Malaria parasites invade red blood cells where they replicate many times, before bursting out into the bloodstream to repeat the process. It’s this cycle and build-up of infected red blood cells which causes the symptoms and sometimes fatal effects of the disease. While drugs and mosquito control have reduced levels of malaria over recent decades, the parasite still kills over 600,000 people every year, infecting least 1,5 millions. Worryingly, it has now developed resistance to many existing antimalarial drugs, meaning new treatments that work in different ways are urgently needed. Researchers at the Francis Crick Institute and the Latvian Institute of Organic Synthesis have designed a drug-like compound which effectively blocks a critical step in the malaria parasite life cycle and are working to develop this compound into a potential first of its kind malaria treatment. In their research, the scientists developed a set of compounds designed to stop the parasite being able to burst out of red blood cells, a process vital to its replication and life cycle.
They found one compound in particular was highly effective in human cell tests. The compound, called a peptido-mimetic (similar to a chain of aminoacids) works by blocking an enzyme called protease SUB1, which is critical for malaria to burst out of red blood cells. Existing antimalarials work by killing the parasite within the cell, but even with the most recent advances and molecular discovery, the parasite find its own way to counteract the drug. So the researchers led by Dr. Mike Blackman, of the group leader of the Malaria Biochemistry Laboratory, Francis Crick Institute, hope this alternative drug action will overcome the resistance the parasite has acquired. Importantly the compound is also able to pass through the membranes of the red blood cell and of the compartment within the cell where the parasites reside. The team is continuing to optimize the compound, making it smaller and more potent. If successful, it will need to be tested in further experiments and in animal and human trials to show it is safe and effective, before being made available to people.
But it is not the only way scientists are trying to fight this old pandemic nobody talks about. Immunology is another active field. A malaria vaccine candidate tested on children in West Africa has shown an efficacy of around 77% hailing it as a breakthrough in the fight against the disease. The R21/Matrix-M vaccine, developed by the Clinical Research Unit of Nanoro (CRUN), Burkina Faso and their partners at the University of Oxford in the UK, is the first malaria vaccine to reach the 75% efficacy target set by the WHO. Researchers recruited 450 children aged five to 17 months in the area of Nanoro, central Burkina Faso, and divided them into three groups for the Phase IIb trial. One group of 150 received the vaccine with a low dose of the Matrix-M adjuvant, which helps create a stronger immune response. Another group of 150 received the vaccine at a higher dose of adjuvant, while the last group of 150 received the rabies vaccine as a control vaccine. The subjects in the study reported no serious side effects from the vaccine, which was found to be safe and can be manufactured at low cost on a large scale.
Despite more than 100 vaccine candidates entering clinical trials in recent decades, none have previously reached the target of 75% efficacy which the WHO set as a target to be achieved by 2030. The Serum Institute of India, which has manufactured the vaccine, says it will be able to deliver more than 200 million doses of the vaccine once it is approved by regulators. Last year the country recorded more than 11 million cases of malaria and almost 4,000 malaria-related deaths, including pregnant women and children, official figures show. A larger Phase III trial will now be conducted involving 4,800 children aged five to three years in four countries. In Burkina Faso, children will be recruited for the next phase in Nanoro and Dande, in the south-west of the country from next month. Researchers hope that by testing the vaccine in different contexts on a larger number of children, its efficacy will be confirmed and the vaccine can be considered for registration.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry
Lidumniece E et al. PNAS USA 2021; 118(20):e2022696118.
Datoo MS et a. Lancet. 2021 May 15; 397(10287):1809-1818.
Yang F, Liu F et al. Parasit Vectors. 2021 May 7; 14(1):241.