From potential new treatment targets, to vaccine development, to genetic surveillance, researchers are transforming their discoveries from laboratories to the people and places that need them most. This World Malaria Day we look at three ambitious projects, backed by the Sanger Institute Technology Transfer Office, which are tackling areas key to eliminating malaria.
A global health concern
Today, most people associate malaria with tropical climates and poorer countries, but it used to affect people on every continent, except Antarctica. During the American Civil War in the mid-19th century, over one million soldiers may have contracted the disease; 10,000 of whom probably died from it. It was not until the end of WWII that concerted public health measures made remarkable progress toward ridding many countries of the malaria-causing parasites and the mosquitoes that harbour them. The use of insecticides and other measures to control mosquito populations, in combination with anti-malarial drugs, virtually eliminated malaria from more affluent regions of the globe by the 1970s. These measures have also significantly decreased infection and mortality rates in other areas of the world. In that respect, one could certainly see the fall in global malaria deaths from 839,000 people to 438,000 people between 2000 and 2015 as a global health success story. Still, malaria remains endemic in most of the tropical and subtropical regions of the world; these include sub-Saharan Africa, India, South-East Asia, and South America. Unsurprisingly, the disease disproportionately affects poor and vulnerable populations. In regions where transmission remains high, it often remains the leading cause of illness and death. In 2017, approximately 219 million people contracted the disease; of 435,000 that died, 90 per cent lived in Africa and over 60 per cent were children under the age of five.
Challenges in the road ahead
In 2015, the World Health Organisation (WHO) set an ambitious, but achievable global target of reducing malaria incidence and mortality rates by 90 per cent by 2030. The world already has many of the tools it needs, but several factors threaten progress toward this goal. Social and environmental obstacles such as increasing population density, poor access to medical care in regions of conflict, and climate change could significantly worsen infection rates and mortality. In addition, a large gap exists between the money needed to meet these targets and the funds actually received; the WHO estimated that investment in malaria control efforts totalled US $2.7 billion in 2016 - well short of the US $6.5 billion required. As a disease that generally afflicts poor populations, malaria does not attract large levels of investment from most major pharmaceutical firms. Medical personnel and researchers battling the disease rely on limited funding from governments and charitable organisations, such as the Bill and Melinda Gates Foundation and Wellcome. The final hurdle to overcome is resistance; mosquitoes have started to develop resistance to the commonly used insecticides, and the disease-causing parasites they carry also show growing resistance to current front-line anti-malarial drugs.
The malaria life cycle - how it evades treatment
Frustratingly, the malaria parasites often stay undetected for most of their complicated life cycle, divide rapidly before causing any symptoms, and spread through their host, reproducing very quickly. This creates many opportunities for the parasite to develop resistance. Any genetic mutation that allows a mosquito or parasite to survive insecticide or drug treatment, respectively, passes onto the next generation, over and over, until most of the surviving population also becomes resistant.
Female mosquitoes that carry malaria parasites can lay over 500 eggs before dying; their life cycle is just 8 – 10 days. The parasites themselves mate and sexually reproduce in female mosquitoes. These female mosquitoes can then infect humans by biting them and transmitting the parasites. Once inside the bloodstream, the parasites travel to the liver where they multiply relatively slowly without causing any symptoms. When they eventually leave the liver to infect red blood cells, they divide much more rapidly killing the cells in the process. If untreated, the number of parasites will eventually increase to be in the billions or trillions. This cycle wreaks havoc and infected individuals finally show symptoms of malaria such as a high temperature, muscle pains, diarrhoea, vomiting, headaches and feeling shivery.
The world needs better tools
Currently, most anti-malarial drugs only work on the parasite once it starts destroying red blood cells. By this time, individuals are already quite sick. Healthcare workers and others could provide medication earlier to stop infections from taking hold, but this requires them to identify the populations that face the greatest risk so that they can target treatment – not always an easy task in areas with poor access to medical treatment.
To boost current efforts to battle malaria, the world will need new tools: vaccines that prevent transmission, new drugs that can target the disease in the liver before it destroys blood cells, and investment in systems that makes existing tools more effective and economical.
Sanger projects that could tackle malaria on a global scale
The ethos at the Sanger Institute rightly demands that infectious diseases disproportionately afflicting lower- and middle-income countries receive equal attention and resource to the diseases of affluence such as cancer and type 2 diabetes. Recent research in the field of malaria highlights this commitment, and also the importance of funding the translation of academic science into viable tools that will make a difference on the ground.
Discoveries made in the lab, however exciting, usually need further development before they will attract enough funding for improvement and deployment at the scale needed to effect meaningful change. Between 2012 and 2017, the Sanger Institute Technology Transfer Office backed three ambitious projects tackling areas key to eliminating malaria.
New targets for anti-malarial drugs
Finding a way to kill malaria parasites before they leave the liver would prevent infected individuals from falling ill. In addition, because the number of parasites are rising, but still relatively low in the liver, it has less opportunity to evolve resistance to any potential drugs. Despite these obvious advantages, developing these anti-malarial drugs is difficult due to a lack of model systems, such as mice, to genetically identify drug targets for the liver stage of the parasite.
In 2015, Oliver Bilker, and his team at Sanger published exciting work describing a technique to genetically identify the targets of drugs in parasites in the blood. Being able to identify a drug’s target provides valuable insights into other compounds that might work, other areas of vulnerability, and potential mechanisms of resistance. The discovery had obvious applications in the discovery of new drug targets for malaria, especially if the system could be applied to parasites in the liver stage. Realising this value, the Sanger funded a successful project that further developed the technique to genetically identify targets in the liver stage. The researchers, including Marcus Lee’s team at Sanger, now have a collaboration with Tres Cantos to use this technology to find potential new drugs to treat malaria.
Developing cost-effective vaccines
While improving medication to treat malaria remains an important global health priority, an effective vaccine could significantly lower infection rates and prevent further transmission. Despite many efforts over several decades, researchers have failed to find a good subunit vaccine target against the family of parasites that cause malaria. Targeting the blood stages of the parasite which recognise and invade red blood cells has long been considered an attractive target because, albeit briefly, the parasite is directly exposed to circulating host antibodies; however, the parasite was able to use many different proteins to invade which act redundantly, making it difficult to make a vaccine that could interfere with them all.
In 2011, teams led by Gavin Wright and Julian Rayner at the Sanger identified a protein known as RH5 which interacted with a red blood cell receptor called basigin and this interaction was shown to be very important for all different strains of parasites for invasion.
“The discovery that the interaction between RH5 and basigin was both essential and universally required by all tested strains of parasite for invasion was a step-change for the field,” explains Wright. Unlike most other targetable parasite proteins involved in invasion, RH5 showed remarkably little variation across all strains of Plasmodium falciparum (the most lethal of the malaria parasite species) making it an excellent vaccine target.
On the back of these results, the Sanger Institute helped set up a collaborative relationship with the Jenner Institute early on to accelerate vaccine development. The Institute also funded a translation project focused on identifying a fragment of the RH5 protein that could still effectively elicit an immune response and yet be cost effective to produce. In theory, vaccine manufacturers could produce a protein fragment much more cheaply than the entire protein - key for a disease primarily affecting the poor.
While results from this project did not produce a protein with the desired activity, current clinical trials testing a vaccine developed by the Jenner Institute using the full-length pfRH5 protein have shown promising results thus far. Pharmaceutical companies will inevitably need to make further improvements to this vaccine and any documented knowledge of what doesn’t work will save time, effort, and money.
Global tracking and disease surveillance
Alongside research focused on targeting vulnerabilities in the infection cycle, Dominic Kwiatkowski’s group at Sanger focuses on developing cutting edge genetic and computational tools to track evolutionary changes in mosquitoes and the malaria parasites, in a project called MalariaGEN. Evolutionary change and adaptation allow the disease to develop resistance to current treatments; understanding how this occurs and doing it quickly will allow more effective management of the disease and provide ways to limit the spread of drug resistant parasites. In 2008, reports emerged from the Mekong Delta that P. falciparum, had started responding much more slowly to front-line treatment involving two drugs combined: DHA-PPQ (dihydroartemisinin and piperaquine). However, today over 50 per cent of the parasites in the region have acquired resistance to these drugs. Worryingly, until 2013 this resistance had spread under the radar and continued use of DHA-PPQ likely hastened this process.
Recognising the need for effective and accessible surveillance tools, the Sanger funded a 12-month project with the aim to test blood samples and detect genetic markers of drug resistance in the parasites, by genotyping. Previous research had shown this could be done using expensive, whole genome sequencing data from large sample volumes. This work defined approximately 100 key spots in the genome, known as single nucleotide polymorphisms (SNPs), that helped identify drug resistant strains of malaria.
The core of the project revolved around detecting resistance quickly and cheaply. Instead of large samples, the team used SNP-genotyping data generated from blood spots on filter paper. This project was completed successfully and the SpotMalaria Project which operates in several malaria hotspots, including the Mekong Delta, now uses the technology to monitor drug resistance.
Facing global health challenges requires effective translation of research
These projects illustrate the potentially huge benefits of encouraging translational research, which moves and applies findings from the lab to a real-world setting.
If we want to beat malaria and other diseases with high unmet need, we need excellent, cutting edge science and the willingness to spend additional resource on developing useful, cost-effective, and scalable technology from those discoveries. Academia is a competitive and fast-moving field that doesn’t always have the time, or support, to embrace the translation of research. The Sanger Institute, however, is dedicated to both research and its applications, and will continue to support ambitious projects with the potential to revolutionise healthcare globally. For more information about our work and our collaborators, go to: www.sanger.ac.uk/innovations or get in touch: translationoffice@sanger.ac.uk
