Basic research the best weapon in the age-old malaria battle
The developing world needs a tool to distinguish falciparum from vivax cases
doi:10.1038/nindia.2018.53 Published online 30 April 2018
More than 100 countries have eliminated malaria in the past century, and 35 countries have joined the malaria-eliminating category. These countries have reduced their malaria burden by an impressive 90% from 1.6 million cases to 0.16 million, and cut death rates by 87%. The WHO has described various strategies for decreasing the global burden in terms of death and incidence by 90% by 20301. A strong surveillance system to identify and classify all foci of transmission, aggressive and timely intervention to block transmission, methods of characterizing high-risk migrant and mobile populations, early capture of drug and insecticide resistance, real-time response for diagnosis and treatment, regional cooperation and data sharing, advocacy for political1 and financial support have all been addressed2.
Malaria is a major problem in India. The country did have a major success through the National Malaria Eradication Programme (NMEP) which brought down malaria incidence of 75 million cases and death of 0.8 million cases in 1953 to 0.1 million cases and no death, respectively, in 1965. However due to technical, operational and financial complexities, incidence had shot up to 6.4 million cases in 1976.
Various programmes of intervention have brought this to a figure of 1.1 million cases and 562 deaths in 2014, although the death figures have been debated. Even if death rates are not considered as a major factor, the morbidity, loss of man hours and economic burden are considered very high, since the country is a target for both falciparum and vivax malaria. India also runs the risk of being a malaria-exporting country since neighbouring Sri Lanka has been malaria-free since 2012, and other nearby countries have malaria-eliminating status.
Malaria interventions are considered highly cost-effective, representing large returns on investment in public health. Therefore, in line with the WHO Global technical strategy 2016-2030, the Ministry of Health and Human Welfare, the government has delineated a strategy for malaria elimination in India. The approaches described are very similar to the strategies described by the WHO, as applied to Indian states falling in three categories representing low, moderate and high transmission rates.
Operational research must be an integral part of the Grand Challenges programme. There are many challenges, well described in the NFMEI document3. To quote a couple of examples, an aggressive intervention in high transmission areas of Odisha, Chattisgarh, Jharkhand, Madhya Pradesh, Maharashtra and the northeast states, which contribute to 70% of all the malaria cases in the country, is a priority. Intensification of control activities in forest, hilly, tribal and conflict-affected areas will be the challenge. Another example is to eliminate vivax malaria. India accounts for 80% of global vivax cases contributed by three countries. As the NFMEI document3 states: “The parasite can survive in cooler climates, is less responsive to conventional methods of vector control, is more difficult to detect using conventional diagnostic tools, treatment of liver stage parasites requires a 14-day course of primaquine which can produce some serious side-effects”.
The use of spurious drugs and artemisinin-based monotherapy have been described as contributing to drug resistance in the malaria origin centres in Southeast Asia4. Surveillance in this context in India is also essential.
“Bugs are smarter than scientists, and this human pathogen is as old as evolution."
There are many aspects that need to be addressed through basic lab research as well. In my opinion, the biggest threat is entry and spread of artemisinin resistance in the country, even as a combination therapy. Resistance to this most effective drug in the greater Mekong Subregion, which includes Cambodia, Laos, Myanmar, Vietnam and China’s Yunnan province4 is a real threat to the already-affected NE states and further spread. Slower clearance of parasites to Artesunate-SP (Sulfadoxine-Pyrimethamine), approved combination to treat falciparum cases in India, is already being reported. A policy is in place to introduce artesunate-lumefantrine combination. Our own studies in animal models have established the efficacy of artemisinin-curcumin combination, both in uncomplicated and Experimental Cerebral Malaria cases5, 6. This is a unique combination, where curcumin has been shown to act through activating host immune mechanism, despite low bioavailability and rapid metabolism. Curcumin can delay the onset of resistance to artemisinin. It would help significantly if this combination is taken through clinical trials at the earliest.
A bigger global challenge is to find a new antimalarial that is as effective as artemisinin. There are candidate molecules undergoing trials, but may not be ready in the next three years. The Grand Challenge has to give priority to study of vivax malaria. More virulent cases are being reported even in P. vivax infection, although chloroquine-based therapy seems to work. Thus, a diagnostic to distinguish between falciparum and vivax cases in the shortest time is needed. Most often, vivax detection is by ruling out falciparum infection. Mixed infection can pose major challenges. Imaging techniques for microscopy need to be upgraded.
Can we find an alternate to primaquine, that involves a 14-day treatment in vivax cases with side-effects? The main difficulty in studying P vivax is the inability to culture this parasite. Partial success for short-term culture has been reported, but the patient remains as the main source for the parasite. The emergence of simian parasites, P. knowlesi and P. cynamolgi as potential human parasites in the region needs to be studied carefully, although the reports may be considered as outlying cases at present. The vacuum created by the elimination of P. falciparum and P. vivax may provide an opportunity for the simian parasites to spread. Bugs are smarter than scientists and this human-pathogen conflict is as old as human evolution!
Most laboratories are carrying out studies with P. falciparum cultures to understand the pathology. These studies need to be taken through a translational mode. P. berghei infected mouse model is the most popular to carry out studies in vivo. It is important to create facilities to use humanized mouse models to study P. falciparum infection and even P. vivax infections as such. Very few laboratories in India study parasite development in the mosquito. Intervention in the sexual stages of parasite development is important in the transmission stage and crucial for malaria elimination.
Creation of more insectories to study malaria parasite development in the mosquito would be useful. While, P. berghei development in the mosquito can give important leads, P. falciparum development studies in the mosquito would need appropriate containment conditions.
I do not believe that an effective malaria vaccine will be available in the next decade, although the RTS,S vaccine may still be introduced in Africa with less than 40% efficacy. The sporozoite vaccine seems to have tantalizing success, but I do not know how it can be made available on a global scale even for falciparum cases. Perhaps, it will have limited application in specific geographical regions.
The best option seems to be quick and correct diagnosis, immediate appropriate drug therapy, vector control measures, strategies for intervention in the transmission stage and ‘Swachh Bharat’ initiatives.
I have already described the priority for basic research. More investments in these areas rather than in more ‘fashionable’ studies based on gene drives to eliminate mosquitoes are welcome. Gene Drive will have huge environment and regulatory issues in India, even if the several technical challenges are successfully addressed. I would like to see India as a malaria-eliminating country rather than as a malaria-controlling country. Malaria eradication is feasible, but not the mosquitoes.
The author is at the Department of Biochemistry, Indian Institute of Science, Bangalore, India.
1. World Health Organization. Global technical strategy for malaria 2016–2030. Geneva: WHO, 2015.
2. Newby, G.,et al. The path to eradication: a progress report on the malaria-eliminating countries. Lancet 387, 1775-1784 (2016).
3. Directorate of National Vector Borne Diseases Control Programme (NVBDCP) and Directorate General of Health Services (DGHS). National framework for malaria elimination in India (2016- 2030) (NFEMI). Ministry of Health and Family Welfare. Government of India. 2016.
4. Roberts, L. Malaria Wars. Science 352, 398-405 (2016)
5. Vathsala, P. G. et al. Curcumin-arteether combination therapy of Plasmodium berghei-infected mice prevents recrudescence through immunomodulation. PLoS One 7, e29442 (2012)
6. Dende, C. et al . Simultaneously targeting inflammatory response and parasite sequestration in brain to treat Experimental Cerebral Malaria. Sci. Rep. 3, e 12671 (2015)
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