FUNDING ORGANIZATION	RESEARCH ORGANIZATION	PROGRAM	DIRECTOR	CITY	COUNTRY	ABSTRACT
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	AN EFFECTIVENESS STUDY OF 7-VALENT PNEUMOCOCCAL CONJUGATE VACCINE ADMINISTERED THROUGH EPI IN THE KILIFI DEMOGRAPHIC SURVEILLANCE SURVEY AREA.	SCOTT, DR ANTHONY	KILIFI	KENYA	View
In the Gambian randomised controlled vaccine trial pneumococcal conjugate vaccine (PCV) reduced radiologically-proven pneumonia in children by 1/3 and childhood mortality by 1/6. In routine use in the USA herd immunity - which cannot be measured in individually randomised trials - prevented twice as many cases of invasive pneumococcal disease (IPD) as did direct vaccine-induced immunity. A small increase was noted in IPD caused by serotypes not included in the vaccine (serotype replacement di sease). Developing countries will introduce PCV based on cost-effectiveness analyses; but how much effectiveness can they anticipate? To measure the real public health gains of a pneumococcal vaccine program I have worked with the Kenya Ministry of Health and Pneumococcal ADIP to introduce PCV into Kilifi District, Kenya, using a catch-up campaign to establish herd protection rapidly. This will estimate direct protection, indirect protection and serotype replacement disease by comparing the i ncidence of serotype-defined IPD for 5 years before and 4 years after PCV introduction. From 2000 onwards, together with colleagues in Kilifi, I have established linked systems of demographic, clinical and microbiological surveillance that will provide the baseline data and future monitoring infrastructure. The results will shape the Kenya government s policy on pneumococcal vaccine use.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	CELLULAR IMMUNE RESPONSES IN CHILDREN WITH PLASMODIUM FALCIPARUM INFECTION.	URBAN, DR BRITTA C	KILIFI	KENYA	View
he diversity of Plasmodium falciparum isolates is an important determinant of the heterogeneity in clinical malaria. Many targets of the humoral immune response are polymorphic or undergo antigenic variation. Clinical immunity maybe the result of cumulative acquisition of a diverse antibody repertoire. Antibody responses to a variety of malarial antigens are short-lived and detectable only during asymptomatic infection. However, the cellular mechanisms determining the nature of antibody responses in P. falciparum infection are not understood. One family of variant proteins, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) mediates adhesion of bloodstage parasites to host cells. Cytoadhesion is associated with (i) pathology, (ii) immune selection, and (iii) immune deviation. I have shown that cytoadhesion of parasites to CD36 modulates dendritic cell function in vitro and systemic cytokine responses in vivo. I now propose to determine the relationship between the phenotype of parasite isolates and the immune responses to PfEMP-1 and how this relationship evolves with exposure. I will define:(i) Whether there are differences in cellular immune responses to PfEMP-1 dependent on the adhesion phenotype of the parasite isolate.(ii) The cellular mechanisms underlying the evolution of unique and cross-reactive antibody responses to PfEMP-1 during the natural history of infection.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	COMMUNICATION FOR HEALTH RESEARCH IN A HOSPITAL SETTING: PROCESS TRAINING WITH HEALTH PROVIDERS FOR IMPROVED COMMUNICATION WITH CLIENTS.	MARSH, DR VICTORIA	KILIFI	KENYA	View
Since August 2009, a team from the KEMRI Wellcome Trust research programme, Kilifi District Hospital (KDH) and the University of Oslo have been developing, implementing and evaluating a communication skills training process targeting health providers in hospitals where research and medical care take place concurrently, towards strengthening understanding of biomedical research and clinical care. The project draws on action research and participatory training approaches for health providers and trainers to maximize effectiveness and sustainability. A key goal is generating local training capacity to run the programme independently in future. The project is showing evidence of perceived impacts on attitudes, communication skills and job satisfaction that are strongly valued by participants and managers in Kilifi and neighbouring districts. An independent, instead of the initially planned in-house, evaluation will be conducted later this year. We are applying now for an extension to undertake additional training of trainers' activities to ensure the generation of a core group of effective independent trainers. This will include developing manuals and holding a further health provider course during which trainers can be supported and manuals piloted. We also aim to hold a dissemination workshop to share project experiences and findings with national health stakeholders.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	COMPREHENSIVE ANALYSIS OF THE ANTIBODY TARGETS OF PLASMODIUM FALCIPARUM MEROZITES AND IDENTIFICATION OF ANTIGENS IMPORTANT IN THE DEVELOPMNET OF NATURALLY-AQUIRED IMMUNITY TO MALARIA.	OSIER, DR FAITH H A	KILIFI	KENYA	View
To date only a limited number of merozoite antigens have been studied in detail as targets of protective antibody-mediated immunity. My aim is to build a comprehensive understanding of the merozoite targets of protective antibodies. The majority of antigens located on the merozoite surface or associated with the surface, and those secreted from their apical organelles have been identified. I will use human sera drawn from malaria-immune adults and an immuno-proteomic strategy to define the sub-set of these antigens that are immunogenic. I will extend this strategy to pools of sera drawn from children whose immune status to clinical has been unambiguously defined from longitudinal cohort studies as either
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	COSTS AND EFFECTS OF A MULTIFACETED INTERVENTION TO IMPROVE THE QUALITY OF CARE OF CHILDREN IN DISTRICT HOSPITALS IN KENYA	BARASA, DR EDWINE	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	CO-TRIMOXAZOLE PROPHYLAXIS AMONG CHILDREN WITH SEVERE MALNUTRITION.	BERKLEY, DR J A	KILIFI	KENYA	View
This project aims to test the hypothesis that mortality after initial stabilisation among Kenyan children with complicated severe malnutrition is due to ongoing vulnerability to infectious disease, and that co-trimoxazole prophylaxis will reduce mortality. It is postulated that the effects of co-trimoxazole will be direct, by preventing life threatening bacterial infections and malaria, and indirect, by preventing less severe infections hence permitting existing nutrient intake and stores to be used for growth and immunological recovery. The objective is therefore to conduct a randomised, double blind, placebo-controlled trial of daily co-trimoxazole prophylaxis among HIV-uninfected Kenyan children with complicated severe malnutrition following stabilization as inpatients and for 6 months after discharge. The primary outcome will be survival at one year. Secondary outcomes are toxicity, hospital admission, survival at two years and growth. A further objective is to investigate the e ffects of co-trimoxazole prophylaxis on microbial ecology and phenotypic and molecular markers of resistance. The study has 90% power to detect a hazard ratio of 0.66 at 5% significance from expected baseline 1 year mortality of 18%.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	DEFINING THE POPULATION AT RISK AND BURDEN OF DISEASE OF PLASMODIUM VIVAX MALARIA.	HAY, DR SIMON I HAY	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	DEVELOPING RESEARCH CAPACITY AND LEADERSHIP IN EAST AFRICA FROM THE KEMRI- WELLCOME TRUST RESEARCH PROGRAMME, KENYA	MARSH, PROF KEVIN	KILIFI	KENYA	View
This proposal aims to develop health-related research capacity and research leadership in East Africa out of the longstanding Wellcome Trust-funded major overseas programme in Kenya. Its central aim is to enable the KEMRI Wellcome Trust Research Programme to produce a cadre of researchers from Kenya and the East African region who are internationally competitive in developing and leading sustainable research programmes throughout the region. The key goals are (1) To provide a coherent car eer development track for health researchers in East Africa. (2) To specifically target key areas of health related research that need particular strengthening in East Africa: translational research, social science research, and clinical trials (3) To build regional research capacity through developing networks with universities and research centres within the region
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	ENGAGING SCHOOL COMMUNITIES WITH HEALTH RESEARCH AND SCIENCE IN KILIFI DISTRICT, KENYA: EXTENSION AWARD.	DAVIES, MR ALUN IWAN DAVIES	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	EPIDEMIOLOGY AND TREATMENT OF EPILEPSY IN SUB-SAHARAN AFRICA.	NEWTON, PROF CHARLES R J C	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	EXPLORING TRANSCRIPTIONAL VARIATION AMONG POPULATIONS OF MALARIA PARASITES.	MACKINNON, DR MARGARET J	KILIFI	KENYA	View
To identify malaria parasite genes and phenotypes involved in adaptation to human immunity we will test whether parasite populations under different amounts of immune pressure show fixed differences in transcription levels of some of their genes. The first step will be to identify genes that are differentially expressed between P. falciparum parasite populations from low, medium and high transmission areas in Sudan, coastal Kenya and western Kenya using whole genome microarrays. Both cDNA and genomic DNA will be analysed for significant and consistent population differences in transcription and gene copy number. Once candidate adaptive genes are identified, 40 of them (selected for their likely role in virulence on the basis of published information) will be assayed by real-time PCR on sets of samples from within a population that contrast in two ways. First, candidate genes will be tested in patients with severe vs. mild disease to determine whether they are associated with virule nce. Second, they will be tested in samples collected before and after a 10-year decline in transmission and immunity to determine whether parasite adaptation to immunity occurs on a time-scale that is relevant to control programmes. This will provide candidate genes for future functional and evolutionary studies.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	IMPROVING THE ABILITY OF HEALTH SYSTEMS TO DELIVER ESSENTIAL, HOSPITAL SERVICES - EXAMINING STRATEGIES TARGETING SERIOUSLY ILL CHILDREN AND NEWBORNS IN KENYA.	ENGLISH, DR MICHAEL CHARLES ENGLISH	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	INTEGRATED STUDIES OF THE TARGETS, REGULATION AND CONSEQUENCES OF HUMAN IMMUNITY TO MALARIA.	MARSH, PROF KEVIN	KILIFI	KENYA	View
This proposal seeks support for an epidemiological and analytical framework developed by us over a number of years in Kilifi, Kenya. Specific elements include longitudinal monitoring of four cohorts of children with detection and careful phenotyping of clinical events in order to relate putative immune functions to immune status. It also includes a carefully documented historical archive of parasite and human samples allowing us to examine the population level consequences of changes in immun ity. Within this framework we will focus on (1) identifying immune targets on the merozoite by using sera of carefully defined immune status to probe both 2D gels and libraries of expressed merozoite proteins; (2) characterizing parasite-derived antigens on the surface of the infected red cell associated with low immunity and virulence; (3) identifying the mechanisms regulating the immune response to malaria; (4) determining which non-antigen genes are subject to immune selection through w hole-transcriptome and whole-genome comparisons of P. falciparum parasites from populations that have been under different intensities of immune selection pressure over a long period of time; and (5) determining the effects of changing transmission on human and parasite populations by a combination of mathematical modelling and next-generation parasite sequencing.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	INVESTIGATION INTO PLASMODIUM FALCIPARUM ROSETTING MECHANISMS AND DEVELOPMENT OF ROSETTE-DISRUPTING INTERVENTIONS TO TREAT OR PREVENT SEVERE MALARIA.	ROWE, PROF J ALEXANDRA	KILIFI	KENYA	View
There is an urgent need for new drugs and vaccines to reduce global mortality from malaria. The development of new interventions is constrained by our incomplete understanding of parasite virulence factors and mechanisms of natural immunity. The only parasite virulence phenotype to date that has been consistently associated with severe malaria in African children is P. falciparum rosetting. My previous work identified members of the variant antigen family PfEMP1 (P. falciparum erythrocyte mem brane protein one) as the parasite ligands for rosetting, opening up the possibility of developing an anti-rosetting vaccine based on PfEMP1. However, there is currently little information on the diversity in rosetting mechanisms between strains, and whether rosette-disrupting antibodies raised to one PfEMP1 variant cross-react with other strains. The work in this proposal specifically targets the need to acquire further detailed information on rosetting mechanisms and cross-reactivity amongst strains that will be essential to inform future vaccine development. I also aim to pursue a therapeutic approach by developing a rosette-disrupting drug with broad-spectrum activity and no anticoagulant side effects. The key goals of this research are to provide a mechanistic understanding of rosetting and to identify rosetting-disrupting vaccine and drug candidates.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	MARSH, PROF K MARSH	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	MALARIA BURDEN AND CONTROL AT NATIONAL, REGIONAL AND GLOBAL SCALES.	SNOW, PROFESSOR ROBERT W	KILIFI	KENYA	View
The work in this application will provide the most complete understanding of the spatial distributions of malaria risk at national, continental and global scales since the 1960's. The approach will allow for a transparent, evidence-driven estimation of the public health burden posed by the malaria parasite and its diversity in space and time. The epidemiological platform will provide the means to articulate needs and model the impact of changing demographics, climate, poverty and intervention between 2005 and 2030. Effective control, however, will be predicated on a number of operational constraints which must be defined and understood to ensure that patients and communities most in need have access to interventions that work. How well interventions are delivered at national scales is the subject of a complementary programme of research: providing the link between the theoretical impacts of disease control and the likely operational efficiency of interventions when delivered as part of national policies in Africa.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	MAPPING THE RISKS OF PLASMODIUM FALCIPARUM INFECTIONS IN AREAS OF LOW TRANSMISSION INTENSITY .	NOOR, DR ABDISALAN M NOOR	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	MEASURING THE IMPACT OF NATURALLY ACQUIRED IMMUNITY ON THE EXPRESSION OF PLASMODIUM FALCIPARUM VARIANT SURFACE ANTIGENS.	BULL, DR PETER BULL	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	NON-VAR-ENCODED VARIANT ANTIGEN FAMILIES IN PLASMODIUM FALCIPARUM AS TARGETS FOR NATURALLY ACQUIRED IMMUNITY TO MALARIA.	THATHY, DR VANDANA	KILIFI	KENYA	View
The Plasmodium falciparum genome contains large multigene families that code for hypervariable antigens, which are exported to the surface of the infected host erythrocyte and represent targets of naturally acquired immunity to malaria. These variant surface antigens (VSA) act at the host-parasite interface, ensuring parasite survival without inducing a sterilizing host immune response. With the exception of the well-demonstrated roles of var-encoded P. falciparum erythrocyte membrane protein (PfEMP)1 in virulence and immune evasion, the biological significance of other VSA and their role in the acquisition of antimalarial immunity in endemic regions is largely unknown. Here we propose to determine whether two other VSA, RIFINs and STEVORs, encoded by the rif and stevor multigene families respectively, are targets of natural immunity and whether the hypervariable regions of these structurally-related proteins are exposed to antibody-mediated immune selection at the erythrocyte surface. We will define the expression patterns and measure the naturally acquired antibody responses to these antigens in wild isolates of P. falciparum from coastal Kenya. By identifying and characterising the molecular targets of naturally acquired immunity, this research will advance current understandings of P. falciparum antigenic variation and the mechanisms of natural acquisition of protective immunity against malaria.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	PATHOGEN SENSING AND RESPONSE IN CHILDHOOD MALNUTRITION.	JONES, DR KELSEY DAVID JOEL	KILIFI	KENYA	View
Malnutrition is responsible for 35% of global child mortality due to an association with increased incidence, severity, and case-fatality of common infectious diseases. While epidemiological evidence suggests a causal relationship between malnutrition and secondary immune deficiency, the cellular and molecular mechanisms underlying this association are undefined. We hypothesise that malnutrition is associated with impaired pathogen sensing and response, resulting in defective clearance of pa thogenic bacteria and their products, and the establishment of a paradoxic chronic inflammatory state. Mucosal disruption and bacterial translocation account for the high incidence of sepsis, and explain the vicious cycle that exists between malnutrition and infection. To test this hypothesis we will characterise innate pathogen sensing and response capability in childhood malnutrition by conducting two longitudinal cohort studies in rural Kenya. These will determine i) the extent to which i nnate immunity is compromised in childhood malnutrition and the dynamics of reconstitution, and ii) the immunologic relationship between malnutrition and sepsis, and the extent to which these conditions are independently immunomodulatory. The study is designed to generate biomarkers of immune status during nutritional rehabilitation. These could be used in trials of different therapeutic and nutritional strategies for management of the severely malnourished child.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	POPULATION IMPACT OF CONJUGATE VACCINE ON PNEUMOCOCCAL TRANSMISSION AND DISEASE IN KENYA.	SCOTT, PROF ANTHONY SCOTT	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	ROAD-MAP: A REPOSITORY FOR OPEN ACCESS DATA COLLECTED BY THE MALARIA ATLAS PROJECT.	SNOW, PROFESSOR ROBERT W	KILIFI	KENYA	View
The Malaria Atlas Project (MAP) has received substantial support for the acquisition of basic malariometric data from the Wellcome Trust. With this investment we have achieved the largest ever assembly of parasite rates (P. falciparum and P. vivax), of the occurrence of medically important anophelines and the gene frequencies of six inherited blood disorders. The demand for this combined information resource is readily apparent in the widespread uptake of our mapped products and the demand for o ur data. This biomedical resources grant seeks resources to sustain this data acquisition, provide robustly curated databases and geographic map products to a range of user communities and hence support the aspirations of other scientists, those involved in control and elimination, and the lay public. The latest advances in the semantic web and the visualization of dynamic maps will be utilized to maximize the dissemination and utility of this information. The resource will enable MAP to highlig ht and champion the public health benefits to all constituents of the international public health community, complementing the equally important dissemination of scientific output through the open-access peer-reviewed literature. In these ways the basic and operational impact of the research funding provided to MAP will be maximized.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	STRENGTHENING COMMUNITY ACCOUNTABILITY IN BIOMEDICAL RESEARCH AND HEALTH DELIVERY.	MOLYNEUX, DR CATHERINE S	KILIFI	KENYA	View
Community accountability is increasingly promoted in sub-Saharan Africa; in biomedical research to strengthen research ethics, relevance and acceptability, and in health delivery as a right in itself, and to enhance quality of care, perceived appropriateness, and patient utilisation. Despite the prominence of community accountability in policy and practice, there is little published experience, leading to calls for further research. The proposed research will produce new thinking, evidence and recommendations around strengthening community accountability in both biomedical research and health delivery in sub-Saharan Africa. Mixed methodology research will be conducted in Kenya and in Tanzania, focusing where relevant on Kilifi and Bagamoyo Districts respectively, where large biomedical research institutions are based. Literature reviews focusing on developing countries, an overview of community accountability mechanisms in Kilifi and Bagamoyo, two prospective research case studies focusing on the two districts (a community based vaccine trial and a hospital based trial), and a national health delivery intervention case study in Kenya, will each be written up separately, but also contribute to the development and testing of a draft framework outlining influences on functioning and impact of community accountability. The findings will be drawn upon to feed into national and international debates and recommendations.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	STRENGTHENING COMMUNITY ENGAGEMENT FOR STUDIES INVOLVING MOST AT RISK POPULATIONS (MARPS) IN KENYA	MOLYNEUX, DR SASSY MOLYNEUX	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	THE CLINICAL AND MOLECULAR EPIDEMIOLOGY OF STREPTOCOCCUS AGALACTIAE (GROUP B STREPTOCOCCUS) MATERNAL COLONISATION IN KENYA AND ASSOCIATION WITH ADVERSE PERINATAL OUTCOMES.	SEALE, DR ANNA SEALE	KILIFI	KENYA
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	THE HEALTH CONSEQUENCES OF INHERITED RED BLOOD CELL DISORDERS IN KENYA.	WILLIAMS, DR THOMAS N	KILIFI	KENYA	View
I will investigate the mechanisms and interactions between a range of human-genetic malaria-protective polymorphisms including HbS, alpha-thalassaemia and G6PD deficiency through both laboratory-based and clinico-epidemiological approaches. Specifically, I will measure the impact of these polymorphisms, both individually and in combination, on well-characterised malaria, and non-malaria phenotypes through laboratory studies and through the analysis of epidemiological data from (i) a birth cohort study of 16,000 children and (ii) a study derived from the continuous surveillance of more than 90,000 paediatric admissions to Kilifi District Hospital in the last 20 years.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	THE POTENTIAL IMPACT OF VACCINATION ON RSV AND OTHER RESPIRATORY VIRUS PNEUMONIA IN THE DEVELOPING COUNTRY SETTING.	NOKES, DR DAVID JAMES	KILIFI	KENYA	View
Predicting the potential impact of introducing a vaccine into a community requires an in-depth understanding of the interactions between the pathogen and host. Key elements of this association are the mechanism by which the virus spreads between individuals and the nature of the immune response to infection. In the case of RSV, an antigenically variable virus, individuals are repeatedly infected throughout life, and it is the nature of this partial immunity that is of central concern in our stud ies. In particular, we wish to elucidate the role of the partially immune in constraining virus spread, but, also in maintenance of transmission, especially to na ve individuals most at risk of disease, and to establish the role of individual strain specific immunity to population dynamics. We argue also that the environment of other respiratory pathogens may influence the single pathogen:host ecology. We plan an inter-related series of studies, in which immunological, epidemiological, and th eoretical investigations will feed into transmission dynamics models of RSV and other respiratory viruses, by which to assess the impact of vaccine intervention. Our goals are to define optimal vaccine strategies for disease prevention, and provide a suitable framework for their practical evaluation.
	Wellcome	KEMRI-WELLCOME TRUST RESEARCH PROGRAMME	USING THE CONTROLLED HUMAN MALARIA INFECTION MODEL TO ASSESS FUNCTIONAL LABORATORY ASSAYS OF IMMUNITY TO MALARIA.	SHEEHY, DR SUSANNE HELENA SHEEHY	KILIFI	KENYA