicated P.falciparum malaria in sub-Saharan Africa.

The model will draw on published and unpublished literature on antimalarial drug quality across the public and private sectors.

Health impact will be measured in terms of additional deaths and disability adjusted life years (DALYs) as a result of increased treatment failure due to poor quality antimalarial drugs. Economic impact will include the cost of additional treatment-seeking and prolonged care.The analysis will inform WHO’s economic impact study of falsified and substandard medicines and provide an initial test case for a wider review of other SSFFC medical products.

K13-independent mechanisms of reduced ACT susceptibility in Plasmodium falciparum: a public health threat in Africa?LSHTM investigators: Ifeyinwa Aniebo, Khalid Beshir, Ryan Henrici, Inke Lubis, Julian Muwanguzi, Colin Sutherland, Donelly van Schalkwyk & David Warhurst.

Funding body: EDCTP; Public Health England.

The development of reduced susceptibility to artemisinins by P. falciparum in the Mekong region is observed using three methodologies: measurement of parasite clearance by very frequent microscopic examination of blood films after treatment, detection of specific mutations in the pfk13 gene, and estimation of in vitro survival of highly synchronised ring-stage parasites after a short pulse of 700nM dihydroartemisinin (the RSA). These approaches are not suitable for studies in African children, and we have developed new approaches to in vivo, in vitro and genetic studies of drug susceptibility in P. falciparum that have proved robust and practical in Kenya, Mali and Burkina Faso. Results to date suggest that artemether-lumefantrine efficacy is slowly waning in east Africa, and changes in the frequency of certain alleles of pfcrt and pfmdr1 may partly explain this. We have shown that pfk13 mutations are not contributing to treatment failure in our Kenyan studies, but other genes, pfap2mu and pfubp1, appear to play some role. Parasite cultures derived from UK malaria patients with recent African travel are providing important new data on variations

in in vitro artemisinin susceptibility, but these variations are not identified using the RSA. Thus determinants of artemisinin effectiveness currently differ between Africa and Asia.

Molecular determinants of sulfadoxine-pyrimethamine resistance in Plasmodium falciparum in Nigeria and the regional emergence of dhps 431V.

LSHTM investigators: Mary Oguike, Daniel Chandramohan, Jane Bruce, Jayne Webster, Colin Sutherland & Cally Roper.

External collaborators: Catherine O. Falade, Elvis Shu (University of Ibadan, Nigeria); Izehiuwa G. Enato (University of Benin Teaching Hospital, Nigeria); Ismaila Watila (Specialist Hospital Maiduguri, Nigeria) Ebenezer S. Baba (Malaria Consortium, Uganda); Prudence Hamade & Sylvia Meek (Malaria Consortium, UK).

Funding body: UK Department for international development (DFID) through the Malaria Consortium and the Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom [Rosemary Weir Runner-up Prize].

There are few published reports of dhps and dhfr mutations in P. falciparum populations in Nigeria, but one previous study has recorded a novel dhps

mutation at codon 431 among infections imported to the United Kingdom from Nigeria. To assess how widespread this mutation is among parasites in different parts of the country, we retrospectively analysed 1000 filter paper blood spots collected in surveys of pregnant women and children with uncomplicated falciparum malaria between 2003 and 2015 in four sites in the south and north.

Point mutations at codons 16, 50, 51, 59, 108, 140 and 164 of the dhfr gene and codons 431, 436, 437, 540, 581 and 613 of the dhps gene were evaluated by nested PCR amplification followed by direct sequencing.

The distribution of the dhps-431V mutation was widespread throughout Nigeria with the highest prevalence in Enugu (46%). In Ibadan where we had sequential sampling, its prevalence increased from 0% to 6.5% between 2003 and 2008. Although there were various combinations of dhps mutations with 431V, the combination 431V+437G+581G+613S was the most common.

The emergence of a new dhps-VAGKGS mutant haplotype in Nigeria is a cause for concern. Consequently, more tailored studies are now underway to assess the effect of 431V on SP efficacy and in particular its implications for continuing use of SP in SMC and IPTp.


Ibadan2008

Maiduguri2010

Enugu2010

Benin City2014

Prevalence of the dhps 431 mutation haplotypes no 431

431+437+581+613

431+437

431+437+613

431+437+581

Paired fluorescent sequencing traces around codon 578 of the pfk13 gene in blood samples taken at different timepoints in a Kenyan child treated for falciparum malaria with dihydroartemisinin-piperaquine. Fwd: forward sequencing reaction; Rev: reverse sequencing reaction from the same parasite DNA preparation.

Prevalence of dhps-431V mutation haplotypes in Nigeria.



Understanding private sector demand for malaria medications in developing countries.LSHTM investigators: Kara Hanson & Benjamin Palafox.

External collaborators: ACTwatch - Population Services International.

Funding body: Economic and Social Research Council UK.

In endemic countries malaria treatment is obtained from a wide range of sources. To capture and analyse this diversity, we developed a novel method of combining household and treatment source data to better characterise household access to treatment, and compare changes over time. This method also allows determinants of consumer demand for treatment to be estimated.

We found large differences in household access to malaria treatment across urban-rural locations, and across countries. While nearly all urban households had reasonable access to at least one treatment source stocking the recommended medication, artemisinin combination therapy (ACT), household access was lower in rural areas. Rural access improved between 2010 and 2012 in Benin, Nigeria and Uganda; however, no change was observed in Zambia.

Several personal and household characteristics, such as caregiver knowledge about malaria and household wealth, were found to influence the decision to seek care for malaria from a source outside the home and the choice of treatment source. The strongest predictors of these choices varied by country.

Among the supply-side factors influencing demand, treatment sources farther from home were consistently less likely to be chosen. In contrast, the price of treatment appeared to have a smaller effect

on the choice of treatment source and on the choice of antimalarial.

When interpreting these results in light of the large shifts in aggregate ACT demand observed in countries with an ACT subsidy programme, three explanations are possible: these changes may have been driven by improvements in access; aggregate demand shifts may have been due to adult demand, which could be more price sensitive than paediatric demand as captured in our household data; or our price elasticity estimates could suffer from residual bias.

Introducing rapid diagnostic tests in drug shops to improve the targeting of malaria treatment.LSHTM investigators: Sian Clarke, Kristian Hansen, Eleanor Hutchinson, Clare Chandler & Sham Lal.

External collaborators: Anthony Mbonye (Ministry of Health, Uganda); Pascal Magnussen (University of Copenhagen, Denmark).

Funding body: The Bill & Melinda Gates Foundation through ACT Consortium.

A cluster-randomised trial in registered drug shops in Uganda aimed to assess the effect of introducing rapid diagnostic tests (RDTs) into drug shops to promote the rational and correct use of ACT drugs. Drug shop vendors were also trained in malaria case management with ACTs and rectal artesunate pre-referral treatment, and when to refer. The trial compared ACT prescription in shops trained to treat based on RDT test result with the current approach of treating patients based solely on their symptoms.

To examine whether RDTs improved targeting of ACT treatment, treatment decisions made by vendors were compared against malaria parasite infection status of the patient determined by expert microscopy on a research blood slide collected at the time of drug shop visit.

The study found the vast majority of patients accepted to purchase a RDT test and that over 85% of drug shop vendors adhered to the results of the test. As a consequence, in drug shops that used RDTs the number of ACT treatments sold reduced and targeting improved dramatically; ACT drugs were appropriately targeted in 73% of the cases compared to 34% in drug shops using presumptive diagnosis. A qualitative evaluation conducted alongside the trial found diagnostic testing was popular with both patients and providers, and fundamentally transformed the reputation of drug shops, which could give patients a false reassurance about vendors’ other skills and services.

Informed by the findings from this trial and other recent studies, RDTs are now being scaled-up more widely within the private retail sector in Uganda and other countries.

Cost-effectiveness analysis of malaria diagnostic testing in drug shops: a cluster-randomised trial in Uganda.LSHTM investigators: Sian Clarke, Kristian Hansen, Eleanor Hutchinson, Clare Chandler & Sham Lal.

External collaborators: Anthony Mbonye (Ministry of Health, Uganda); Pascal Magnussen (University of Copenhagen, Denmark).

Funding body: The Bill & Melinda Gates Foundation through ACT Consortium.

Private sector drug shops are an important source of malaria treatment in Africa. Diagnosis without parasitological testing is common among these providers. Accurate rapid diagnostic tests for malaria (mRDTs) require limited training and present an opportunity to increase access to correct diagnosis. The present study was a cost-effectiveness analysis of the introduction of mRDTs in Ugandan drug shops.

The intervention trained drug shops to perform and sell subsidised mRDTs and artemisinin-based

combination therapies (ACTs) while the control arm offered ACTs following presumptive diagnosis. The effect on the proportion of customers with fever ‘appropriately treated of malaria with ACT’ was captured from a previous trial in Mukono District, Uganda. Health sector costs included: training of drug shop vendors, community sensitisation, supervision and provision of RDTs and ACTs to drug shops. Household costs of treatment-seeking were captured in a representative sample of drug shop customers.

The introduction of mRDTs in drug shops led to a large improvement of diagnosis and treatment of malaria resulting in low incremental costs for the health sector at US$0·55 per appropriately treated patient. High expenditure on non-ACT drugs by households contributed to higher incremental societal costs of US$3·83. The sensitivity analysis showed that increased malaria prevalence and lower adherence to negative mRDT results would make mRDTs less cost-effective compared to presumptive diagnosis.

mRDTs improved drug shop services for malaria and are likely to be considered cost-effective compared to presumptive diagnosis although high costs borne by households are a concern.


Community-based case management

A key area of our work focuses on understanding and evaluating interventions to improve case management of malaria with rapid diagnostic tests and of artemisinin-based combination therapy in the community (private retail outlets, community health workers and schools).

Open-air market stalls selling antimalarials in Benin.



Introduction of malaria rapid diagnostic tests (mRDT): Lessons from cross-project analyses of mRDT trials in six countries.LSHTM investigators: ACT Consortium RDTs in Context working group.

External collaborators: Collaborators from LSHTM; Health Protection and Research Organization, Afghanistan; University of Yaoundé, Cameroon; Copenhagen University, Denmark; Ghana Health Service, Ghana; Kintampo Health Research Centre, Ghana; University of Nigeria, Nigeria; Karolinska Institutet, Sweden; Ifakara Health Institute, Tanzania; Joint Malaria Programme, Tanzania; National Malaria Control Programme, Tanzania; Makerere University, Uganda; Ministry of Health, Uganda; Liverpool School of Tropical Medicine, UK; University of California, San Francisco, USA; Centers for Disease Control & Prevention, USA; Zanzibar Malaria Control Program, Zanzibar.

Funding body: The Bill & Melinda Gates Foundation through the ACT Consortium.

The ACT Consortium conducted ten research studies designed to evaluate the health-care and economic impacts of introducing malaria mRDTs in various settings. mRDTs were introduced in studies in six

countries across Africa and Asia, in a variety of epidemiological settings and health service sectors – public, community, and private retail – accompanied by different interventions. Cross-project analyses have been conducted to systematically compare results across these ten studies, to explore variation in mRDT use and impact on other health-care behaviours.

Our results suggest that introducing mRDTs can improve targeting of ACTs in most contexts, but that traditional capacity strengthening is essential though insufficient to improve prescribing behaviour. Care providers were most likely to follow mRDT guidelines when they were motivated by the intervention and the tests fitted with their existing beliefs and consultation practices.

Where acceptable alternative treatments for test-negative patients were lacking, non-adherence to test results (i.e. antimalarial prescription) was more likely and referral and post-consultation treatment seeking increased. In addition, antibiotic use increased in most settings where mRDTs were introduced. Notably, mRDTs were not associated with a clear difference in self-reported health outcomes.

Ensuring patients with positive and negative mRDT test results receive appropriate treatment requires interventions that go beyond basic training and are tailored to address specific contextual factors.

Modelling the cost-effectiveness of introducing malaria rapid diagnostic tests in the private retail sector in sub-Saharan Africa.LSHTM investigators: David Bath, Catherine Goodman, Clare Chandler & Shunmay Yeung.

The Bill & Melinda Gates Foundation through the ACT Consortium.

In recent years, major changes have occurred in the diagnosis of malaria in primary level public health facilities in endemic countries, as rapid diagnostic tests (RDTs) have been widely deployed. There are now increasing calls for RDTs to be made available outside public health facilities and in particular through the private retail sector where many people with suspected malaria seek care. Although private

sector RDTs are already available in several African countries, robust evidence on the value for money of these strategies is not yet available.

Drawing on recent data, we developed a cost-effectiveness decision tree model of management of febrile illness in a theoretical sub-Saharan African private retail setting, which follows febrile patients from initial presentation to final health outcome.

The model identifies the conditions under which RDTs would be cost-effective in the private sector. It examines which parameters have the greatest impact on cost-effectiveness, including the treatment received with a positive/negative/no test, the case fatality rate for untreated malaria, and the probability that malaria becomes ‘severe’ upon treatment failure or no treatment.

The updated model is customisable and can be used to consider the introduction of RDTs in different epidemiological or health system settings.


Modelled treatment pathway for uncomplicated febrile illness.

Blood sampling to test RDTs.



Use of rapid diagnostic tests to improve malaria treatment in the community.LSHTM investigators: Sian Clarke, Kristian Hansen, Clare Chandler & Sham Lal.

External collaborators: Richard Ndyomugyenyi (Ministry of Health, Uganda); Pascal Magnussen (University of Copenhagen, Denmark).


This randomised trial aimed to assess whether the use of rapid diagnostic tests (RDTs) by community health workers (CHWs) can improve rational and correct use of ACT drugs in community-based treatment programmes.

The trial compared malaria case management based on RDT diagnostic testing with the current approach of treating patients based solely on their symptoms, in two areas of high and low malaria transmission

in rural Uganda. CHWs were also trained on how to prescribe ACTs, rectal artesunate pre-referral treatment, and when to refer. To determine whether use of RDTs improved targeting of ACT treatment, treatment decisions made by CHWs were evaluated against the malaria parasite infection status of the patient determined by expert microscopy on a research blood slide collected at the time of consultation.

The study found it is feasible to train community volunteers to perform and interpret an RDT correctly. Over 85% of CHWs complied with the RDT test results, reducing the number of ACTs used by over 60% in both transmission settings. ACTs were more accurately targeted to malaria-parasite positive patients in communities where CHWs used RDTs compared to where CHWs made a diagnosis based on symptoms alone: 79% vs 31% in high transmission villages, and 90% vs 8% in low transmission villages respectively. However, RDTs did not detect light infections with fewer than 200 parasites per microlitre of blood, leading to some febrile children not receiving a malaria treatment.

Examining the effects of community management of malaria using rapid diagnostic tests and artemisinin combination therapy on the public health system in Uganda.LSHTM investigators: Sham Lal, Sian Clarke & Daniel Chandramohan.

External collaborators: Pascal Magnussen & Kristian Hansen (University of Copenhagen, Denmark); Richard Ndyomugenyi (Ministry of Health, Uganda).


This project has been conducted as part of a cluster randomised trial that evaluated the impact of mRDTs on appropriate treatment in Western Uganda.

We aim to examine the broader effects of introducing a CHW programme on the public health systems.

We found that utilisation of health facilities declines shortly after the introduction of a community based programme and utilisation remains lower when compared to the absence of a programme.

Ongoing work will examine whether running costs change and whether their budgets can be allocated more efficiently

In addition, we will be exploring the referral processes from the community level to public health facilities. This will be investigated in a number of stages, firstly understand the conditions under which CHWs are adhere to referral guidelines, secondly we’ll describe the referrals made by CHWs, the final component will explore the conditions that facilitated the completion of referral by caregivers.

Improving treatment provision for childhood infections in urban settings.LSHTM investigators: Siân Clarke, Daniel Chandramohan & Sham Lal.

External collaborators: Anthony Mbonye (Ministry of Health, Uganda); Phyllis Awor (Makerere University School of Public Health, Uganda); Pascal Magnussen & Kristian Hansen (University of Copenhagen, Denmark).

Funding body: MRC/ESRC/DfiD/Wellcome Trust: Development Grant (Health Systems Research).

Pneumonia, malaria and diarrhoea are major causes of death in African children, yet if diagnosis and treatment are available most of these deaths can be prevented. Integrated Community Case Management (iCCM) by community health workers can improve access to treatment in rural areas, but has not been tested in urban areas.

Retail outlets could also provides a means to increase access to basic health services, but is subject to debate on whether retailers can provide services of acceptable quality and price.

Formative research in the city of Kampala, Uganda aims to explore which of two alternative strategies to deliver iCCM services in urban areas (community volunteers or drug shop vendors) would be most feasible and acceptable to the local population and national health authorities.

Observations in drug shops and interviews with providers, patients and local leaders will be used to identify suitable ways to supervise and support treatment providers, integrate them into the local health system, and assure the quality of the services they provide.

The findings will be used to develop a new community-based intervention strategy to improve access to treatment for children living in unplanned urban areas, which will be tested in future studies.

Towards a strategy for malaria in pregnancy in Afghanistan: Analysis of clinical realities and women’s perceptions of malaria and anaemia.LSHTM investigators: Natasha Howard, Mark Rowland & Toby Leslie.

External collaborators: Sayed Enayatullah (HealthNet-TPO (HNTPO), Afghanistan); Nader Mohammad & Ismail Mayan (Health Protection and Research Organization (HPRO), Afghanistan); Zohra Shamszai (Care International, Kabul, Afghanistan).

Funding body: WHO; Unicef.

Afghanistan has some of the worst maternal and infant mortality indicators in the world and malaria is a significant public health concern. Study objectives were to assess prevalence of malaria and anaemia, related knowledge and practices, and malaria prevention barriers among pregnant women in eastern Afghanistan.

Three studies were conducted: (1) a clinical survey of maternal malaria, maternal anaemia, and neonatal

birthweight in a rural district hospital delivery-ward; (2) a case–control study of malaria risk among reproductive-age women attending primary-level clinics; and (3) community surveys of malaria and

anaemia prevalence, socioeconomic status, malaria knowledge and reported behaviour among pregnant women.

Among 517 delivery-ward participants (1), one malaria case (prevalence 1.9/1000), 179 anaemia cases (prevalence 346/1000), and 59 low-birthweight deliveries (prevalence 107/1000) were detected. Anaemia was not associated with age, gravidity, intestinal parasite prevalence, or low-birthweight at delivery. Among 141 malaria cases and 1010 controls (2), no association was found between malaria infection and pregnancy (AOR 0.89; 95 % CI 0.57– 1.39), parity (AOR 0.95; 95 % CI 0.85–1.05), age (AOR 1.02; 95 % CI 1.00–1.04), or anaemia (AOR 1.00; 95 % CI 0.65–1.54). Those reporting insecticide-treated net usage had 40 % reduced odds of malaria infection (AOR 0.60; 95 % CI 0.40– 0.91). Among 530 community survey participants (3), malaria and anaemia prevalence were 3.9/1000 and 277/1000 respectively, with 34/1000 experiencing severe anaemia. Despite most women having no formal education, malaria knowledge was high. Most expressed reluctance to take malaria preventive medication during pregnancy, deeming it potentially unsafe.

Given the low malaria risk and reported avoidance of medication during pregnancy, intermittent preventive treatment is hard to justify or implement. Preventive strategy should instead focus on long-lasting insecticidal nets for all pregnant women.




Community-based scheduled screening and treatment of malaria in pregnancy for improved maternal and infant health: a cluster-randomized trial (COSMIC).

LSHTM investigators: Umberto D’Alessandro & Susana Scott.

External collaborators: Henk Schallig, (Royal Tropical Institute, The Netherlands); Halidou Tinto (Centre Muraz, Burkina Faso); Alain Nahum (Centre de Recherches Entomologiques de Cotonou (CREC), Benin); Koen Peeters Grietens (ITM, Belgium); Lesong Conteh (Imperial College London, UK); Maxime Drabo (Centre Muraz, Burkina Faso); Jamie Guth (TDR, WHO, Switzerland).

Funding body: European Union Seventh Framework 620 Programme (FP7/2002-2016).

In sub-Saharan Africa, malaria continues to cause over 10,000 maternal deaths and 75,000 to 200,000 infant deaths. Successful control of malaria in pregnancy could save lives of mothers and babies

and is an essential part of antenatal care in endemic areas. The primary objective is to determine the protective efficacy of community-scheduled screening and treatment (CSST) using community health workers (CHW) against placental malaria, maternal anaemia, maternal peripheral infection, low birth weight, selection of sulfadoxine-pyrimethamine (SP) resistance markers, and on antenatal clinic (ANC) attendance and coverage of intermittent preventive treatment during pregnancy (IPTp-SP).

This is a multi-centre cluster-randomised controlled trial involving three sub-Saharan countries with varying malaria endemicity; low (The Gambia) versus high transmission (Burkina Faso and Benin), and varying degrees of SP resistance (high in Benin and moderate in Gambia and Burkina Faso).

In villages randomised to the intervention, CHW will receive specific training on community-based case management of malaria in pregnancy. All women in both study arms will be enrolled at the first ANC visits in their second trimester, when they will receive their first dose of IPTp-SP. Thereafter, CHW in the intervention arm will perform scheduled monthly screening and treatment in the women’s homes. At time of delivery, a placental biopsy will be collected from all women to determine placental malaria.

Evaluation of a teacher-led programme of school-based malaria case management on daily child attendance to school in southern Malawi: the Learner Treatment Kit.LSHTM investigators: Katherine Halliday, Stefan Witek-McManus, Charles Opondo, Elizabeth Allen & Simon Brooker.

External collaborators: Don Mathanga & Andy Bauleni (Malaria Alert Centre, College of Medicine, Malawi); Doreen Ali & John Sande (National Malaria Control Programme, Ministry of Health, Malawi); Charles Mazinga (Ministry of Education, Science and Technology, Malawi); Austin Mtali, Tiyese Chimuna & David Melody (Save the Children International, Malawi); Natalie Roschnik (Save the Children USA).

Funding body: International Initiative for Impact Evaluation (3ie); Save the Children Sponsorship Fund.

Evidence from Malawi has highlighted the significantly higher burden of malaria infection in school children than any other age group, while also

being less likely to be brought for any type of malaria treatment than younger children.

Implemented by the National Malaria Control Programme in partnership with Save the Children, the Learner Treatment Kit (LTK) is a simple first aid kit available to all school children for the management of basic health problems, including uncomplicated malaria. In 29 randomly selected primary schools, between two and four trained teachers received training and on-going support in the use of the LTK, including the use of rapid diagnostic tests (RDTs) and artemether-lumefantrine (ACT) for the testing and treatment of malaria.

Researchers at LSHTM and Malaria Alert Centre (College of Medicine, University of Malawi) monitored the daily attendance of school children between January 2014 to March 2015. In addition, nested sub-studies to evaluate the cost-effectiveness, acceptability and uptake of the intervention took place during implementation. Further secondary outcomes of malaria parasitaemia and anaemia were assessed during an endline survey conducted in March 2015.

Final analysis is ongoing with result expected to be available from April 2016.


Treatment seeking: hospital waiting area in Mukono, Uganda.Testing for malaria for trial.

SummaryEffective malaria surveillance, and the

monitoring and evaluation of control and

elimination efforts, are essential to track

progress with malaria control and to know

where best to target resources to maximise

their impact.

The science of malaria surveillance, monitoring and evaluation have been relatively neglected in the past but recently brought centre stage by two key documents to guide global efforts for malaria control 2016-2030: the World Health Organization’s Global Technical Strategy and the Roll Back Malaria Partnership’s Action and Investment for a malaria free world.

LSHTM Malaria Centre members engage in surveillance, monitoring and evaluation at multiple

levels. Malaria control improves at different rates in different places, both at national and sub-national, as well as even sub-village, scales. Understanding the spatial epidemiology of malaria risk is important to enable the geographic targeting of interventions.

The LINK programme is working to improve the use of available data to inform sub-national malaria control activities in 14 countries. At the other end of the spectrum, the REDHOT project identified malaria hotspots at sub-district level in Kenya and evaluated alternative approaches to control malaria in the hotspots.

It is not entirely clear how traditional measures of malaria risk relate to each other at different levels of transmission. Comprehensive monitoring of malaria risk is taking place both in the PRISM programme in Uganda, which works in three Ugandan sub-counties with a wide range of malaria transmission intensities, and in the Bioko Island Malaria Control Project. The data generated by these projects will help improve our understanding of the different malaria metrics

88 Malaria surveillance, monitoring and evaluation


Malaria surveillance, monitoring and evaluation 89


and enable the evidence-informed deployment of intervention strategies.

The malaria community has benefited greatly from nationally representative household surveys, such as Malaria Indicator Surveys and the Demographic and Health Surveys. However these are expensive to do and undertaken at intervals of a few years, and their utility in areas of low malaria prevalence is questionable.

In such settings it is important to understand the performance of alternative methods of detecting infections, such as PCR-detected versus RDT-detected infections, and the performance of serological measures, and to adjust sample size calculations and analytical approaches accordingly. In between surveys the use of easy access groups – such as school children – can provide useful information on malaria risk in the community.

At all levels of transmission it is important to understand the pros and cons of different approaches to data collection, such as the extent of the bias when

observing health worker performance. Understanding the geospatial epidemiology of malaria can enable geographic targeting and facilitate the identification of high risk groups who may benefit from specific intervention strategies. Malaria is often most difficult to control in mobile and migrant populations – so-called ‘hot pops’ – and work to understand risk factors and opportunities to improve control in such groups is key.

Novel approaches to risk mapping, such as participant photo mapping, can help unravel the intricacies of transmission and identify opportunities for action.

Efficacious interventions need to be included in scalable, multi-faceted strategies for malaria control. Understanding how the multiple components of such ‘complex interventions’ interact with each other can help optimise control strategies.


Program for Resistance, Immunology,

Surveillance and Modelling of Malaria in

Uganda (PRISM): Estimating the impact

of population-level malaria control

interventions at 3 sites in Uganda with

varying transmission intensity.

LSHTM investigators: Sarah Staedke & Chris Drakeley.

External collaborators: Agaba Katureebe, & Emmanuel Arinaitwe (Infectious Diseases Research Collaboration, Uganda); Kate Zinszer (McGill University, Montreal, Canada); Martin Donnelly (Liverpool School of Tropical Medicine, UK); Philip J Rosenthal, Grant Dorsey & Bryan Greenhouse (University of California, San Francisco, USA); Steve Lindsay (Durham University, UK); David Smith (University of Washington, USA); Moses R Kamya (Makerere University, Uganda).

Funding body: US National Institutes of Health.

Monitoring the impact of malaria control interventions under operational settings is challenging. Comprehensive malaria surveillance is currently on-going in Uganda, focusing on children aged 0.5-10

years in 3 sub-counties: Walukuba (EIR=2.8), Kihihi (EIR=32), and Nagongera (EIR=310). Activities include health facility-based surveillance for malaria test positivity rate (TPR) and cohort studies of children from 100 randomly-selected households per site to estimate incidence.

Following universal distribution of insecticide-treated bednets (LLINs) and indoor residual spraying of insecticide (IRS), comparisons were made. LLIN distribution in Walukuba was associated with a 27% decrease in TPR (p<0.001) and 53% decrease in incidence (p=0.001); in Kihihi, 24% decrease in TPR (p<0.001) and 33% decrease in incidence (p<0.001); and in Nagongera, 21% decrease in TPR (p<0.001) but no significant change in incidence (p=0.12). Adding IRS to ITNs in Nagongera was associated with a 47% decrease in TPR (20.0% vs. 37.5%, p<0.001) and a 70% decrease in malaria incidence (0.99 vs. 3.22, p<0.001).

Universal LLIN distribution was associated with a moderate decrease in TPR and a decrease in incidence at two lower transmission sites, but no change in incidence at the highest transmission site (Nagongera). Adding IRS in Nagongera was associated with the largest decrease in TPR and incidence.




LINK – Data for malaria decision

making.

LSHTM investigators: David Schellenberg, Jayne Webster, Caroline Lynch, Jonathan Cox, Sarah Saleheen & Cesaire Ahanhanzo.

External collaborators: Abdisalan Noor (KEMRI-Wellcome Trust Programme, Kenya); Robert Snow & Caroline Jones (KEMRI-Wellcome Trust Programme, Kenya & Oxford University, UK).

Funding body: The UK Department for International Development.

The LINK programme is working to improve the availability and use of existing data to guide malaria control in endemic countries in Africa. Funded by DFID, the programme is working with a broad network of partners at global and national levels to produce epidemiological profiles of malaria in 14 countries over 4 years. We support national and sub-national stakeholders to strengthen their evidence-based decision making to improve malaria control.

The programme is building on a first set of profiles developed in eight high-burden countries during 2013-2014 (Phase I). We assemble existing data and use model-based geostatistics to develop maps summarising malaria risk and intervention coverage at the district level, the operational unit at which malaria control is implemented.

Countries are selected on the basis of malaria burden, the availability of relevant data and the national malaria planning cycles. The profiles inform programme management, intervention selection, resource allocation, monitoring and evaluation in resource constrained environments.

In the first 15 months of the project we developed and disseminated malaria profiles in Senegal, Mozambique and Sierra Leone, are engaged in Burkina Faso, The Gambia, Kenya, the Republic of Sudan and South Sudan, and are working to update the malaria profiles produced in phase I for Tanzania and Uganda.

Number of malaria cases in 2014

1 to < 500

500 to < 1000

1000 to < 5000

5000 to <10,000

10,000 to < 20,000

Number of malaria cases per1000 population in 2014

< 1

1 to < 5

5 to 50

> 50 to 100

> 100 to 370

Test positivity rate in 2014

< 1.0%

1.0% to < 5.0%

5.0% to < 10%

10% to < 30%

30% to 50%

> 50% to 75%

> 75% to 100%

Senegal: Comparison of PAPfPR2-10, cases, Test Positivity Rate and Case

Incidence in 2014 by Health District

Study participants.


Bioko Island Malaria Control Project.

LSHTM investigators: Jackie Cook, Chris Drakeley, John Bradley, Andrea Rehman, Jo Lines & Immo Kleinschmidt.

External collaborators: Christopher Schwabe (Medical Care Development International); Michel Slotman (Texas A&M University, USA); Ministry of Health and Social Services, Equatorial Guinea.

Funding body: Marathon Oil Co-operation & Ministry of Health and Social Services, Equatorial Guinea via Medical Care Development International.

Changes in transmission are extensively monitored through a surveillance system consisting of: (1) annual household malaria indicator surveys; (2) patient information systems; (3) entomological surveillance including biting rates both in- and outdoors, and phenotypic and genotypic insecticide resistance monitoring; (4) serological surveys to assess immunological changes in the human population; and (5) assessment of all-cause child mortality. The third five year phase of the project began in 2014.

Findings to date include: Major reductions in malaria transmission and associated all-cause under five mortality were documented since the initiation of the project.

Travel to destinations with considerably higher transmission levels such as mainland Equatorial Guinea is associated with significantly higher risk of malaria infection not just for travellers themselves, but also for non-travellers living in close proximity of places with high proportions of travellers.

Whilst overall mosquito biting rates have declined considerably during the course of the intervention, the proportion of bites occurring outdoors has increased as indoor biting has dropped more rapidly following the scale up of vector control interventions. However, currently there is no evidence that people spending more time outdoors at night are at risk of higher infection levels than those who spend little or no time outdoors at night.

In settings of year-round transmission there is a compelling need for longer-lasting IRS insecticides, due to the rapid decline of IRS insecticidal effectiveness three months after spraying with insecticides like bendiocarb.

Insecticide treated nets with holes provide limited protection, compared to nets that are intact. IRS is of limited effectiveness unless coverage levels are at least 80%. Children living in houses with closed eaves and/or screened windows are at significantly lower risk of infection compared to houses without these improvements.

Elimination of malaria in Haiti.

LSHTM investigators: Chris Drakeley, Gillian Stresman, Nuno Sepulvda, Kevin Tetteh & Lotus Van den Hoogen.

External collaborators: Centre for Disease Control and Prevention, USA; Clinton Health Access Initiative, USA; Pan American Health Organization, USA; Tulane University, USA; The Carter Centre, USA; Ministere de le Sante Publique et Population, Haiti; CENCET, Dominican Republic.

Funding body: The Bill and Melinda Gates Foundation under the Malaria Zero Alliance.

Hispaniola is the only remaining focus of active transmission of malaria in the Caribbean, largely driven by malaria in Haiti. This project will assist Haiti to accelerate the timeline towards malaria elimination and achieve a malaria-free status by 2020. This will be accomplished by working in conjunction with the Haitian ministry of health to develop and implement an evidence based strategy and operational plan for eliminating malaria transmission.

A significant focus is being placed on strengthening the malaria surveillance system as well as to identify operationally tractable strategies to identify where transmission is and is not occurring.

The first phase will focus on generating current data to identify where transmission is occurring as well as to calibrate different sources of data including that generated through the surveillance system and convenience sampling in easy access groups. We will also identify the bias associated with different malaria metrics according to sampling type including both metrics of infection and exposure to get a better understanding of true levels of malaria transmission and how to measure interruption of transmission.

The second phase will then involve identifying best practices from phase one to scale up across the country to identify areas where there is current malaria transmission to target interventions appropriately (e.g. conduct targeted mass drug administration, case detection, standard vector control etc.). The final phase will involve monitoring the progress towards elimination and ultimately lead to certification of malaria-free status.




Comparison of diagnostics for the

detection of asymptomatic Plasmodium

falciparum infections to inform control and

elimination strategies.

LSHTM investigators: Lindsey Wu, Lotus van den Hoogen & Chris Drakeley.

External collaborators: Hannah Slater, Patrick Walker, Azra Ghani & Lucy Okell (Imperial College London, UK).

Funding body: The Bill & Melinda Gates Foundation through the Diagnostics Modelling Consortium.

The global burden of malaria has been substantially reduced over the past two decades. Future efforts to reduce malaria further will require moving beyond the treatment of clinical infections to targeting malaria transmission more broadly in the community. As such, the accurate identification of asymptomatic infections is becoming a vital component of control and elimination programmes.

We determined the relationship across common diagnostics used to measure malaria prevalence — polymerase chain reaction (PCR), rapid diagnostic test (RDT) and microscopy — for the detection of Plasmodium falciparum infections in endemic populations based on a pooled analysis of cross-sectional data.

We included data from more than 170,000 individuals comparing the detection by RDT and microscopy, and 30,000 for detection by RDT and PCR. On average, RDTs detected 41% (95% confidence interval = 26–66%) of PCR-positive infections. While microscopy captured 87% (95% confidence interval = 74–102%) of RDT-positive infections. Data for the comparison of RDT to PCR detection at high transmission intensity and in adults were sparse.

Our results show that the detection capability of RDTs is comparable with, and often greater than, microscopy. The extent to which this higher RDT detection reflects increased sensitivity, lack of specificity or both, is unclear. However, in comparison with PCR, RDTs still miss a substantial proportion of infections. The role of these undetected infections in onward transmission to mosquitoes across all levels of endemicity remains unclear.


Plasmodium falciparum parasitaemia and

clinical malaria among school children

living in a high transmission setting in

western Kenya.

LSHTM investigators: Rachel Pullan, Katherine Halliday, Birgit Nikolay, Elizabeth Allen, Jorge Cano & Simon Brooker.

External collaborators: Stella Kepha, Fred Nuwaha & Joaniter Nankabirwa (Makerere University, Uganda); Charles Mwandawiro & Damaris Matoke-Muhia (KEMRI, Nairobi).

Funding body: Dissecting the Immunological Interplay between Poverty Related Diseases and Helminth Infections: An African-European Research Initiative (IDEA) consortium, which is funded by the European Union through its FP7-HEALTH-2009 programme.

Stella Kepha, is supported by a PhD training fellowship from THRiVE (Training Health Researchers into Vocational Excellence in East Africa) consortium, which is funded by the Wellcome Trust (087540).

Simon Brooker, is supported by a Wellcome Trust Senior Fellowship in Basic Biomedical Science (098045) which also supports RLP.

This study investigated the burden and risk factors of Plasmodium falciparum infection, and clinical malaria among 2,346 school children aged 5-15 years, who were enrolled in an individually randomized trial evaluating the effect of anthelmintic treatment on the risks of malaria. At baseline, children were assessed for anaemia and nutritional status and information on household characteristics was collected.

Children were followed-up for 13 months to assess the incidence of clinical malaria by active detection, and P. falciparum infection and density evaluated using repeated cross-sectional surveys over 15 months. On average prevalence of P. falciparum infection was 42% and ranged between 32% and 48% during the five cross-sectional surveys.

Plasmodium falciparum prevalence was significantly higher among boys than girls. The overall incidence of clinical malaria was 0.26 episodes per person year (95% confidence interval [CI], 0.24-0.29) and was significantly higher among girls (0.23 versus 0.31, episodes per person years).

Both infection prevalence and clinical disease varied by season. In multivariable analysis, P. falciparum infection was associated with being male, lower socioeconomic status and stunting. The risk of clinical malaria was associated with being female.




New strategies for estimating malaria

transmission: using serology to get a more

precise estimate of local-level variation in

transmission.

LSHTM investigators: Gillian Stresman, Nuno Sepulvda, Jonathan Cox, Teun Bousema & Chris Drakeley.

External collaborators: Emanuele Giorgi (University of Lancaster, UK); Michael White (Imperial College London, UK); Amrish Baidjoe (Radboud University Medical Centre, The Netherlands); Jennifer Stevenson (Johns Hopkins Bloomberg School of Public Health, USA).

Funding body: The Bill & Melinda Gates Foundation under the Malaria Transmission Consortium and the Grand Challenges Grant.

Metrics of malaria transmission are typically restricted to population-level estimates limiting their utility for understanding the more granular, local-level heterogeneities inherent in malaria epidemiology.

The seroconversion rate (λ) estimated by the reverse catalytic model (RCM) is a useful proxy metric for transmission intensity at the population level. However, in a homogeneous population, a person of the same age with comparable exposure history should have a similar antibody profile suggesting that a more precise estimate of λ is possible.

To test this, we extended the RCM to incorporate determinants of exposure to obtain a more refined estimate of λ using data from a large cross-sectional survey in the western Kenyan highlands. Including covariates in the RCM identified elevation as the most important driver of transmission in this population and identified spatial patterns consistent with known areas of increased exposure (figure 1).

This work highlights the potential to use a more precise estimate of malaria transmission, thus, providing insight into the complex nature of local level transmission dynamics. We are currently interested in extending the model to be useful in different epidemiological settings, including elimination and characterising λ for different disease systems.

Spatial distribution of estimated malaria antibody responses in household members.


Statistical challenges of using sero-

epidemiological metrics in populations

on the cusp of malaria elimination and

eradication.

LSHTM investigators: Nuno Sepúlveda & Chris Drakeley.

External collaborators: Carlos Daniel Paulino (Centre for Statistics and Applications of University of Lisbon, Portugal).

Funding body: The Wellcome Trust and the Bill & Melinda Gates Foundation.

According to the latest World Malaria Report, global disease incidence and mortality rates have been following a decreasing trend over the years. In the same report, there is a list of at least 30 countries with short-to-intermediate term goals to achieve disease elimination and eradication. With the decrease of disease burden in these populations, it is very unlikely to sample infected individuals in surveillance studies,

thus, limiting the use of infection-based epidemiological measures in this context.

To overcome this problem, an alternative epidemiological approach based anti-malarial antibody data has been proposed and tested in different epidemiological settings. In this approach, it is of interest to estimate the seroprevalence - the prevalence of seropositive individuals in a sample - and the seroconversion rate - the rate by which seronegative individuals become seropositive that can be seen as a proxy of a malaria transmission intensity. However, the use of these serological measures brings statistical challenges in terms of sample design.

With this in mind, different sample size calculators have been proposed (1) to estimate these measures with a given precision and under the assumption of a stable disease transmission and (2) to detect changes in disease transmission intensity with a given probability. Future work will be carried out to determine the optimal sampling design and corresponding sample sizes to detect a malaria elimination event.


0 20 40 60 80

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Sample size calculations and corresponding reversible catalytic models for detecting a change point in malaria transmission.



Spatial patterns and association of

landscape factors with Plasmodium

knowlesi in Sabah, Malaysia.

LSHTM investigators: Kimberly Fornace, Chris Drakeley, Neal Alexander & Jon Cox.

External collaborators: Paddy Brock (Glasgow University, UK); Timothy William, Tommy Rowel Abidin (Infectious Disease Society Kota Kinabalu, Malaysia); Matthew Grigg, Amanda Murphy (Menzies School of Health Research, Australia).


Deforestation and associated environmental changes have been hypothesized as the main drivers of the increased number of Plasmodium knowlesi cases reported in Sabah, Malaysia. This study gathered village-level data on reported incidence for the districts

of Kudat and Kota Marudu in Sabah, Malaysia for 2008- 2012, adjusting microscopy records to reflect diagnostic uncertainty. Spatial autoregressive models were developed to assess potential associations between P. knowlesi incidence and environmental variables derived from satellite remote-sensing data.

Significant spatial heterogeneity in incidence was observed and numbers of cases were positively associated with both forest cover and historical forest loss in surrounding areas, suggesting a link between deforestation and P. knowlesi transmission in these areas. Further work is on-going to collect community-level data on infection and past exposure to P. knowlesi and evaluate detailed environmental risk factors for this disease.

Publication: Fornace KM, Abidin TR, Alexander N, Brock P, Grigg MJ, Murphy A, et al. Association between Landscape Factors and Spatial Patterns of Plasmodium knowlesi Infections in Sabah, Malaysia. Emerging infectious diseases. 2016 Feb;22(2):201-9.

Forest cover and estimated village level incidence of Plasmodium knowlesi cases (per 1000) in Northern Sabah, Malaysia from 2008-2012.


The impact of hotspot targeted

interventions on malaria transmission in

the western Kenyan Highlands: a cluster-

randomized controlled trial.

LSHTM investigators: Teun Bousema, Gillian Stresman, John Bradley, Jennifer Stevenson, Chris Drakeley & Jonathan Cox.

External collaborators: Amrish Baidjoe, Will Stone, Robert Sauerwein (Radboud University Medical Centre, Netherlands); Victor Osoti, Euniah Makori, Chrispin Owaga, Wycliffe Odongo, Pauline China, Shehu Shagari & Simon Kariuki (KEMRI-Kisumu, Kenya).

Funding body: The Bill & Melinda Gates Foundation (as part of the Malaria Transmission Consortium and REDHOT research programmes).

Malaria transmission is highly heterogeneous, generating malaria hotspots that can fuel malaria transmission across a wider area. Targeting hotspots may represent an efficacious strategy for reducing malaria transmission. We determined the impact of interventions targeted to serologically defined malaria hotspots on malaria transmission both inside hotspots and in surrounding communities.

We detected twenty-seven serologically defined malaria hotspots in a survey that included 17,503 individuals from 3,213 compounds in a 100 km2 area in Rachuonyo district, Kenya. In a cluster-randomized trial in 2012, we randomly allocated 5 clusters to hotspot-targeted interventions with larviciding, distribution of long-lasting insecticide-treated nets, indoor residual spraying and focal mass drug administration; 5 control clusters received malaria control following Kenyan national policy.

Intervention coverage exceeded 87 % for all interventions. Hotspot-targeted interventions did not result in a change in nPCR parasite prevalence outside hotspot boundaries (p≥0.187). We observed an average reduction in nPCR parasite prevalence of 10·2% (95% CI -1·3 – 21·7%) inside hotspots 8 weeks post-intervention that was statistically significant after adjustment for covariates (p=0·024), but not after 16 weeks.

Our trial was not powered to detect subtle effects of hotspot-targeted interventions nor designed for effects of interventions over multiple transmission seasons. Despite high coverage, the impact of interventions targeting malaria vectors and human infections on nPCR parasite prevalence was modest, transient and restricted to the targeted hotspot areas.

Our findings suggest that transmission may not primarily occur from hotspots to the surrounding areas and that areas with highly heterogeneous but widespread malaria transmission may currently benefit most from an untargeted community-wide approach. Hotspot-targeted approach may have more validity in settings where human settlement is more nuclear.




An assessment of risk factors associated

with mobile and migrant populations

working plantations and the implications

from elimination programming in

Cambodia.

LSHTM investigators: Shunmay Yeung & Rebecca Thomson.

External collaborators: Phok Sochea, Amanda MacDonald, Abigail Pratt, Henrietta Allen, Steve Poyer, Gary Mundy (Population Services International, Cambodia); Didier Ménard (Institut Pasteur du Cambodge (IPC), Cambodia).

Funding body: The Bill & Melinda Gates Foundation through a grant to Population Services International.

We carried out a survey in plantation workers in Northeast Cambodia in order to understand more about the risk factors for and to inform potential intervention design. Forty plantations (mainly rubber) were visited in June (dry season) and October (wet season) and included a total of 4,198 plantation workers.

Overall malaria prevalence was lower than expected among plantation workers - roughly 1% by polymerase chain reaction, and surprisingly this was similar in both seasons. The prevalence of P.falciparum was slightly higher than P. Vivax. Malaria prevalence was very heterogenous with clustering of infections in a few plantations. Also surprisingly, workers who were categorised as temporary migrants were not more likely to be infected than permanent residents.

The findings of the survey helped to feed into the design and scale up of plantation-based interventions.

Research assistant, Kim Daro, interviewing a plantation worker in an empty school room.

Children playing in rubber plantation during rainy season.

Identification, classification, selection and evaluation of clusters for the trial.


Assessing methodologies

for the evaluation of complex

health service interventions for

malaria.

LSHTM investigators: Deborah DiLiberto, Sarah Staedke, Elizabeth Allen & Clare Chandler.

Funding body: Methodological research funded as a PhD studentship by the Economic and Social Research Council through the Bloomsbury Doctoral Training Centre. PRIME trial and PROCESS study funded by the Bill & Melinda Gates Foundation through the ACT Consortium.

The aim of this research is to investigate the application of different statistical and anthropological methodologies to evaluate a complex intervention to improve care for malaria at health centres in rural Uganda.

Using social theory to structure a multidisciplinary approach, this research seeks to generate empirical examples demonstrating how different evaluation methodologies generate evidence on the impact, effectiveness and change processes of complex health interventions.

Data for this research are drawn from the evaluation of the PRIME intervention including a cluster randomised trial (PRIME trial) which assessed the impact of the intervention on community health outcomes and a mixed-method study (PROCESS study) which assessed the implementation, mechanisms of change and context of the intervention.

The research is ongoing. Initial findings reveal points of theoretical and methodological tension when different statistical and anthropological methodologies are applied within a cluster randomised trial framework. Understandings of causality, context and impact within and alternative to the experimental trial design are being explored.

This research aims to contribute to the on-going emphasis from health policy and funding organizations for improved methodologies and increased evidence to inform the selection and scale-up of effective interventions.


Image B: RDTs showing results in Uganda.

Image A: RDT being administered by a health worker.



Monitoring patient care through health

facility exit interviews: an assessment of

the Hawthorne effect in a trial of adherence

to malaria treatment guidelines in Tanzania.

LSHTM investigators: Baptiste Leurent, Hugh Reyburn & David Schellenberg.

External collaborators: Florida Muro & Hilda Mbakilwa (Joint Malaria Programme, Kilimanjaro Christian Medical Centre, Moshi, Tanzania).

Funding body: the Bill & Melinda Gates Foundation through the ACT Consortium.

Interviewing patients exiting health facilities is a common way to assess consultation practices within the facilities. However, it is unclear whether conducting such interviews affects health professionals’ practices. This so-called ‘Hawthorne effect’ could have important consequences for interpreting research and monitoring indicators. We used data from a randomised controlled trial to improve malaria diagnostic and treatment in public health facilities in Tanzania.

Patient exit-interviews were conducted by a member of the community on two random days a week, as part of the trial. We used the facility’s routine register to assess how the recorded practice differed on days when exit interviews were conducted, compared with the days without exit interviews. Although modest,

there was some suggestion of better practice by health professionals on days when exit interviews were conducted. For example, the odds of having a malaria rapid diagnostic test result reported was 11% higher on days when exit surveys were conducted (odds ratio = 1.11, 95%CI: 0.98-1.26).

Researchers should be aware of the potential Hawthorne effect, and take into account assessment methods when generalising findings. This effect is likely to be very context dependent, and further evaluation across different settings should be conducted.

Participatory Photo Mapping in Kudat,

Malaysia: investigating how human

movement may effect individual risk of

infection with Plasmodium knowlesi.

LSHTM investigators: Dalia Iskander, Kimberly Fornace, Chris Drakeley, Jonathan Cox & Caroline Jones.

External collaborators: Kntayya Mariappan & Paul Porodong (Universiti Malaysia Sabah, Malaysia); Timothy William (Infectious Disease Society Kota Kinabalu, Sabah, Malaysia).


Although movement is likely to play a crucial role in determining human exposure to disease hosts and vectors, there is a current dearth of knowledge regarding fine-scale individual movement patterns in different land cover types and the related frequency and timing of possible exposure of individuals to malaria risk.

This study used the methodology of participatory photo mapping (PPM) with 17 participants to collect participant-led data on individual human movement in the Kudat region of Malaysian Borneo where the number of human infections with the simian malaria parasite Plasmodium knowlesi has increased markedly in recent years.

PPM is an integrated suite of digital tools including participatory photography, lived-experience interviews and public participation geographic information systems which are combined to capture both the qualitative and quantitative dimensions of people’s experience of place and health.

Participants revealed that they consider malaria-related spaces to be those that attract mosquitoes by virtue of being ‘wet’, dirty’, ‘forested’ or inhabited by ‘animals’ including macaques. Individual movement maps showed that men, women and children regularly move through such areas in order to conduct a wide range of practices that they consider everyday and that they regularly encounter macaques, mosquitoes and mosquito bites during these activities.

Hawthorne effect of patient exit interviews on three primary indicators. Odds ratio and 95% confidence intervals, comparing practices recorded in register on days when exit interviews were conducted compared with days without exit interviews.


PPM helped reveal and contextualise fine-scale individual human movement patterns by integrating different data that showed not just where people move but how and why. In doing so, this study suggests extending the classic focus on adult males who conduct forest-based activities to include women and children who also regularly move through a range of ‘risky’ land-cover types.

PPM has potential utility in helping to determine individual exposure risk for the transmission of P. knowlesi. It can help better guide malaria surveillance and control efforts in ways that involve local communities as ‘resident experts’.

Refining the Furvela tent-trap.LSHTM investigators: Jacques Derek Charlwood & Corey Le Clair.

External collaborators: Erzelia Tomás (MOZDAN project, Mozambique); Alex Egyir-Yawson (Biotechnology and Nuclear Agriculture Research Institute, Ghana); Jason Pitts (Vanderbilt University, USA); Patricia Salgueiro, (Centro de Malária e outra Doenças Tropicais, Portugal); John Morgan (Liverpool School of Tropical Medicine, UK); Siv Sovannaroth (Centro Nacional de Malaria, Cambodia).

Funding body: The Medical Research Council, the UK Department for International Development & Danida.

The WHO recently recognized the necessity for novel sampling tools to conduct entomological surveillance outdoors. We have developed a trap for such purposes: the Furvela tent-trap. https://www.youtube.com/watch?v=irgBPrDQ2Pw. Mosquitoes are attracted to potential hosts by odour and carbon-dioxide. By leaving an opening in the door of an off-the shelf tent near the head of the sleeper(s) their odour and breath are concentrated at a single point. Approaching mosquitoes are trapped in a standard suction-trap (a CDC-light-trap without the light or lid) horizontally attached to the outside of the tent close to the opening. Only some species of mosquito enter houses to feed. Although others will happily bite people outside they do not enter houses. Unlike other tent-traps, the Furvela trap tent does not require mosquitoes to show any ‘entry’

behaviour. Thus it really does sample the outdoor biting fraction of the population.

We have worked with it in Mozambique, where it was used to map outdoor biting mosquitoes in villages around an irrigation scheme; in Ghana where survival rates and bionomics of Anopheles coluzzi were monitored and in Cambodia where the effect of a spatial repellent on outdoor biting rates was determined. Presently it is being used to monitor the outdoor fraction of the mosquitoes in the PAMVERC project (described elsewhere in this report). Modifications of the trap for the collection of day biting vectors, such as Aedes aegypti and Ae. albopictus are in the pipeline.


Individual movement map created by a male participant aged 8 during PPM process. The map shows his activities in a ‘risky’ palm oil plantation and local community hall that led to him being bitten by mosquitoes.

The Furvela tent-trap Mk 1.1.



Gradual acquisition of immunity to severe

malaria with increasing exposure.

LSHTM investigators: Hugh Reyburn, Chris Drakeley & Eleanor Riley.

External collaborators: Jamie Griffin, Deirdre Hollingsworth, Neil Ferguson, Christl Donnelly & Azra Ghani (Imperial College London, UK).

Funding body: The Medical Research Council, Imperial College London & the Wellcome Trust.

It has been suggested that immunity to non-cerebral severe malaria due to Plasmodium falciparum is acquired after only a few infections, whereas longitudinal studies show that some children experience multiple episodes of severe disease, suggesting that immunity may not be acquired so quickly. By fitting a mathematical model for the acquisition and loss of immunity to severe disease to the age-distribution of severe malaria cases stratified by symptoms from a

range of transmission settings in Tanzania we found that immunity to severe malaria was acquired more gradually with exposure than previously thought. The model also suggests that physiological changes, rather than exposure to infection/immunity may alter the symptoms of disease with increasing age, suggesting that a later age at infection would be associated with a higher proportion of cases presenting with cerebral malaria regardless of exposure. This has consequences for the expected pattern of severe disease as transmission intensity changes. Careful monitoring of the decline in immunity associated with reduced transmission will therefore be needed to ensure rebound epidemics of severe and fatal malaria are avoided.

Publication: Griffin, J.T, Hollingsworth, T.D., Reyburn, H., Ferguson, N.M., Donnelly, C.A., Drakeley, C.J., Riley, E.M. and Ghani, A.C. (2015) Gradual acquisition of immunity to severe malaria with increasing exposure. Proceedings Royal Soc. B., 282: 20142657.

Geographical characteristics of study area, severe disease incidence, population density andtravel time to hospital by ward.

Geographical characteristics of study area, severedisease incidence, population density and traveltime to hospital by ward. The study was conductedin northeastern Tanzania, where (a) the altitudeincreases from the coast in the southeast to themountains in the northwest of the study area(altitude of each ward in metres). There is alsogeographical variation in (b) the incidence of severemalaria according to admissions to hospital per1000 head of population, (c) population density perkm2 and (d) median travel time to the hospitalwhere the case was admitted by ward, in hours, asreported by patients' families (with the hospitals inthe study marked with yellow diamonds).

104 Publications 2014-2016

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Pacific journal of tropical biomedicine 4(6): 492-497.

Ajua, A., B. Lell, S. Agnandji, K. Asante, S.

Owusu-Agyei, G. Mwangoka, M. Mpina, N.

Salim, M. Tanner, S. Abdulla, J. Vekemans,

E. Jongert, M. Lievens, P. Cambron, C.

Ockenhouse, P. Kremsner and B. Mordmüller

(2015). “The effect of immunization

schedule with the malaria vaccine

candidate RTS,S/AS01E on protective

efficacy and anti-circumsporozoite protein antibody avidity in African infants.” Malar

J 14(1): 72.

Al-Khattaf, F., A. Tremp and J. Dessens

(2015). “Plasmodium alveolins possess

distinct but structurally and functionally

related multi-repeat domains.” Parasitology

research 114(2): 631-639.

Alam, M., L. Solyakov, A. Bottrill, C. Flueck, F.

Siddiqui, S. Singh, S. Mistry, M. Viskaduraki, K. Lee, C. Hopp, C. Chitnis, C. Doerig, R.

Moon, J. Green, A. Holder, D. Baker and A.

Tobin (2015). “Phosphoproteomics reveals

malaria parasite Protein Kinase G as a

signalling hub regulating egress and

invasion.” Nat Commun 6: 7285.


Publications 2014-2016 105


Alifrangis, M., S. Nag, M. Schousboe, D.

Ishengoma, J. Lusingu, H. Pota, R. Kavishe,

R. Pearce, R. Ord, C. Lynch, S. Dejene, J.

Cox, J. Rwakimari, D. Minja, M. Lemnge

and C. Roper (2014). “Independent Origin

of Plasmodium falciparum Antifolate

Super-Resistance, Uganda, Tanzania, and

Ethiopia.” Emerging infectious diseases

20(8): 1280-1286.

Allen, E., C. Chandler, U. Mehta, N.

Mandimika, C. Pace and K. Bames (2015).

“Optimising Methods for Collecting

Participant-Reported Safety Endpoints in

Antimalarial Drug Clinical Research.” 38:

963-963.

Andrés, M., L. Lorenz, E. Mbeleya and S. Moore (2015). “Modified mosquito landing boxes dispensing transfluthrin provide effective protection against Anopheles

arabiensis mosquitoes under simulated

outdoor conditions in a semi-field system.” Malar J 14(1): 255.

Ansah, E., S. Narh-Bana, H. Affran-Bonful,

C. Bart-Plange, B. Cundill, M. Gyapong and

C. Whitty (2015). “The impact of providing

rapid diagnostic malaria tests on fever

management in the private retail sector in

Ghana: a cluster randomized trial.” BMJ

(Clinical research ed) 350: h1019.

Anselmi, L., M. Lagarde and K. Hanson

(2014). “Equity in the allocation of public

sector financial resources in low- and middle-income countries: a systematic

literature review.” Health policy and

planning: 1-18.

Anstey, N., S. Auburn, J. Baird, K. Battle,

A. Bobogare, A. Chancellor, S. Chasombat,

Q. Cheng, G. Domingo, C. Drakeley, T.

Drukpa, L. Dysoley, F. Espino, P. Gething, P.

Ghimire, R. Gosling, P. Grewal-Daumerie,

S. Hay, R. Howes, J. Hwang, J. Karim,

W. Khan, J. Kim, B. Ley, K. Mannion, J.

McCarthy, W. Keong, I. Mueller, R. Namgay,

R. Price, G. Qi, M. Rebueno, J. Reeder,

J. Richards, J. Sattabongkot-Prachumsri,

G. Shanks, C. Sibley, A. Surya, G. Taleo,

D. Thang, V. Thongpaseuth, K. Thriemer,

H. Trimarsanto, L. Vestergaard, L. von

Seidelein, M. Whittaker and G. Vivax Working

(2015). “Targeting vivax malaria in the

Asia Pacific: The Asia Pacific Malaria Elimination Network Vivax Working

Group.” Malaria Journal 14: 11.

Anstey, N., R. Price, T. Davis, H.

Karunajeewa, I. Mueller, H. Karunajeewa,

U. D’Alessandro, A. Massougbodji, F.

Nikiema, J. Ouedraogo, H. Tinto, I. Zongo, J. Ouedraogo, H. Tinto, A. Same-Ekobo,

M. Kone, H. Menan, A. Toure, W. Yavo, W.

Yavo, P. Kofoed, B. Alemayehu, D. Jima, E.

Baudin, E. Espie, C. Nabasumba, L. Pinoges,

B. Schramm, M. Cot, P. Deloron, J. Faucher,

M. Cot, P. Deloron, J. Faucher, J. Faucher,

J. Guthmann, B. Lell, S. Borrmann, B. Lell,

G. Adjei, P. Kofoed, J. Ursing, E. Tjitra, S.

Borrmann, K. Marsh, J. Peshu, E. Juma, B.

Ogutu, S. Omar, P. Sawa, A. Talisuna, A.

Talisuna, M. Khanthavong, M. Mayxay, P.

Newton, M. Mayxay, P. Piola, A. Djimde, O.

Doumbo, B. Fofana, I. Sagara, Q. Bassat,

R. Gonzalez, C. Menendez, F. Smithuis, F.

Smithuis, T. Bousema, P. Kager, P. Mens, P.

Mens, H. Schallig, I. van Den Broek, M. van

Vugt, M. Ibrahim, C. Falade, M. Meremikwu,

M. Meremikwu, J. Gil, C. Karema, M. Ba,

B. Faye, O. Faye, O. Gaye, J. Ndiaye, M.

Pene, D. Sow, K. Sylla, R. Tine, L. Penali, K.

Barnes, L. Workman, K. Barnes, L. Workman,

Q. Bassat, R. Gonzalez, C. Menendez, I.

Mueller, A. Lima, I. Adam, N. Gadalla, E.

Malik, A. Bjorkman, J. Gil, A. Martensson,

B. Ngasala, J. Ursing, L. Rombo, L. Rombo,

L. Rombo, P. Aliu, S. Duparc, S. Filler, B.

Genton, B. Genton, E. Hodel, P. Olliaro,

S. Abdulla, E. Kamugisha, B. Ngasala, Z. Premji, S. Shekalaghe, S. Shekalaghe,

E. Ashley, V. Carrara, R. McGready, F.

Nosten, E. Ashley, A. Faiz, S. Lee, N.

White, V. Carrara, A. Dondorp, J. Smith,

U. D’Alessandro, J. Tarning, J. Achan, H.

Bukirwa, A. Yeka, E. Arinaitwe, S. Staedke,

M. Kamya, F. Kironde, C. Nabasumba,

T. Bousema, C. Drakeley, N. Gadalla,

M. Oguike, C. Sutherland, F. Checchi, P.

Dahal, J. Flegg, P. Guerin, C. Moreira, P.

Newton, C. Nsanzabana, R. Price, C. Sibley,

K. Stepniewska, J. Tarning, P. Dahal, A.

Dondorp, J. Flegg, P. Guerin, S. Lee, K.

Marsh, R. McGready, C. Moreira, P. Newton,

F. Nosten, C. Nsanzabana, P. Olliaro, R.

Price, J. Tarning, N. White, P. Gething, S.

Hay, B. Greenwood, E. Hodel, S. Ward, S.

Staedke, I. van Den Broek, P. Winstanley,

G. Dorsey, B. Greenhouse, P. Rosenthal, N.

Gadalla, J. Gil, A. Grivoyannis, K. Hamed, J.

Hwang, P. Kachur, J. Hwang, C. Sibley and

M. Nambozi (2015). “The effect of dose on

the antimalarial efficacy of artemether-lumefantrine: a systematic review and

pooled analysis of individual patient

data.” The Lancet infectious diseases 15(6):

692-702.

Ashton, R., T. Kefyalew, E. Batisso, T. Awano,

Z. Kebede, G. Tesfaye, T. Mesele, S. Chibsa, R. Reithinger and S. Brooker (2016). “The

usefulness of school-based syndromic

surveillance for detecting malaria

epidemics: experiences from a pilot

project in Ethiopia.” BMC Public Health

16(1): 20.

Ashton, R., T. Kefyalew, A. Rand, H. Sime,

A. Assefa, A. Mekasha, W. Edosa, G.

Tesfaye, J. Cano, H. Teka, R. Reithinger, R.

Pullan, C. Drakeley and S. Brooker (2015).

“Geostatistical Modeling of Malaria

Endemicity Using Serological Indicators

of Exposure Collected Through School

Surveys.” The American journal of tropical

medicine and hygiene 93(1):168-77.

Assefa, S., C. Lim, M. Preston, C. Duffy, M.

Nair, S. Adroub, K. Kadir, J. Goldberg, D.

Neafsey, P. Divis, T. Clark, M. Duraisingh,

D. Conway, A. Pain and B. Singh (2015).

“Population genomic structure and

adaptation in the zoonotic malaria parasite

Plasmodium knowlesi.” Proceedings of the

National Academy of Sciences of the United

States of America 112(42): 13027-13032.

Assefa, S., M. Preston, S. Campino, H.

Ocholla, C. Sutherland and T. Clark (2014).

“estMOI: Estimating multiplicity of

infection using parasite deep sequencing

data.” Bioinformatics (Oxford, England).

Awine, T., M. Belko, A. Oduro, S.

Oyakhirome, H. Tagbor, D. Chandramohan,

P. Milligan, M. Cairns, B. Greenwood and

J. Williams (2016). “The risk of malaria in

Ghanaian infants born to women managed

in pregnancy with intermittent screening

and treatment for malaria or intermittent

preventive treatment with sulfadoxine/

pyrimethamine.” Malar J 15(1): 46.

Ba, H., C. Duffy, A. Ahouidi, Y. Deh, M.

Diallo, A. Tandia and D. Conway (2016).

“Widespread distribution of Plasmodium

vivax malaria in Mauritania on the

interface of the Maghreb and West Africa.”

Malar J 15(1): 80.

Badu, K., B. Gyan, M. Appawu, D. Mensah,

D. Dodoo, G. Yan, C. Drakeley, G. Zhou, E. Owusu-Dabo and K. Koram (2015).

“Serological evidence of vector and

parasite exposure in Southern Ghana:

the dynamics of malaria transmission

intensity.” Parasit Vectors 8(1): 251.



Baiden, F., J. Bruce, J. Webster, M. Tivura, R.

Delmini, S. Amengo-Etego, S. Owusu-Agyei

and D. Chandramohan (2016). “Effect of

Test-Based versus Presumptive Treatment

of Malaria in Under-Five Children in Rural

Ghana - A Cluster-Randomised Trial.”

PLoS One 11(4): e0152960.

Baiden, F., K. Malm, C. Bart-Plange, A.

Hodgson, D. Chandramohan, J. Webster

and S. Owusu-Agyei (2014). “Shifting from

presumptive to test-based management of

malaria - technical basis and implications

for malaria control in ghana.” Ghana

medical journal 48(2): 112-122.

Baiden, R., A. Oduro, T. Halidou, M.

Gyapong, A. Sie, E. Macete, S. Abdulla,

S. Owusu-Agyei, A. Mulokozi, A. Adjei, E.

Sevene, G. Compaoré, I. Valea, I. Osei, A. Yawson, M. Adjuik, R. Akparibo, B. Ogutu,

G. Upunda, P. Smith and F. Binka (2015).

“Prospective observational study to

evaluate the clinical safety of the fixed-dose artemisinin-based combination

Eurartesim® (dihydroartemisinin/

piperaquine), in public health facilities in

Burkina Faso, Mozambique, Ghana, and

Tanzania.” Malar J 14(1): 160.

Banek, K., M. Lalani, S. Staedke and D.

Chandramohan (2014). “Adherence to

artemisinin-based combination therapy

for the treatment of malaria: a systematic

review of the evidence.” Malar J 13(1): 7.

Banek, K., J. Nankabirwa, C. Maiteki-

Sebuguzi, D. Diliberto, L. Taaka, C. Chandler

and S. Staedke (2014). “Community

case management of malaria: exploring

support, capacity and motivation of

community medicine distributors in

Uganda.” Health policy and planning

30(4):451-61.

Bastiaens, G., T. Bousema and T. Leslie

(2014). “Scale-up of Malaria Rapid

Diagnostic Tests and Artemisinin-Based

Combination Therapy: Challenges and

Perspectives in Sub-Saharan Africa.”

PLoS medicine 11(1): e1001590.

Behrens, R. (2015). “The Raised Potential

for Vector-Borne Diseases in European

Travelers Following the EU’s Biocide

Directive on DEET Dosing.” Journal of

travel medicine 22(3):203-5.

Behrens, R., P. Neave and C. Jones (2015).

“Imported malaria among people who

travel to visit friends and relatives: is

current UK policy effective or does it need

a strategic change?” Malar J 14(1): 149.

Beisel, U., R. Umlauf, E. Hutchinson and

C. Chandler (2016). “The complexities of

simple technologies: re-imagining the role

of rapid diagnostic tests in malaria control

efforts.” Malar J 15(1): 64.

Bejon, P., T. Williams, C. Nyundo, S. Hay, D.

Benz, P. Gething, M. Otiende, J. Peshu, M.

Bashraheil, B. Greenhouse, T. Bousema, E.

Bauni, K. Marsh, D. Smith and S. Borrmann

(2014). “A micro-epidemiological analysis

of febrile malaria in Coastal Kenya

showing hotspots within hotspots.” Elife

3: e02130.

Betson, M., J. Sousa-Figueiredo, A. Atuhaire,

M. Arinaitwe, M. Adriko, G. Mwesigwa, J.

Nabonge, N. Kabatereine, C. Sutherland and

J. Stothard (2014). “Detection of persistent

Plasmodium spp. infections in Ugandan

children after artemether-lumefantrine

treatment.” Parasitology: 1-11.

Biggs, H., R. Lester, B. Nadjm, G. Mtove, J.

Todd, G. Kinabo, R. Philemon, B. Amos, A.

Morrissey, H. Reyburn and J. Crump (2014).

“Invasive Salmonella Infections in Areas

of High and Low Malaria Transmission

Intensity in Tanzania.” Clinical infectious

diseases 58(5): 638-647.

Bousema, T., A. Eziefula, H. Pett and C.

Drakeley (2014). “Low-dose primaquine for

falciparum malaria.” The Lancet infectious

diseases 14(8): 677.

Bousema, T., L. Okell, I. Felger and C.

Drakeley (2014). “Asymptomatic malaria

infections: detectability, transmissibility

and public health relevance.” Nature

reviews Microbiology (12):833-40.

Bowyer, P., L. Stewart, H. Aspeling-Jones,

H. Mensah-Brown, A. Ahouidi, A. Amambua-

Ngwa, G. Awandare and D. Conway (2015).

“Variation in Plasmodium falciparum

erythrocyte invasion phenotypes and

merozoite ligand gene expression across

different endemic populations.” Infection

and immunity 83(6): 2575-2582.

Bradley, J., J. Lines, G. Fuseini, C. Schwabe,

F. Monti, M. Slotman, D. Vargas, G. Garcia,

D. Hergott and I. Kleinschmidt (2015).

“Outdoor biting by Anopheles mosquitoes

on Bioko Island does not currently impact

on malaria control.” Malar J 14(1): 170.

Brady, O., H. Godfray, A. Tatem, P. Gething,

J. Cohen, F. McKenzie, T. Alex Perkins, R.

Reiner, L. Tusting, T. Scott, S. Lindsay, S.

Hay and D. Smith (2015). “Adult vector

control, mosquito ecology and malaria

transmission.” Int Health 7(2): 121-129.

Brady, O., H. Godfray, A. Tatem, P. Gething,

J. Cohen, F. McKenzie, T. Perkins, R.

Reiner, L. Tusting, M. Sinka, C. Moyes, P.

Eckhoff, T. Scott, S. Lindsay, S. Hay and

D. Smith (2016). “Vectorial capacity and

vector control: reconsidering sensitivity

to parameters for malaria elimination.”

Transactions of the Royal Society of Tropical

Medicine and Hygiene 110(2): 107-117.

Briggs, M., A. Kalolella, K. Bruxvoort, R.

Wiegand, G. Lopez, C. Festo, P. Lyaruu,

M. Kenani, S. Abdulla, C. Goodman and

S. Kachur (2014). “Prevalence of Malaria

Parasitemia and Purchase of Artemisinin-

Based Combination Therapies (ACTs)

among Drug Shop Clients in Two Regions

in Tanzania with ACT Subsidies.” PLoS

One 9(4): e94074.

Britton, S., Q. Cheng, M. Grigg, C. Poole,

C. Pasay, T. William, K. Fornace, N.

Anstey, C. Sutherland, C. Drakeley and J.

McCarthy (2016). “Sensitive Detection

of Plasmodium vivax Using a High-

Throughput, Colourimetric Loop Mediated

Isothermal Amplification (HtLAMP) Platform: A Potential Novel Tool for

Malaria Elimination.” PLoS neglected

tropical diseases 10(2): e0004443.

Brochet, M., M. Collins, T. Smith, E.

Thompson, S. Sebastian, K. Volkmann,

F. Schwach, L. Chappell, A. Gomes, M.

Berriman, J. Rayner, D. Baker, J. Choudhary

and O. Billker (2014). “Phosphoinositide

Metabolism Links cGMP-Dependent

Protein Kinase G to Essential Ca2+

Signals at Key Decision Points in the Life

Cycle of Malaria Parasites.” PLoS biology

12(3): e1001806.

London School of Hygiene & Tropical Medicine Malaria Centre Report 2014-2016


Brock, P., K. Fornace, M. Parmiter, J. Cox,

C. Drakeley, H. Ferguson and R. Kao (2016).

“Plasmodium knowlesi transmission:

integrating quantitative approaches from

epidemiology and ecology to understand

malaria as a zoonosis.” Parasitology: 1-12.

Broderick, C., B. Nadjm, V. Smith, M. Blaze,

A. Checkley, P. Chiodini and C. Whitty (2015).

“Clinical, geographical, and temporal

risk factors associated with presentation

and outcome of vivax malaria imported

into the United Kingdom over 27 years:

observational study.” BMJ (Clinical

research ed) 350: h1703.

Bruxvoort, K., C. Festo, M. Cairns,

A. Kalolella, F. Mayaya, S. Kachur, D.

Schellenberg and C. Goodman (2015).

“Measuring Patient Adherence to Malaria

Treatment: A Comparison of Results from

Self-Report and a Customised Electronic

Monitoring Device.” PLoS One 10(7):

e0134275.

Bruxvoort, K., C. Festo, A. Kalolella, M.

Cairns, P. Lyaruu, M. Kenani, S. Kachur,

C. Goodman and D. Schellenberg (2014).

“Cluster Randomized Trial of Text

Message Reminders to Retail Staff in

Tanzanian Drug Shops Dispensing

Artemether-Lumefantrine: Effect on

Dispenser Knowledge and Patient

Adherence.” The American journal of tropical

medicine and hygiene 91(4):844-53.

Bruxvoort, K., C. Goodman, S. Kachur and

D. Schellenberg (2014). “How patients take

malaria treatment: a systematic review of

the literature on adherence to antimalarial

drugs.” PLoS One 9(1): e84555.

Bruxvoort, K., A. Kalolella, M. Cairns, C.

Festo, M. Kenani, P. Lyaruu, S. Kachur,

D. Schellenberg and C. Goodman (2015).

“Are Tanzanian patients attending public

facilities or private retailers more likely to

adhere to artemisinin-based combination

therapy?” Malar J 14(1): 87.

Cairns, M., Y. Cheung, Y. Xu, K. Asante, S. Owusu-Agyei, D. Diallo, A. Konate, A. Dicko,

D. Chandramohan, B. Greenwood and P.

Milligan (2015). “Analysis of Preventive

Interventions for Malaria: Exploring Partial

and Complete Protection and Total and

Primary Intervention Effects.” American

journal of epidemiology 181(12):1008-17.

Cairns, M. and P. Walker (2015). “Monthly

malaria chemoprevention shows potential

in an area of very high, perennial malaria

transmission.” Evidence-based medicine

20(3):110.

Caputo, B., D. Nwakanma, F. Caputo, M.

Jawara, E. Oriero, M. Hamid-Adiamoh, I. Dia,

L. Konate, V. Petrarca, J. Pinto, D. Conway

and A. Della Torre (2014). “Prominent

intraspecific genetic divergence within Anopheles gambiae sibling species

triggered by habitat discontinuities across

a riverine landscape.” Molecular ecology

23(18): 4574-4589.

Chaccour, C., N. Rabinovich, H. Slater,

S. Canavati, T. Bousema, M. Lacerda, F.

Ter Kuile, C. Drakeley, Q. Bassat, B. Foy

and K. Kobylinski (2015). “Establishment

of the Ivermectin Research for Malaria

Elimination Network: updating the

research agenda.” Malar J 14(1): 243.

Chandler, C., J. Meta, C. Ponzo, F. Nasuwa,

J. Kessy, H. Mbakilwa, A. Haaland and H.

Reyburn (2014). “The development of

effective behaviour change interventions

to support the use of malaria rapid

diagnostic tests by Tanzanian clinicians.”

Implement Sci 9: 83.

Chaponda, E., D. Chandramohan, C.

Michelo, S. Mharakurwa, J. Chipeta and

R. Chico (2015). “High burden of malaria

infection in pregnant women in a rural

district of Zambia: a cross-sectional

study.” Malar J 14(1): 380.

Charlwood, J., S. Nenhep, N. Protopopoff, S.

Sovannaroth, J. Morgan and J. Hemingway

(2016). “Effects of the spatial repellent

metofluthrin on landing rates of outdoor biting anophelines in Cambodia,

Southeast Asia.” Medical and veterinary

entomology 30(2):229-34.

Cheeseman, I., B. Miller, J. Tan, A. Tan, S.

Nair, S. Nkhoma, M. De Donato, H. Rodulfo,

A. Dondorp, O. Branch, L. Mesia, P. Newton,

M. Mayxay, A. Amambua-Ngwa, D. Conway,

F. Nosten, M. Ferdig and T. Anderson (2015).

“Population structure shapes copy

number variation in malaria parasites.”

Molecular biology and evolution 33(3):603-20.

Chen-Hussey, V., R. Behrens and J. Logan

(2014). “Assessment of methods used

to determine the safety of the topical

insect repellent N,N-diethyl-m-toluamide

(DEET).” Parasit Vectors 7(1): 173.

Chen, I., S. Clarke, R. Gosling, B. Hamainza,

G. Killeen, A. Magill, W. O’Meara, R. Price

and E. Riley (2016). “’Asymptomatic’

Malaria: A Chronic and Debilitating

Infection That Should Be Treated.” PLoS

medicine 13(1): e1001942.

Chico, R., S. Dellicour, E. Roman, V.

Mangiaterra, J. Coleman, C. Menendez,

M. Majeres-Lugand, J. Webster and J. Hill

(2015). “Global call to action: maximize

the public health impact of intermittent


pregnancy in sub-Saharan Africa.” Malar J

14(1): 207.

Chico, R. and W. Moss (2015). “Prevention

of malaria in pregnancy: a fork in the

road?” Lancet.

Chugh, M., C. Scheurer, S. Sax, E. Bilsland,

D. van Schalkwyk, K. Wicht, N. Hofmann, A.

Sharma, S. Bashyam, S. Singh, S. Oliver, T.

Egan, P. Malhotra, C. Sutherland, H. Beck,

S. Wittlin, T. Spangenberg and X. Ding (2014). “Identification and Deconvolution of Antimalarial Compounds Cross-

Resistance Signals using Multidrug-

Resistant Plasmodium falciparum

Strains.” Antimicrobial agents and

chemotherapy 59(2):1110-8.

Conway, D. (2015). “Paths to a malaria

vaccine illuminated by parasite

genomics.” Trends in genetics.

Cook, J., W. Xu, M. Msellem, M. Vonk, B. Bergstrom, R. Gosling, A. Al-Mafazy, P.

McElroy, F. Molteni, A. Abass, I. Garimo,

M. Ramsan, A. Ali, A. Martensson and A.

Bjorkman (2015). “Mass screening and

treatment on the basis of results of a

Plasmodium falciparum-specific rapid diagnostic test did not reduce malaria

incidence in Zanzibar.” The Journal of

infectious diseases 211(9): 1476-1483.




Cooke, M., S. Kahindi, R. Oriango, C.

Owaga, E. Ayoma, D. Mabuka, D. Nyangau,

L. Abel, E. Atieno, S. Awuor, C. Drakeley,

J. Cox and J. Stevenson (2015). “’A bite

before bed’: exposure to malaria vectors

outside the times of net use in the

highlands of western Kenya.” Malar J

14(1): 259.

Coulibaly, B., M. Pritsch, M. Bountogo, P.

Meissner, E. Nebié, C. Klose, M. Kieser, N. Berens-Riha, A. Wieser, S. Sirima,

J. Breitkreutz, R. Schirmer, A. Sié, F. Mockenhaupt, C. Drakeley, T. Bousema

and O. Müller (2014). “Efficacy and safety of triple combination therapy

with artesunate-amodiaquine-methylene

blue for falciparum malaria in children:

a randomised controlled trial in Burkina

Faso.” The Journal of infectious diseases

211(5):689-97.

Cox, J., L. Dy Soley, T. Bunkea, S.

Sovannaroth, K. Soy Ty, S. Ngak, S. Bjorge,

P. Ringwald, S. Mellor, D. Sintasath and S.

Meek (2014). “Evaluation of community-

based systems for the surveillance of day

three-positive Plasmodium falciparum

cases in Western Cambodia.” Malar J

13(1): 282.

Cox, J., S. Sovannaroth, L. Dy Soley, P.

Ngor, S. Mellor and A. Roca-Feltrer (2014).

“Novel approaches to risk stratification to support malaria elimination: an example

from Cambodia.” Malar J 13(1): 371.

Cundill, B., H. Mbakilwa, C. Chandler, G.

Mtove, F. Mtei, A. Willetts, E. Foster, F. Muro,

R. Mwinyishehe, R. Mandike, R. Olomi, C.

Whitty and H. Reyburn (2015). “Prescriber

and patient-oriented behavioural

interventions to improve use of malaria

rapid diagnostic tests in Tanzania: facility-

based cluster randomised trial.” BMC Med

13(1): 118.

Cunha, M., E. Silva, N. Sepúlveda, S.

Costa, T. Saboia, J. Guerreiro, M. Póvoa,

P. Corran, E. Riley and C. Drakeley (2014).

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Streatfield, P., W. Khan, A. Bhuiya, S. Hanifi, N. Alam, E. Diboulo, A. Sié, M. Yé, Y. Compaoré, A. Soura, B. Bonfoh, F. Jaeger, E. Ngoran, J. Utzinger, Y. Melaku, A. Mulugeta,

B. Weldearegawi, P. Gomez, M. Jasseh, A.

Hodgson, A. Oduro, P. Welaga, J. Williams, E.

Awini, F. Binka, M. Gyapong, S. Kant, P. Misra,

R. Srivastava, B. Chaudhary, S. Juvekar, A.

Wahab, S. Wilopo, E. Bauni, G. Mochamah,

C. Ndila, T. Williams, M. Desai, M. Hamel, K.

Lindblade, F. Odhiambo, L. Slutsker, A. Ezeh,

C. Kyobutungi, M. Wamukoya, V. Delaunay, A.

Diallo, L. Douillot, C. Sokhna, F. Gómez-Olivé, C. Kabudula, P. Mee, K. Herbst, J. Mossong,

N. Chuc, S. Arthur, O. Sankoh, M. Tanner and

P. Byass (2014). “Malaria mortality in Africa

and Asia: evidence from INDEPTH health

and demographic surveillance system

sites.” Global health action 7: 25369.

Stresman, G., A. Baidjoe, J. Stevenson, L.

Grignard, W. Odongo, C. Owaga, V. Osoti,

E. Makori, S. Shagari, E. Marube, J. Cox, C.

Drakeley and T. Bousema (2015). “Focal

screening to identify the subpatent

parasite reservoir in an area of low and

heterogeneous transmission in the Kenya

highlands.” The Journal of infectious

diseases 212(11):1768-77.

Stresman, G., J. Stevenson, N. Ngwu, E.

Marube, C. Owaga, C. Drakeley, T. Bousema

and J. Cox (2014). “High Levels of

Asymptomatic and Subpatent Plasmodium

falciparum Parasite Carriage at Health

Facilities in an Area of Heterogeneous

Malaria Transmission Intensity in the

Kenyan Highlands.” The American journal of

tropical medicine and hygiene 91(6):1101-8.

Sullivan, R., C. Kim, M. Fontana, M. Feeney,

P. Jagannathan, M. Boyle, C. Drakeley,

I. Ssewanyana, F. Nankya, H. Mayanja-

Kizza, G. Dorsey and B. Greenhouse

(2015). “FCRL5 Delineates Functionally

Impaired Memory B Cells Associated with

Plasmodium falciparum Exposure.” PLoS

pathogens 11(5): e1004894.

Sullivan, R., I. Ssewanyana, S. Wamala,

F. Nankya, P. Jagannathan, J. Tappero, H.

Mayanja-Kizza, M. Muhindo, E. Arinaitwe,

M. Kamya, G. Dorsey, M. Feeney, E. Riley,

C. Drakeley and B. Greenhouse (2016).

“Erratum to: B cell sub-types following

acute malaria and associations with

clinical immunity.” Malar J 15(1): 188.

Tadesse, F., H. Pett, A. Baidjoe, K. Lanke,

L. Grignard, C. Sutherland, T. Hall, C.

Drakeley, T. Bousema and H. Mamo (2015).

“Submicroscopic carriage of Plasmodium

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low endemic area in Ethiopia where no

parasitaemia was detected by microscopy

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Tagbor, H., G. Antwi, P. Acheampong,

C. Bart Plange, D. Chandramohan and

M. Cairns (2016). “Seasonal malaria

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seasonal transmission in Ashanti, Ghana:

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Tropical medicine & international health 21(2):

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K. Kayentao, J. Williams, I. Abubakar, F.

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A. Soulama, M. Djimdé, E. Guirou, T. Awine, S. Quaye, F. Njie, J. Ordi, O. Doumbo,

A. Hodgson, A. Oduro, S. Meshnick, S.

Taylor, P. Magnussen, F. Ter Kuile, A.

Woukeu, P. Milligan, D. Chandramohan

and B. Greenwood (2015). “A Non-

Inferiority, Individually Randomized Trial


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Takala-Harrison, S., C. Jacob, C. Arze, M.

Cummings, J. Silva, A. Dondorp, M. Fukuda,

T. Hien, M. Mayxay, H. Noedl, F. Nosten,

M. Kyaw, N. Nhien, M. Imwong, D. Bethell,

Y. Se, C. Lon, S. Tyner, D. Saunders, F.

Ariey, O. Mercereau-Puijalon, D. Menard, P.

Newton, M. Khanthavong, B. Hongvanthong,

P. Starzengruber, H. Fuehrer, P. Swoboda,




W. Khan, A. Phyo, M. Nyunt, M. Nyunt, T.

Brown, M. Adams, C. Pepin, J. Bailey, J. Tan,

M. Ferdig, T. Clark, O. Miotto, B. MacInnis,

D. Kwiatkowski, N. White, P. Ringwald and

C. Plowe (2014). “Independent emergence

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Takem, E., A. Roca and A. Cunnington

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the RTS,S/AS01 malaria vaccine shows

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Tawiah, T., K. Asante, R. Dwommoh, A.

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Taylor, S., C. Parobek, D. DeConti, K.

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A. Mårtensson, B. Ngasala, M. Conrad,

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211(5): 680-688.

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Theisen, M., W. Roeffen, S. Singh, G.

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“Operational challenges to continuous

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Thomson, R., C. Festo, B. Johanes, A.

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Y. Ye, A. Mann, R. Ren, B. Willey, F. Arnold,

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208.

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M. Kamya, C. Bottomley, D. Johnston, J.

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“Measuring Socioeconomic Inequalities

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94(3):650-8.

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M. Affara, S. Allen, C. Proietti, S. Ceesay,

G. Targett, U. D’Alessandro, B. Greenwood,

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Malar J 14(1): 416.

van Schalkwyk, D. and C. Sutherland (2015).

“Malaria resistance to non-artemisinin

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Venkatesan, M., N. Gadalla, K. Stepniewska,

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Dorsey, C. Sutherland, P. Guérin, T. Davis,



D. Ménard, I. Adam, G. Ademowo, C. Arze, F. Baliraine, N. Berens-Riha, A. Björkman,

S. Borrmann, F. Checchi, M. Desai, M.

Dhorda, A. Djimdé, B. El-Sayed, T. Eshetu, F. Eyase, C. Falade, J. Faucher, G. Fröberg,

A. Grivoyannis, S. Hamour, S. Houzé, J. Johnson, E. Kamugisha, S. Kariuki, J.

Kiechel, F. Kironde, P. Kofoed, J. LeBras, M.

Malmberg, L. Mwai, B. Ngasala, F. Nosten, S.

Nsobya, A. Nzila, M. Oguike, S. Otienoburu,

B. Ogutu, J. Ouédraogo, P. Piola, L. Rombo, B. Schramm, A. Somé, J. Thwing, J. Ursing, R. Wong, A. Zeynudin, I. Zongo, C. Plowe, C. Sibley, A. M. M. S. Group and W. AL

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91(4): 833-843.

Vontas, J., S. Moore, I. Kleinschmidt, H.

Ranson, S. Lindsay, C. Lengeler, N. Hamon,

T. McLean and J. Hemingway (2014).

“Framework for rapid assessment and

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Trends in parasitology 30(4):191-204.

Walker, P. and M. Cairns (2015). “Value of

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WAMIN consortium authors include: A.

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A. Bei, D. Conway, M. Diakite, M. Duraisingh,

J. Rayner and Z. Zenonos (2015). “Malaria

Vaccine Development: Focusing

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Phenotypic Diversity: The West African

Merozoite Invasion Network (WAMIN).”

Trends in parasitology 32(4):274-83.

Wanzirah, H., L. Tusting, E. Arinaitwe, A.

Katureebe, K. Maxwell, J. Rek, C. Bottomley,

S. Staedke, M. Kamya, G. Dorsey and S.

Lindsay (2015). “Mind the gap: house

structure and the risk of malaria in

Uganda.” PLoS One 10(1): e0117396.

Watermeyer, J., V. Hale, F. Hackett, D.

Clare, E. Cutts, I. Vakonakis, R. Fleck, M.

Blackman and H. Saibil (2016). “A spiral

scaffold underlies cytoadherent knobs

in Plasmodium falciparum-infected

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Webster, J., F. Baiden, J. Bawah, J. Bruce,

M. Tivura, R. Delmini, S. Amenga-Etego, D.

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“Management of febrile children under

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Wesolowski, A., G. Stresman, N. Eagle,

J. Stevenson, C. Owaga, E. Marube, T.

Bousema, C. Drakeley, J. Cox and C. Buckee

(2014). “Quantifying travel behavior for

infectious disease research: a comparison

of data from surveys and mobile phones.”

Sci Rep 4: 5678.

West, P., N. Protopopoff, A. Wright, Z. Kivaju, R. Tigererwa, F. Mosha, W. Kisinza,

M. Rowland and I. Kleinschmidt (2014).

“Indoor Residual Spraying in Combination

with Insecticide-Treated Nets Compared

to Insecticide-Treated Nets Alone for

Protection against Malaria: A Cluster

Randomised Trial in Tanzania.” PLoS

medicine 11(4): e1001630.

West, P., N. Protopopoff, A. Wright, Z. Kivaju, R. Tigererwa, F. Mosha, W. Kisinza,

M. Rowland and I. Kleinschmidt (2015).

“Enhanced Protection against Malaria by

Indoor Residual Spraying in Addition to

Insecticide Treated Nets: Is It Dependent

on Transmission Intensity or Net Usage?”

PLoS One 10(3): e0115661.

White, M., J. Griffin, O. Akpogheneta, D. Conway, K. Koram, E. Riley and A. Ghani

(2014). “Dynamics of the antibody

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White, M., C. Nielsen, R. McGregor, E.

Riley and M. Goodier (2014). “Differential

activation of CD57-defined natural killer cell subsets during recall responses to

vaccine antigens.” Immunology 142(1):

140-150.

White, M., R. Verity, J. Griffin, K. Asante, S. Owusu-Agyei, B. Greenwood, C. Drakeley, S.

Gesase, J. Lusingu, D. Ansong, S. Adjei, T.

Agbenyega, B. Ogutu, L. Otieno, W. Otieno,

S. Agnandji, B. Lell, P. Kremsner, I. Hoffman,

F. Martinson, P. Kamthunzu, H. Tinto, I.

Valea, H. Sorgho, M. Oneko, K. Otieno, M.

Hamel, N. Salim, A. Mtoro, S. Abdulla, P.

Aide, J. Sacarlal, J. Aponte, P. Njuguna,

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(2015). “Immunogenicity of the RTS,S/

AS01 malaria vaccine and implications

for duration of vaccine efficacy: secondary analysis of data from a phase

3 randomised controlled trial.” The Lancet


White, N., E. Ashley, J. Recht, M. Delves,

A. Ruecker, F. Smithuis, A. Eziefula, T.

Bousema, C. Drakeley, K. Chotivanich, M.

Imwong, S. Pukrittayakamee, J. Prachumsri,

C. Chu, C. Andolina, G. Bancone, T. Hien,

M. Mayxay, W. Taylor, L. von Seidlein, R.

Price, K. Barnes, A. Djimde, F. Ter Kuile, R.

Gosling, I. Chen, M. Dhorda, K. Stepniewska,

P. Guerin, C. Woodrow, A. Dondorp, N. Day

and F. Nosten (2014). “Assessment of

therapeutic responses to gametocytocidal

drugs in Plasmodium falciparum malaria.”

Malaria Journal 13: 483.

Willey, B., S. Tougher, Y. Ye, The

ACTwatchGroup, A. ) Mann, R. Thomson,

I. Kourgueni, J. Amuasi, R. Ren, M.

Wamukoya, S. Rueda, M. Taylor, M. Seydou,

S. Nguah, S. Ndiaye, B. Mberu, O. Malam, A.

Kalolella, E. Juma, B. Johanes, C. Festo, G.

Diap, D. Diallo, K. Bruxvoort, D. Ansong, A.

Amin, C. Adegoke, K. Hanson, F. Arnold and

C. Goodman (2014). “Communicating the

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communication and training interventions

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Williams, J., M. Cairns, F. Njie, S. Laryea

Quaye, T. Awine, A. Oduro, H. Tagbor, K.

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Woukeu, P. Milligan, D. Chandramohan and

B. Greenwood (2015). “The performance

of a rapid diagnostic test in detecting

malaria infection in pregnant women and

the impact of missed infections.” Clinical


Williams, J., F. Njie, M. Cairns, K. Bojang,

S. Coulibaly, K. Kayentao, I. Abubakar, F.

Akor, K. Mohammed, R. Bationo, E. Dabira,

A. Soulama, M. Djimdé, E. Guirou, T. Awine, S. Quaye, J. Ordi, O. Doumbo, A.

Hodgson, A. Oduro, P. Magnussen, F. Ter

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Greenwood and D. Chandramohan (2016).

“Non-falciparum malaria infections in

pregnant women in West Africa.” Malar J

15(1): 53.


Members 123



Abbreviations

Wilson, A., M. Boelaert, I. Kleinschmidt, M.

Pinder, T. Scott, L. Tusting and S. Lindsay

(2015). “Evidence-based vector control?

Improving the quality of vector control

trials.” Trends in parasitology 31(8):380-90.

Wong, M., T. Chua, C. Leong, L. Khaw, K.

Fornace, W. Wan-Sulaiman, T. William, C.

Drakeley, H. Ferguson and I. Vythilingam

(2015). “Seasonal and Spatial Dynamics

of the Primary Vector of Plasmodium

knowlesi within a Major Transmission

Focus in Sabah, Malaysia.” PLoS neglected


Ye, Y., F. Arnold, A. Noor, M. Wamukoya,

J. Amuasi, S. Blay, B. Mberu, R. Ren, C.

Kyobutungi, F. Wekesah, H. Gatakaa, M.

Toda, J. Njogu, I. Evance, K. O’Connell, T.

Shewchuk, S. Thougher, A. Mann, B. Willey,

C. Goodman and K. Hanson (2015). “The

Affordable Medicines Facility-malaria

(AMFm): are remote areas benefiting from the intervention?” Malar J 14(1): 398.

Zhou, Y., N. Lobo, A. Wolkon, J. Gimnig, A. Malishee, J. Stevenson, Sulistyawati, F.

Collins and G. Madey (2014). “PGMS: A

Case Study of Collecting PDA-Based Geo-

Tagged Malaria-Related Survey Data.” The


hygiene 91(3):496-508.

Steering Committee

David Baker

Reader in Parasite Molecular Biology

Clare Chandler

Lecturer in Social Science

Daniel Chandramohan

Professor of Public Health

Brian Greenwood

Professor of Clinical Tropical Medicine

Immo Kleinschmidt

Reader in Epidemiology

Jo Lines

Reader of Malaria Control and Vector Biology

Paul Milligan

Reader in Epidemiology and Medical

Statistics

Eleanor Riley

Professor of Immunology

David Schellenberg

Professor of Malaria & International Health,

ACT Consortium Director, MCDC Deputy

Director

Mark Rowland

Professor of Medical Entomology and Malaria

Control

Colin Sutherland

Head of Department of Immunology and

Infection, Reader in Parasitology

Chris Drakeley

Malaria Centre Director Professor of Infection and Immunity

Catherine Goodman

Malaria Centre Deputy Director Senior Lecturer in Health Economics and Policy

Dalia Iskander

Malaria Centre CoordinatorResearch Fellow in Anthropology


AE - Adverse Event

AL - Artemether-Lumefantrine

ANC - Antenatal Care

API - Active Pharmaceutical Ingredient

APPMG - All-Party Parliamentary Groupon

Malaria and Neglected Tropical Diseases

AQ - Amodiaquine AS - Artesunate

ASC - Antibody Secreting Cell

AZ - Azithromycin

BBC - British Broadcasting Corporation

B cell - B-Lymphocyte

BBSRC - Biotechnology and Biological

Sciences Research Council

CDC - Centres for Disease Control

CFP - Chlorfenapyr

CGD - Career Development Group

CHW - Community Health Worker

CI - Confidence IntervalCNN - Cable News Network

CS - Circumsporozoite

CSST - Community-Scheduled Screening

and Treatment

DALY - Disability-Adjusted Life Year

DCE - Discrete Choice Experiments

DELTAS - Developing Excellence in

Leadership, Training and Science

DFID - Department for International

Development

DNA - Deoxyribonucleic acid

DP - Dihydroartemisinin-PiperaquineEDCTP - European & Developing Countries

Clinical Trials Partnership

EIR - Entomological Inoculation Rate

EMA - European Medicines Agency

ESRC – Economic and Social Research

Council

GLP - Good Laboratory Practice

GSK- GlaxoSmithKline

iCCM - Integrated Community Case

Management

IHI - Ifakara Health Institute

IPT - Intermittent Preventive Treatment

IPTp - Intermittent Preventive Treatment for

malaria in pregnancy

IRS - Indoor Residual Spraying

IST - Intermittent Screening and Treatment

ISTp - Intermittent Screening and Treatment

in Pregnancy

ITD - Infectious Tropical Diseases

Department (LSHTM)

ITL - Insecticide-Treated Livestock

ITN - Insecticide -Treated Net

ITWL - Insecticide-Treated Wall Lining

IVCC - Innovative Vector Control Consortium

LACT - Long-acting Artemisinin-based

Combination Therapy

LD - Linkage DisequilibriumLSHTM - London School of Hygiene &

Tropical Medicine

LTK - Learner Treatment Kit

LLIN - Long Lasting Insecticide-treated Net

MARCAD - Malaria Research Capacity

Development

MC - Malaria Centre (LSHTM)

MCDC - Malaria Capacity Development

Consortium

MiP - Malaria in Pregnancy

MOI - multiplicity of infection

MSc - Master of Science

MRC - Medical Research Council

mRDT - Malaria Rapid Diagnostic Test

NERC - Natural Environment Research

Council

NGO - Non Governmental Organization

NK - Natural Killer

NPR - National Public Radio

P. - Plasmodium

PAMVERC - Pan African Malaria Vector

Research Consortium

PCR - Polymerase Chain Reaction

PDP - Personal Development Planning

Pf - Plasmodium falciparum

Pk - Plasmodium knowlesi

PhD - Doctor of Philosophy

PKG - Protein Kinase

PPM - Participatory Photo Mapping

RAVC - Reactive Targeted Vector Control

RBC - Red Blood Cell

RCM - Reverse Catalytic Model

RDT – Rapid Diagnostic Test

SMC - Seasonal Malaria Chemoprevention

SNP - Single Nucleotide Polymorphisms

SPN - Subpellicular Network

SSFFC - Substandard, Spurious, Falsely-

labelled, Falsified and CounterfeitTPR - Test Positivity Rate

UCL - University College London

UK - United Kingdom

US - United States

USA - United State of America

WHO - World Health Organization

WHOPES - World Health Organization

Pesticide Evaluation Scheme Malaria Centre members at annual Retreat 2016.

124 Members Members 125


Central Services

Vanessa Chen-Hussey: Scientist and

Clinical Trials Manager

Anne Mills: Deputy Director & Provost,

Professor of Health Economics and Policy

Faculty of Infectious & Tropical Diseases

Dawn Britten: Higher Scientific Officer Quality Manager and Biomedical Scientist

Sue Passarelli: Higher Scientific OfficerClaire Rogers: Head of Teaching and

Diagnostic Unit, Principal Scientific OfficerJulie Tucker: Principal Scientific OfficerEmma Victory: Scientific OfficerCheryl Whitehorn: Principal Scientific Officer

Department of Clinical Research

Eleanor Challenger: Assistant Manager,

ACT Consortium

Peter Chiodini: Honorary Professor

Robin Bailey: Professor of Tropical

Medicine, Professor Consultant Physician in

Infectious Diseases and Tropical Medicine,

Hospital for Tropical Diseases

Ron Behrens: Senior Lecturer & Research

Degree co-ordinator

Michael Brown: Senior lecturer in infectious

diseases and tropical medicine

Bianca DSouza: Manager, ACT Consortium

Alison Elliott: Professor of Tropical Medicine

Peter Godfrey-Faussett: Professor of

International Health (Currently seconded to

UNAIDS)

Benjamin Judkewitz: Sir Henry Wellcome

Postdoctoral Fellow

Harparkash Kaur: Lecturer of Pharmacology

David Mabey: Professor of Communicable

Diseases

Alexandra Miller: Programme Manager

Debora Miranda: Technical Communications

Officer, ACT ConsortiumPaul Newton: Honorary Senior Lecturer

Sarah Staedke: Senior Lecturer

Rebecca Tremain: PA to ACT Consortium

Director

Philippe Verstraete: Assistant Manager, ACT

Consortium

Christopher Whitty: Professor of public &

International Health

Department of Disease Control

Cesaire Ahanhanzo: Overseas Scientific Coordinator

Patricia Aiyenuro: Research Assistant

Amit Bhasin: Manager, Malaria Capacity

Development Consortium

David Bradley: Professor

Simon Brooker: Professor of Epidemiology

Jane Bruce: Lecturer

Mary Cameron: Senior Lecturer

Matthew Chico: Lecturer of Maternal,

Newborn and Child Health

Manuela Claite: Overseas Project

Coordinator

Sian Clarke: Senior Lecturer in Malaria

Research and Control

Frank Cox: Visiting Professor

Jonathan Cox: Senior Lecturer

Caterina Fanello: Honorary Lecturer

Ulrike Fillinger: Research Fellow Medical

Entomology & Malaria Control

Katherine Halliday: Research Fellow

Heidi Hopkins: Senior Lecturer in Malaria &

Diagnostics

Caroline Jones: Senior Lecturer

Mojca Kristan: Graduate Teaching Assistant

in Medical Entomology

Matt Kirby: Lecturer of Medical Entomology

Sham Lal: Research Fellow

Toby Leslie: Lecturer, ACT Consortium

James Logan: Senior Lecturer in Medical

Entomology and Scientific Director for arctec Lena Lorenz: Research Fellow in Medical

Entomology

Caroline Lynch: Lecturer Program Design

and Evaluation

Tanya Marchant: Senior Lecturer

Hazel Mccullough: Professional

Development and Educational Advisor,

Malaria Capacity Development Consortium

Sarah Moore: Lecturer in Medical

Entomology Corine Ngufor: Research

Assistant in Medical Entomology

Raphael N’Guessan: Research Fellow in

Medical Entomology

Corine Ngufor: Research Fellow /Field

Project Manager

Terri O’Halloran: Overseas Project

Administrator

Richard Oxborough: Research Fellow

Lucy Paintain: Lecturer

Rachel Pullan: Lecturer

Hugh Reyburn: Senior Lecturer in Clinical

Epidemiology

Joanna Schellenberg: Reader in

Epidemiology & International Health

Wolf-Peter Schmidt: Lecturer in

Epidemiology

Sarah Saleheen: Overseas Scientific Coordinator

Karen Slater: PA to Prof Brian Greenwood

Nina Stanczyk: Research Fellow

Harry Tagbor: Clinical Lecturer, MiP Trial

Coordinator

Chantelle Thomas: Project Finance OfficerLien Tran: Project Administrator, Malaria

Capacity Development Consortium

Jayne Webster: Senior Lecturer

Laith Yakob: Lecturer in Disease Vector

Biology

Layla Yiannikaris: Overseas Project

Coordinator

Department of Immunology & Infection

Khalid Beshir: Research Fellow

Teun Bousema: Senior Lecturer

Hollie Burrell-Saward: Research Assistant

Rebekah Burrow: Trainee Scientific OfficerPatrick Corran: Honorary Senior Lecturer

Simon Croft: Professor of Parasitology

Rebecca Dabbs: Scientific OfficerBrian deSouza: Honorary Senior Lecturer,

Module Organizer for Distance learning

IDM503 Malaria Module

Hazel Dockrell: Professor of Immunology

Elizabeth Downe: Project Administrator

Kimberley Fornace: Research Fellow

Bronner Goncalves: Research Fellow

Lynn Grignard: Research Fellow

Julius Hafalla: Senior Lecturer in

Immunology, Royal Society University

Research Fellow

Tom Hall: Research Assistant

Helena Helmby: Senior Lecturer

Franziska Mohring: Research Fellow

Rob Moon: Lecturer

Mary Oguike: Research Fellow

Tate Oulton: Scientific OfficerNuno Sepulveda: Lecturer

Carolyn Stanley: Laboratory Manager

Gillian Stresman: Research Fellow

Geoff Targett: Emeritus Professor of

Immunology of Parasitic Diseases

Kevin Tetteh: Lecturer

Don Van Schalkwyk: Research Fellow

Department of Pathogen Molecular Biology

Samuel Assefa: Research Fellow in

Population Genomics

Paul Bowyer: Research Fellow

Antoine Claessens: Research Fellow

Taane Clark: Reader in Genetic

Epidemiology and Statistics

David Conway: Professor of Biology

Johannes Dessens: Senior Lecturer in

Parasite Cell Biology

Laura Drought: Research Fellow

Craig Duffy: Research Fellow

Christian Flueck: Research Fellow

John Kelly: Professor of Molecular Biology,

Head of Department of pathogen Molecular

Biology

Michael Miles: Professor of Medical

Protozoology

Debbie Nolder: Principal Scientific Officer in Molecular Diagnostics

Avnish Patel: Research Fellow

Mark Preston: Research Fellow

Cally Roper: Senior Lecturer in Malaria

Genetics

Lindsay Stewart: Laboratory Technician

Sarah Tarr: Research Fellow

Eloise Thompson: Higher Scientific OfficerAnnie Tremp: Research Assistant

David Warhurst: Emeritus Professor of

Protozoan Chemotherapy

Faculty of Epidemiology & Population Health

Department of Infectious Disease Epidemiology

Neal Alexander: Reader in Medical Statistics

and Epidemiology

John Bradley: Research Fellow

Matthew Cairns: Lecturer in Epidemiology

Simon Cousens: Professor of Epidemiology

and Medical Statistics

Jackie Cook: Lecturer in Malaria

Epidemiology

Bonnie Cundill: Lecturer in Medical

Statistics & Epidemiology

John Edmunds: Professor

Clare Flach: Research Fellow

Paul Fine: Professor of Communicable

Disease Epidemiology

Neil French: Reader in Infectious Disease

Epidemiology

DiTanna GianLuca: Lecturer in Medical

Statistics & Epidemiology

Lorna Gibson: Lecturer

David Heymann: Chair of the Health

Protection Agency

Baptiste Leurent: Lecturer in Medical

Statistics and Epidemiology

Andrea Mann: Distance Learning Tutor, MSc

Epidemiology (Distance Learning)

Joshua Mendelsohn: Research Fellow

Maureen OLeary: Lecturer of Epidemiology

Andrea Rehman: Lecturer in Medical

Statistics

Susana Scott: Lecturer

Peter Smith: Professor of Tropical

Epidemiology

Paul Snell: Data Manager, ACT Consortium

Rhosyn Tuta: Manager, ACCESS SMC

Philippa West: Research Fellow

Department of Non-communicable Disease Epidemiology

Dorothea Nitsch: Clinical Lecturer

Department of Nutrition & Public Health Intervention Research

Paula Dominguez-Salas: Research Fellow

of Public Health Nutrition

Seyi Soremekun: Lecturer of Epidemiology

Department of Medical Statistics

Diana Elbourne: Professor of Healthcare

Evaluation

Faculty of Public Health & Policy

Department of Global Health & Development

Helen Burchett: Research Fellow

Richard Coker: Professor of Public Health

Sike Fernandes: Research Fellow

Eleanor Grieve: Research Fellow in Health

Economics

Ulla Griffiths: Senior Lecturer in Health

Economics

Philippe Guyant: Research Fellow Project

Manager

Kristian Hansen: Lecturer in Health

Economics

Kara Hanson: Reader in Health System

Economics

Sheila Harvey: Lecturer

Natasha Howard: Lecturer in Global Health

and Conflict Eleanor Hutchinson: Research Fellow

Frida Kasteng: Research Fellow in Health

Economics

Marcus Keogh-Brown: Lecturer

Lindsay Mangham-Jefferies: Lecturer in

Health Economics

Benjamin Palafox: Research Fellow in

Pharmaceutical Policy & Economics

Edith Patouillard: Lecturer in Health

Economics and Systems Analysis

Catherine Pitt: Lecturer in Health Economics

Andreia Santos: Lecturer

Annemarie terVeen: Distance Learning

Lecturer in Infectious & Tropical Diseases; Conflict & Health Sergio Torresrueda: Research Fellow in

Health Economics

Sarah Tougher: Research Fellow in

Pharmaceutical Policy & Economics

Barbara Willey: Lecturer in Epidemiology

Shunmay Yeung: Senior Lecturer


PhD studentsFatimah Al-Khattaf

Ify Aniebo

Emmanuel Arinaitwe

Harvey Aspeling-Jones

Kristin Banek

Matthew Chico

Ernest Diez Benavente

Deborah DiLiberto

Paul Divis

Bianca Dsouza

Christina Due

Chi Eziefula

Kimberly Fornace

Christopher Gamble

Matt Gibbins

Ryan Henrici

Lou Herman

Natasha Howard

John Hustedt

Ronnie Kasirye

Simon Peter Kigozi

Mojca Kristan

Sham Lal

Mirza Lalani

Marie Lamy

Jonathan Lambo

Inke Lubis

Zawadi MageniLouisa Messenger

Frank Mng’ong’o

Lee Murray

Enesia Ngulubu

Lucy Paintain

Catherine Pitt

Matt Ravenhall

Joanna Reynolds

Ailie Robinson

Samuel Sherratt

Ebako Takem

Katherine Theiss-Nyland

Eloise Thompson

Samuel Thorburn

Patrick Tungu

Lucy Tusting

Lotus van den Hoogen

John Williams

Asia Sophia Wolf

Lindsey Wu

126 Obituary


Sylvia Meek

Sadly, during the making of this report, our great colleague and friend Sylvia Meek passed away in May 2016. Sylvia was known to many in the Malaria Centre and will be remembered as a fantastically energetic person who was passionately committed to making improvements in public health in developing countries. She was extremely knowledgeable about many things (from mosquitoes to cake tasting), tremendously motivational and excellent fun. She will be hugely missed by all of us and the wider malaria community.

Sylvia was a leading scientist-practitioner in the field of malaria control. She was responsible for the design and implementation of numerous malaria control programmes in a wide range of settings around the world and made major contributions to malaria policy development at the global level. Sylvia will be particularly remembered as the principal founder and mentor of the successful non-governmental organization (NGO), the Malaria Consortium.

Sylvia was born in 1954, grew up in Hull, and went to Oxford University for her first degree. She made a switch from English to Zoology and completed an MSc in Animal Parasitology at Bangor University. Her PhD was on the genetic consequences of natural Wolbachia infection in the mosquito vectors of lymphatic filariasis in the Pacific Islands. After her studies, she went to work for the United Nations in refugee camps on the Thai-Cambodia border. As a result, she spent most of the 1980s implementing control programmes against malaria and other infectious diseases. From 1988 to 1993, she worked for the World Health Organization in the Solomon Islands, Namibia and Cambodia.

1994 brought Sylvia back to Britain and to academia as she was recruited to run the Malaria Consortium Resource Centre. This was a joint venture between the London School of Hygiene and Tropical Medicine and the Liverpool School of Tropical Medicine which had core support from the UK Department for International Development (DFID). Its mandate was to provide specialist technical assistance and consultancy services to DFID, health advisers, country offices and their partners.

It soon became clear that operating in an academic setting was a mixed blessing for a resource centre. While it gave access to a pool of high-level technical expertise, it also limited what the centre could do to support itself. Although it could offer technical input into the design and evaluation of large-scale public health projects, it could not bid to manage projects directly. When DFID’s funding came to an end, the team faced a difficult choice. One option was for staff to

leave behind the world of practical malaria control and go back to the conventions of an academic life. The alternative (scary option), was to transform the centre into an independent NGO. Sylvia chose the latter. With the help of some very capable friends, the Malaria Consortium was reborn as an independent charity, with new roles and new ambitions.

Although this was a very risky venture, the Malaria Consortium succeeded. This was of course due to prodigious amounts of hard work and dedication by numerous colleagues but, it was also because of Sylvia’s expertise, good judgement and international reputation. Importantly, thanks to Sylvia, the Malaria Consortium’s emphasis on solid science and technical rigour has never been relaxed. Over the last decade, the Malaria Consortium has grown: it is now much bigger than the academic department it left behind, and in the world of Global Health, it is a major player among technical NGOs.

These practical achievements are attributable to Sylvia’s combination of intelligence and quiet determination. However, it was her kindness, her unselfishness, her instincts for courtesy and generosity and her acute sense of responsibility that made such a lasting impression on the hearts of the people that Sylvia worked with all over the world. Many of us are familiar with the notion that the life of a public health professional (implementing practical disease control programmes) has different demands to the life of an academic scientist (the research, the papers, the teaching etc.) and sometimes we have to make choices about what to prioritize. In Sylvia’s case, the need to choose was forced upon her. However, she was used to doing both and refused to choose. Instead she found a way to combine the two through the Malaria Consortium. The world is certainly a better place for it. For this and for her friendship, we are immensely grateful to have known Sylvia. She will be deeply missed.

If you would like to donate to the Sylvia Meek Scholarship for Entomology, please visit the JustGiving page: https://www.justgiving.com/remember/339335/Sylvia-Meek

The authoritative academic

voice on malaria research

Malaria CentreLondon School of Hygiene & Tropical MedicineKeppel Street, London, WC1E 7HT, UKhttp://malaria.lshtm.ac.uk/[email protected]

Copies of this report may be obtained at http://malaria.lshtm.ac.uk/ or by writing to the address above.Cover image: Matt Murphy/Handsome Frank

Improving health worldwide July 2016

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