Today, many partners are concerned with reducing malaria (WHO, National Control Programmes, The Global Fund, etc ) and the current best practice for malaria control is the use of Artemisinin-based combination therapies , e.g. Coartem®, and long-lasting impregnated nets (LLINs) for vector control tool. Many countries are also using indoor residual spraying (IRS) as it is a passive and a highly equitable intervention and DDT is very suitable for rural areas. In 2009, 29 countries in Africa were using IRS at the same time as LLIN and 13 were using IRSwith DDT, including The Gambia. Yet there is very little information about the effectiveness of DDT-IRS in Africa, particularly in areas with high bednet coverage, and it is essential to determine if IRS with DDT will provide additional protection against malaria over current best practice. This is the primary aim of the S.A.N.T.E. (Spraying And Nets Towards malaria Elimination) study which was developed in partnership with the Gambian National Malaria Control Programme (NMCP). DDT is considered highly suitable for IRS but we need to test alternative insecticides, not only because of environmental considerations but also to manage insecticide resistance. Thus, in addition to the monitoring insecticide resistance in the vectors, we will compare the anti-mosquito properties and persistence of two alternative insecticides to DDT in a small pilot study.

The study is in the middle of the second year of field work. In the Upper River Region in 2010 we enrolled 96 villages into 70 clusters, and working with the NMCP, half of these received either LLIN and LLIN plus IRS with DDT. The study is large enough to make it probable that differences between the two groups will be greater than that due to chance alone. The primary measure is the effect of these interventions on malaria cases in children resident in study villages and a cohort of almost 8000 children aged 6 months to 14 years has been enrolled. The SANTE field team is working with the Regional Health Team, community health nurses and village health workers to detect malaria attacks during the malaria transmission seasons in 2010 and 2011. The major secondary measure is the number malaria mosquitoes, and their infection with malaria parasites, inside study houses to estimate the effect of IRS on the exposure of the population to malaria infection. Also the additional cost of malaria cases averted by IRS with DDT against a background of complete coverage with LLIN will be determined based on material and labour costs. The final field survey will take place in late 2011 and results are expected in mid 2012.

Alias	PI – 1	PI – 2	Start	End	Ext.	Donors
S.A.N.T.E.	Steve Lindsay	Margaret Pinder	Jan 2010	Dec 2012	-	MRC UK

Trachoma is the leading infectious cause of blindness worldwide and affects millions of people in poor and rural regions. The Partnership for the Rapid Elimination of Trachoma (PRET) is a cluster randomized control trial taking place in three countries: The Gambia, Tanzania and Niger. It aims to answer two main questions:

1. The WHO recommends that districts where the prevalence of follicular trachoma is 10% or more in children aged 1 to 9 years be mass treated with azithromycin annually for at least three years. After three years you re-assess the prevalence then decide whether or not you need to continue mass treatment. We are looking at whether you actually need to treat every three years or whether less frequent treatment is possible.
2. The WHO recommends that mass treatment coverage should be 80% or more. The PRET trial is providing the evidence to support this recommendation by comparing 80% treatment coverage with an attempt at obtaining 90%.

The data gathered will be used to better manage the scarce resources that are available for trachoma control.

Alias	PI – 1	PI – 2	Start	End	Ext.	Donors
Partnership for rapid elimination of Trachoma – PRET	Sarah Burr	Robin Bailey	-	-	-	LSHTM, BMGF

Tuberculosis (TB) is a major health problem especially in the developing world. It has been estimated that one third of the global population is latently infected with Mycobacterium tuberculosis. Despite years of effort we currently have no reliable biomarkers for identifying protective immunity against TB and for the various disease states, or for predicting response to intervention. In this component of the TB Grand Challenge Projects, we will establish TB case contact cohorts to facilitate the identification of biomarkers and signature profiles of protective immunity and TB disease. Biomarkers may become important tools to facilitate the design and the monitoring of novel TB interventions, including TB vaccines and new anti-mycobacterial drugs. These case contact cohorts will form a central component of our TB case contact study platform and enable the use of molecular and immunological tools to study the host response to recent M. tuberculosis infection, dormancy and progression to disease.

We will perform cross-sectional analyses of immune responses in healthy TB case contacts with and without HIV-1 co-infection. We will conduct immunological studies during a 2 year follow up of household contacts of sputum smear positive TB index cases, in order to observe longitudinal changes in candidate biomarkers in relation to acquisition of new infection with M. tuberculosis, dormancy, reactivation and disease progression. The study of disease progression will benefit from combining data from multiple African sites as part of the Gates Grand Challenge Biomarkers consortium.

Pneumococcal disease, primarily bacteraemic pneumonia, is a leading cause of childhood mortality. Pneumococcal conjugate vaccines (PCVs) have enormous potential to reduce the burden of pneumococcal diseases. Currently, three pneumococcal conjugate vaccines containing 7, 10 and 13 pneumococcal serotypes respectively are available for use in infants and toddlers. Despite improved serotype coverage with higher valency conjugate vaccines, global control of pneumococcal disease will be difficult to achieve by using serotype specific polysaccharide conjugates alone, as there are technical limitations as to the number of pneumococcal serotypes that can be included in a vaccine. Moreover, there is also concern of emerging serotype replacement, especially in nasopharyngeal pneumococcal colonisation, which may be associated with an increase of diseases caused by non-vaccine types. One approach to this challenge is to increase coverage beyond a given number of serotypes by the development of pneumococcal vaccines based on common, conserved pneumococcal proteins. GSK Biologicals is developing a new pneumococcal candidate vaccine containing two highly conserved pneumococcal proteins: pneumolysin toxoid (dPly) and histidine triad protein D (PhtD), which have been combined with the 10-valent PCV. This proposal is to conduct a clinical trial to evaluate its safety, immunogenicity, non-interference with other EPI vaccines, and impact on nasopharyngeal carriage of pneumococcus in infants. Although the target population will be infants, to ensure safety this study will be a step wise phase II, single centre, randomized, controlled study whereby a pilot safety assessment will be conducted first in young children aged 2 to 4 years (Cohort 1) before progressing to infants (Cohort 2).

The available tuberculosis vaccine, BCG, provides incomplete protection against pulmonary tuberculosis. Due to natural inhibition of a second dose, a BCG revaccination does not provide additional protection. MVA85A/AERAS-485 vaccine incorporates a tuberculosis antigen within a live but non-replicating virus vector, which increases specific- T-cell immunity, and thus protection against tuberculosis. MVA85A/AERAS-485 has been administered in clinical trials to over 500 subjects, including 62 adult subjects who were HIV-positive, without any vaccine-related serious adverse events (including no clinically significant effect on either CD4 count or HIV viral load) and shows evidence of immunogenicity. Following licensure, MVA85A/AERAS-485 will be made available in areas of high HIV prevalence. It is therefore important to study the efficacy and safety of the vaccine in HIV-positive individuals. This study will evaluate the immunogenicity, safety and protective efficacy against TB disease of MVA85A/AERAS-485 in

Mycobacterium tuberculosis(Mtb), is responsible for about 9 million new cases of TB and 1.6 million deaths each year. BCG prevents disseminated TB in young children but not primary TB. A study in Cape Town showed that over 3% of infants developed pulmonary TB within 2 year of BCG vaccination (Hawkridge et al., 2008), thus children would benefit from any vaccination that would help prevent primary TB.

The M72/AS01E candidate TB vaccine is designed to boost immune responses induced by BCG or by infection with Mtb. Two doses have been well tolerated and induced strong, persistent and polyfunctional immune response in PPD-negative and positive adults. The EPI programme has been highly successful at increasing the coverage of basic vaccines across the developing world. A TB vaccine that could be integrated within the EPI would make it accessible. Integration of M72/AS01E into the EPI scheme in Sub-Saharan Africa may require the co-administration of M72/AS01E with other EPI antigens.

This study is designed to evaluate the safety and immunogenicity of one or two doses of M72/AS01E in infants when given concomitantly with their EPI vaccines or after completion of primary EPI vaccination containing the combined diphtheria, tetanus, whole cell pertussis, hepatitis B, Haemophilus influenzae vaccine, the pneumococcal conjugate vaccine and the Oral polio vaccine.

At the present time there are no data demonstrating the effectiveness of pneumococcal conjugate vaccines (PCV) when used in EPI schedules in Africa. Questions remain regarding the magnitude of the effectiveness of PCV when delivered in a routine EPI, herd protection for unimmunised individuals, serotype replacement, cost-effectiveness, and effectiveness against particular pneumococcal serotypes which are prevalent in Africa.  The pneumococcal surveillance project is evaluating the effectiveness of the introduction of PCV in the EPI in The Gambia. The project is a collaboration between MRC and The Gambia Government. The PCV effectiveness study is located in rural Gambia, based at the MRC Field Station in Basse. Prospective, population-based surveillance operates in the Basse Health and Demographic Surveillance System, which covers the area of the south bank of Upper River Region (population 160,000). Surveillance among all ages for cases of meningitis, sepsis and pneumonia has been underway since 2008. The 7-valent PCV was introduced in August 2009. A 13-valent PCV was introduced in April 2011. Surveillance will continue until December 2014 and compare the incidence of invasive pneumococcal disease and radiological pneumonia before and after introduction of PCV. The study is will also describe the indirect effects of PCV and track serotype-specific pneumococcal disease. The cost-effectiveness of PCV will also be determined.

The PCV effectiveness study is currently expanding to also operate in the Fuladu West district of Central River Region. A case-control study of the effectiveness of 13-valent PCV will be conducted throughout the expanded study area. This study will provide some of first data on the effectiveness of 13-valent PCV against disease endpoints. These studies will provide evidence that will assist decision-makers concerning national and international policy on pneumococcal vaccination.

Alias	PI – 1	PI – 2	Start	End	Ext.	Donors
Pneumococcal Surveillance Project – PSP	Grant Mackenzie	-	-	-	-	Bill & Melinda Gates Foundation

The World Health Organization (WHO) ranks diarrheal disease as the second (only after pneumonia) leading cause of mortality among children under five years (60 months) of age in developing countries, accounting for 18% of the 10.6 million children death each year in this age group. It is important to understand and estimate the disease burden, the different clinical picture, aetiology, both short and long term consequences (e.g. nutritional faltering, cognitive deficiency, death) and risk factors of diarrhoeal disease in this population in a well designed study. Due to various reasons most of these information are sparse in studies conducted so far. There should also be endeavour to assess the perception of the disease, health care seeking behaviour and economic burden amongst a defined set population. On this background a consortium was formed with four sub Saharan and three South East Asian countries where the childhood mortality is high, to understand the nature and magnitude of the problem mentioned above. The study is popularly known as Global Enteric Multicentre Study (GEMS) and MRC unit, The Gambia is one of the participating sites.

A Demographic Surveillance System (DSS) was set up in the south bank of river Gambia in the Upper River Region (URR) with an area of 1084 square KM and comprising of 223 villages where basic demographic information such as resident status, birth, death, migration are collected three times in a year. A Health Utilization and Attitude Survey (HUAS) was conducted to understand the perception of diarrhoeal disease and the health seeking behaviour in this population. The three 3-year case control study followed to help quantify the burden, microbiologic aetiology, and sequelae of moderate to severe diarrhoea (MSD) along side a brief version of HUAS to understand if there is any change in the health seeking behaviours. The multi-centre, case-control study has been extended; thereby allow recruiting children with less severe diarrhoea (LSD) alongside those with moderate to severe diarrhoea (MSD). It is anticipated that the outcome of this extended version of the study together with the results of the recently concluded study will be able to give enough evidence to formulate a uniform guideline for the management and lead in the development and implementation of enteric vaccines and other public health interventions that can diminish morbidity and mortality from diarrheal diseases. The first phase of the study warrants embarking on future studies looking at the rota virus effectiveness (after government implement this in their EPI), promotion of ORS and scaling up of Zn in reducing the morbidity and mortality in children. A low technology, low cost and acceptable water filtration technique is also high in the research agenda. The platform is also working on the nutritional front addressing the issue of nutritional faltering after an episode of diarrhoea.