Award Title: NIHR Global Health Research Group on genomic surveillance of malaria in West Africa at the Wellcome Trust Sanger Institute.
Funder: Department of Health and Social Care

Abstract: DRUG AND INSECTICIDE RESISTANCE ARE ROADBLOCKS TO SUSTAINABLE MALARIA_x000D_
CONTROL IN AFRICA_x000D_
Malaria is a major cause of childhood mortality and socioeconomic disruption in Africa. Malaria_x000D_
control efforts have been ramped up over the past 15 years and this has made a significant impact,_x000D_
e.g. it has halved the number of deaths due to malaria. However there is a serious risk that these_x000D_
gains could be reversed in the foreseeable future, because Plasmodium parasites (that cause_x000D_
malaria) and Anopheles mosquitoes (that transmit the parasites from one person to another) are_x000D_
becoming increasingly resistant to malaria control interventions. In West Africa, the most immediate_x000D_
concern is the rise in Anopheles resistance to the insecticides that are used to treat bednets and to_x000D_
spray the insides of houses, which are absolutely crucial for sustainable malaria control in this region._x000D_
There is also worldwide concern about a new form of Plasmodium resistance to the first line_x000D_
antimalarial drug (artemisinin combination therapy or ACT) that is rapidly speading across Southeast_x000D_
Asia, and while there is no evidence that this has yet spread to West Africa, it is an incipient threat_x000D_
particularly in northern parts of the region where the ecological conditions are ripe for resistance to_x000D_
take root._x000D_
WHY WE NEED TO START PUTTING IN PLACE MODERN GENOMIC SURVEILLANCE SYSTEMS_x000D_
It is essential that national malaria control programmes (NMCPs) have effective tools to monitor_x000D_
resistance, both to know what are the best drugs and insecticides to use, and also to provide early_x000D_
warning that their interventions are causing resistance to rise to dangerous levels, indicating the need_x000D_
for a change in strategy. However current methods of monitoring drug and insecticide resistance are_x000D_
cumbersome, time consuming and not always accurate. Over the past few years there have been_x000D_
major technical advances in genome sequencing as a surveillance tool for antimicrobial resistance in_x000D_
other infectious diseases, and this is rapidly becoming the standard method used in UK public health_x000D_
labs. There are many technical challenges in getting this to work for malaria parasites and_x000D_
mosquitoes, but we now have proof of concept in our UK research lab and it is time to start putting_x000D_
these systems in place in Africa._x000D_
WHAT WE AIM TO ACHIEVE WITH THIS FUNDING_x000D_
We will establish laboratory and computational systems for genomic surveillance of malaria at the_x000D_
University of Ghana in Accra and the MRC Unit in The Gambia. These two sites have been selected_x000D_
because of their excellent laboratory infrastructure, their critical mass of scientific expertise, their_x000D_
strong links with NMCPs, and the many different challenges for malaria control in the two locations._x000D_
Once the technical systems are in place, we will work with local partners to optimise the pipeline for_x000D_
reliability, scalability and cost-effectiveness, and to learn how to integrate it most effectively into_x000D_
NMCP operations. We aim to learn how to translate genomic data into actionable knowledge, e.g. by_x000D_
providing early warning of newly emerging resistance, and by showing how specific interventions are_x000D_
causing levels of resistance to rise or fall. By the end of this project, we aim to have sufficient proof of_x000D_
concept to start integrating these systems into the routine working practices of NMCPs in Ghana and_x000D_
The Gambia, and to provide a working example of how such systems could be deployed at other_x000D_
locations in Africa.

Lay Abstract: BACKGROUND OF STRATEGIC INVESTMENT_x000D_
The Sanger Institute has played a pioneering role in genome research on infectious pathogens. One_x000D_
of the first genomes to be sequenced at Sanger was the malaria parasite Plasmodium falciparum, and_x000D_
in 2006 the Institute committed to a major programme of basic research on malaria, with the long term_x000D_
goal of translating this into new tools to control and eliminate the disease. Our 2016-21 quinquennial_x000D_
plan comprises five major scientific programmes in Cancer, Malaria, Infection Genomics, Human_x000D_
Genetics and Cellular Genetics. Sanger researchers have made seminal discoveries about how_x000D_
parasites invade human red blood cells, genetic resistance to malaria in African children, Plasmodium_x000D_
drug resistance, Anopheles insecticide resistance and other fundamental parasite biology. Sanger_x000D_
has also made an impact on malaria research worldwide through the large data resources and novel_x000D_
technologies that it has developed and made openly available to the research community._x000D_
From its inception, the Sanger Malaria Programme has worked in close collaboration with research_x000D_
groups in developing countries. Together with the MRC Centre for Genomics and Global Health at_x000D_
Oxford University, it serves as the resource centre for MalariaGEN, a data-sharing network of malaria_x000D_
researchers in more than 35 malaria-endemic countries (www.malariagen.net). Over the past 12_x000D_
years, MalariaGEN has established an international reputation for generating large open access_x000D_
datasets, which have become the benchmark for Plasmodium and Anopheles population genomics;_x000D_
for promoting equitable data sharing between researchers in rich and poor countries; and for research_x000D_
capacity building in malaria endemic countries._x000D_
STRATEGIC CASE FOR DECENTRALISATION_x000D_
This proposal represents a major shift in the way that we work with our collaborators in malaria_x000D_
endemic countries. When we started out on genome sequencing of Plasmodium parasites and_x000D_
Anopheles mosquitoes from field samples, there were massive technical and computational_x000D_
challenges to overcome, and both we and our collaborators saw it primarily as basic rather than_x000D_
applied research. It also required expensive capital equipment and infrastructure, and it made_x000D_
practical sense for the genome sequencing to be done at Sanger. There has been remarkable_x000D_
progress in all of these areas over the past few years, and it now makes both the economic and the_x000D_
technical for the genome sequencing done to be locally._x000D_
The case for decentralisation is in large measure a successful consequence of our past strategic_x000D_
investment. Having put in place the scientific foundations and developed much of the underlying_x000D_
technology required for genomic surveillance of malaria, we are now in a good position to translate_x000D_
this into practical tools and procedures that will help national malaria control programmes (NMCPs) to_x000D_
achieve their objectives. Making the transition from centralised to local genome sequencing is not just_x000D_
a matter of installing the equipment and training local staff, because genomic surveillance is one of_x000D_
the most rapidly growing areas of 'Big Data', i.e. the data generated by a local sequencing machine is_x000D_
greatly amplified in information content and practical value if it is part of a global data sharing network._x000D_
For example, if a new form of parasite drug resistance or mosquito insecticide resistance emerges_x000D_
elsewhere in the world, it will greatly help an NMCP to monitor and manage the problem if the_x000D_
genomic analysis software is continually updated to incorporate the most useful genetic markers,_x000D_
which are likely to have been discovered elsewhere. Therefore, as well as installing the equipment_x000D_
and providing training, it is crucial to build local leadership in the new science of genomic_x000D_
epidemiology, combined with mechanisms of sharing data across different sequencing labs. It_x000D_
requires the development of informatic systems to share data, and also the development policies and_x000D_
guidelines for international data-sharing that are acceptable to all stakeholders._x000D_
Through our work in coordinating MalariaGEN, we have considerable experience and track record in_x000D_
working with a wide range of local partners, but the transition from centralised to local genome_x000D_
sequencing is a game-changer. It will involve a learning process on both sides, i.e. we need to get a_x000D_
deeper and more detailed understanding of the practical problems confronting NMCPs, and NMCPs_x000D_
need to know about what new genetic approaches can potentially offer, so that we can work together_x000D_
to develop surveillance tools that will be useful and effective in the real world._x000D_
CHOICE OF LOCATIONS TO DO THIS PILOT WORK_x000D_
One of the strategic questions that we considered in formulating this proposal was how many partner_x000D_
labs to involve and where they should be located. Since we are actively collaborating with labs in_x000D_
many different countries on the ODA list there were multiple options. In view of the budget we decided_x000D_
to restrict it to two labs, as we think that a budget of ~£700k over 3 years is the minimum that will be_x000D_
required to get things up and running effectively and sustainably at a single location. Thus 70% of the_x000D_
£2m budget request will go to two labs in different malaria endemic countries. It should be noted that_x000D_
the ~£500k requested for work at Sanger will be used primarily for project management, training,_x000D_
informatic support and operational support; this will be underpinned by a substantial amount of R&D_x000D_
work to be undertaken by Sanger using its core funding from the Wellcome Trust._x000D_
The selection of Ghana and The Gambia as the two pilot sites was based on the following_x000D_
considerations._x000D_
1. Developing two labs in different parts of the same region will help to build critical mass and regional_x000D_
cooperation._x000D_
2. It will allow us to optimise surveillance tools for different malaria control use cases in a range of_x000D_
epidemiological settings, from holoendemic to near-elimination. Many parts of West Africa have_x000D_
extremely high malaria transmission, e.g. at our Navrongo partner site in northern Ghana, but there_x000D_
are also parts that now have very low transmission, e.g. in the coastal regions of The Gambia and_x000D_
northern Senegal._x000D_
3. West Africa has rising levels of insecticide resistance, which have the potential to disrupt vector_x000D_
control. Resistance to artemisinin and partner drugs is currently not a problem but there is a real risk_x000D_
that it could emerge due to high levels of selective pressure at the fringes of transmission in north of_x000D_
the region._x000D_
4. The University of Ghana and MRC Gambia both have excellent laboratory infrastructure, with_x000D_
suitable genome sequencing equipment (Illumina MiSeq) already in place. This will enable us both to_x000D_
benefit from and contribute to local know-how, and to get up and running as quickly as possible._x000D_
5. The project will have outstanding local leadership and institutional support at both locations. At the_x000D_
Institutional level, Profs. Awandare and d'Alessandro are both renowned malaria experts. The two_x000D_
local project leads, Drs. Amambua Ngwa and Amenga-Etego, are among the most technically_x000D_
accomplished African researchers working in the field of malaria population genetics, with significant_x000D_
experience in epidemiological, laboratory and analytical aspects of proposed work._x000D_
6. Once we have established proof of concept for genomic surveillance at these two locations, there is_x000D_
great potential to disseminate expertise and know-how to other labs through regional and Africa-wide_x000D_
capacity building networks: WACCBIP led by Prof. Awandare; PAMGEN led by Drs. Amambua Ngwa_x000D_
and Amenga-Etego; and DELGEME led by our close colleague Prof. Abdoulaye Djimde in Mali._x000D_
7. The strong engagement of NMCPs is critical for the success of this project, and both in Ghana and_x000D_
The Gambia this project will build on strong foundation of NMCP partnership, and a great deal of local_x000D_
enthusiasm for the work proposed.

Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.1 PHARMACEUTICALS
Health Categories: INFECTION