Malaria remains one of the top killer diseases across the world accounting for around 200 million cases and half a million deaths primarily among young children, infants and pregnant women residing in some of the most impoverished countries of the world. Unfortunately, India is still endemic to this deadly disease that has plagued the human race for many centuries. The war against malaria has been fought on several fronts and while there have been some very useful advancement in terms of developing novel malaria intervention strategies, it is crucial to continue these efforts with great vigour in order to counteract the different species of the highly complex malaria pathogen, Plasmodium.
Malaria vaccine effort
One of the biggest success stories has been the DBT funded efforts of the ICGEB Malaria group to develop recombinant blood-stage experimental vaccine (JAIVAC-1) and conduct a Phase I human clinical trial. JAIVAC-1 was the first ever malaria vaccine trial against Plasmodium falciparum in India with a recombinant molecule produced in an Indian laboratory (Chitnis 2015 PLOS One). It was funded jointly by DBT and the European Vaccine Initiative. JAIVAC-1 was the culmination a strong public-private partnership between ICGEB and Bharat Biotech, a Hyderabad based Biotech company that has developed vaccines against several disease including the recent Rotavac that has come through the support of DBT. Human malaria is caused by both P. falciparum and P. vivax, and ICGEB has also developed a sub-unit recombinant vaccine (PvDBPII) against P. vivax malaria that is also being taken forward for clinical evaluation in a Phase I trial.
Importantly, DBT was quick to recognise that vaccine development steps beyond the bench require an expertise that is lacking in academically oriented scientists and thus DBT in partnership with the Bill & Melinda Gates Foundation created a separate entity with translational expertise known as the Malaria Vaccine Development Program (MVDP). ICGEB and MVDP have partnered in conducting the JAIVAC-1 trial and are further in the process of developing an advanced vaccine, JAIVAC-2 against P. falciparum as well as the PvDBPII vaccine against P. vivax.
In a recent highly noted effort supported by DBT, scientists at ICGEB and the School of Biotechnology, JNU have discovered a novel multi-protein adhesion complex, which is essential for the malaria parasite P. falciparum to invade human erythrocytes (Reddy 2015PNAS; Du Toit 2015 Nature Reviews Microbiology). This complex presents the essential PfRH5 parasite ligand to its red cell receptor and is anchored by another protein, CyRPA that is associated with the parasite surface. Abrogation of this key protein complex has been demonstrated to neutralize the parasite, which provides a paradigm shift in the mechanism of action of parasite neutralising antibodies that instead of inhibiting ligand-receptor interactions are impeding key protein-protein interactions between parasite molecules (PNAS 2015). This discovery has laid the foundation for the development of a new generation blood-stage candidate vaccine targeting PfRH5 and CyRPA.
Curcumin as anti-malarial
Another translational malaria project being supported by DBT is the development of curcumin as an antimalarial. Studies in the Indian Institute of Science have shown that curcumin synergizes with ART as an antimalarial to potently kill the parasite as well as primes the immune system to protect against parasite recrudescence (Padmanaban 2012 Curr. Science). The results indicate a potential for the novel use of ART–curcumin combination against recrudescence/relapse in falciparum and vivax malaria. In addition, studies have also suggested the use of curcumin as an adjunct therapy against cerebral malaria. Steps for the further clinical evaluation of the ART-curcumin combinations with DBT support are being undertaken.
It is expected that a simple therapeutic option with the use of arteether/curcumin (nanocurcumin) and/or Artemisia annua whole leaf powder/curcumin (or turmeric powder) may emerge out of these studies in the animal model.
In one more project supported under the COE scheme on understanding blood stage growth of malarial parasites, significant strides have been achieved by ICGEB, New Delhi. A combination of three blood stage parasite proteins has been taken up for development of a novel vaccine candidate against malaria. Further, signaling mechanisms have been defined that trigger the egress of mature merozoites from mature schizonts and the timely release of parasite ligands from apical organelles enabling receptor engagement during invasion of host erythrocytes.
In a research study supported jointly at C. Abdul Hakeem College, Malvisharam, ICGEB, New Delhi and Vellore Institute of Technology University, Vellore under the “Expert Group on Translational Research for Products and Processes from Medicinal and Aromatic Plants” various medicinal plants were explored for antimalarial compounds. Crude extracts of leaves of Phyllanthus acidus and Phyllanthus emblica showed significant antiplasmodial potency and the extracts are being characterized and standardized for bioactive constituents.
DBT supports human resource excellence
DBT’s support has produced a critical mass of Indian scientists involved in malaria research and some significant contributions in our basic understanding of parasite biology. Some notable achievements include the discovery of heme biosynthesis in the parasite that is essential for its liver and mosquito stages (Nagraj 2013, PLOS Path.). Extensive research on the erythrocyte invasion process has highlighted the significance of the Merozoite surface proteins, MSP-1, MSP-3 (Mazumdar 2010 Infect. Immun; Imam 2014 J. Biol. Chem.) and the Reticulocyte binding-like homologous (PfRH) proteins (Sahar 2011 PLOS One; Reddy 2014 Infect. Immun.). The parasite signalling pathways responsible for its egress from the infected red cell and subsequent invasion into naïve red cells have been elucidated (Sharma & Chitnis 2013 Curr. Opin. Micro.). An enzyme, enolase has been shown to be also localised on the surface of the ookinete, the mosquito stage of the parasite (Mukherjee 2015 Insect Biochem. Mol. Biol.) and is thus being considered as an attractive transmission blocking target antigen.
Early success against malaria came in the late-1940s and early-1950s with the advent of insecticide spraying for vector control and discovery of drugs like chloroquine for malaria treatment. These developments laid the basis for the first eradication programme conceived in the mid-1950s. Consequently, malaria was successfully eliminated from much of the developed world as well as parts of Asia including India with the exception of sub-Saharan Africa. However this triumph led to a false sense of eradication that led to reduced attention to malaria control programs and resulted in re-emergence of the disease in a more aggressive form. It thus became very clear that serious malaria control leading to eradication would entail sustained development of novel diagnostic tools, more effective drugs and insecticides. In this regard, the increased use of insecticide treated bed nets (ITNs) and administration of the wonder drug “Artemisinin” have led to a steady decline in malaria mortality during the past decade. The discovery of Artemisinin was recognised in the award of the Nobel Prize for Medicine in 2015 to the Chinese chemist Youyou Tu. However, the emergence of early resistance to artemisinin within a relatively short time frame inspite of it being administered in the form of artemisinin based combination therapies (ACTs) has cast a shadow on the future efficacy of the artemisinin based therapies and warrants efforts to develop novel antimalarials that are more effective than the current ACTs.
It has been widely believed that an efficacious vaccine against malaria will be a major tool or weapon in combating the disease. However, several obstacles that have thwarted its development have hindered the process of developing an efficacious malaria vaccine. Infact, there is no successful vaccine available against any parasitic pathogen substantiating the complexity of these organisms and their ability to modulate human immunity. However, there have been several highly promising advancements in the recent past that provide hope for the development of a successful malaria vaccine. The most advanced malaria vaccine, RTSS that targets the liver stage of the parasite life cycle has been developed through a three decade old association between the Walter Reed Army Institute of Research (WRAIR, US military) and Glaxo Smith Kline (GSK). The recent Phase III results have shown that the vaccine elicits a maximum protective efficacy of 50% against clinical malaria in young children (RTS,S Clinical Trials Partnership 2015 Lancet). While, this is clearly not sufficient, the RTSS vaccine still does have the potential to save lives in Africa, which carries most of the burden of global malaria mortality. In addition, it does serve as a platform to further build upon and produce a vaccine with the higher optimal efficacy. The fact that individuals residing in malaria endemic regions develop natural immunity against the disease does suggest that it should be possible to develop malaria vaccines that mimic natural immunity. However, the challenge remains for us to advance our understanding of malaria immunity and identify the correlates of protective immunity. In parallel to RTSS, there have several efforts to characterize novel target antigens at all three stages (liver, blood and mosquito) of the parasite’s complex life cycle and evaluate their vaccine potential in human clinical trials. Recently, a whole organism approach based vaccine, PfSpz, comprising of sporozoites attenuated by irradiation have shown remarkable efficacy in naïve human volunteers and is being taken forward for field efficacy trials (Hoffman 2015 Am. J. Prev. Med.).
India has been at the centre of malaria research as the landmark discovery of Sir Ronald Ross in 1897 describing the whole sexual cycle of Plasmodium through the Culex mosquito was made during his posting in India. Malaria research in India has been funded primarily by the Indian government agencies, the Department of Biotechnology (DBT) and the Indian Council of Medical Research (ICMR). ICMR has developed a network of malaria field stations across the countries to study malaria epidemiology and vector biology. DBT has provided special attention to basic R&D that has improved our understanding of the parasite biology as well as on translational research aiming to develop novel antimalarials and vaccines.
Inspite of this optimism, we need to take bigger strides towards understanding the complexity of the Plasmodium pathogen and finally producing tools for successful intervention of the disease. The war against Malaria is a long drawn one comprising of several battles that have still yet to be won. In this regard, the support of DBT in this endeavour is highly appreciated and remains essential for our country to overcome this debilitating disease.
With inputs from :
Deepak Gaur, JNU; Jyoti Logani; Kalaivani Ganeshan and Alpana Saha
Photo sources from:
Dr Pawan Malhotra, ICGEB.