Translating Basic Research towards the Development of Novel Malaria Vaccines & Drugs
- Dr Deepak Gaur -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 significant advancement in terms of developing novel malaria intervention strategies, it is crucial to continue these efforts with great vigor in order to counteract the different species of the highly complex malaria pathogen, Plasmodium. Malaria control strategies have primarily involved the use of insecticide treated bed nets (ITNs), indoor residual spraying and therapy with anti-malarials such as chloroquine, artemisinin, which have led to a steady decline in malaria mortality during the past decade. The discovery of Artemisinin was recognized in the award of the Nobel Prize for Medicine in 2015 to the Chinese chemist Youyou Tu. However, the continuous development of drug resistance by the parasite and insecticide resistance by the mosquito vector has proved to be a major challenge in achieving malaria elimination. It has been widely believed that an efficacious vaccine against malaria will be a major public health tool in combating the disease. However, the process of developing an efficacious malaria vaccine has been hindered by several obstacles that have thwarted its development. In fact, there is no successful vaccine available against any parasitic pathogen substantiating the complexity of these organisms and their ability to modulate human immunity. While, a successful malaria vaccine remains a big challenge, 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,SClinical 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. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive scientific opinion for RTS,S (July 2015). The World Health Organization (WHO) has issued a position paper for RTS,S (also knownas MosquirixTM)in which it recommends large-scale pilot implementations of RTS,S. Importantly, recent clinical trials with fractionalization of RTSS dosage has increased its efficacy to 80%, which is highly encouraging (Regules, JID 2016).RTS,S does serve as a significant 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 anti-malarials and vaccines. One of the biggest success stories has been 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 recombinant molecules 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. Another vaccine formaulation against P. falciparum, JAIVAC-2 has been developed by ICGEB along with Zydus Cadlia that is being taken forward for a Phase I trial. 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 has also been clinically evaluated in a Phase I trial. Importantly, DBT was quick to recognize that vaccine development steps beyond the bench requires 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 and PvDBPII trials. In a recent highly noted effort supported by DBT, scientists at the School of Biotechnology (SBT), JNU and ICGEB have discovered a novel multi-protein adhesion complex which is essential for the malaria parasite P. falciparum to invade human erythrocytes (Reddy 2015 PNAS; Du Toit 2015 Nature Reviews Microbiology). This complex comprises of three proteins (RH5, CyRPA, and Ripr) and facilitates the interaction between the essential PfRH5 parasite ligand to its red cell receptor, Basigin. 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 neutralizing antibodies that instead of inhibiting ligand-receptor interactions are impeding key protein-protein interactions between parasite molecules (Reddy 2015 PNAS). This discovery has laid the foundation for the development of a new generation blood-stage candidate vaccine, JAIVAC-3targeting PfRH5 and CyRPA, which is being spearheaded by SBT, JNU with DBT support through their vaccine Grand Challenge Program. DBT initiated a strong collaborative program between basic and clinical researchers known as GLUE through which JNU, ICGEB and an ICMR institute, NIRTH Jabalpur undertook a partnership aimed at studying Plasmodium vivax malaria in Central India. The collaboration identified the functional domains of P. vivax RBP proteins involved in specific host cell (reticulocyte) invasion and demonstrated that naturally acquired human antibodies against the PvRBP proteins were functionally binding-inhibitory, thus substantiating their promise as key vaccine candidates against P. vivax (Gupta 2017 JID). 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). Further, nanocurcumin has been shown to be superior to native curcumin in preventing degenerative changes in experimental cerebral malaria (Dende 2017 Sci Rep). 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. In yet another significant project funded by DBT through their nanobiotechnology program, scientists at Jawaharlal Nehru University (Special Centre for Molecular Medicine and School of Biotechnology) and National Institute of Immunology (NII) are working on producing nanoparticle based formulations of the drug acriflavin and targeting it to the parasite through specific antibodies. JNU has a US patent for the antiparasitic activity of Acriflavine (Dana et al. ACS Chem Biol. 2014), which it wishes to harness in the development of a novel and highly efficacious antimalarial drug. 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 that have been undertaken by leading institutions and universities across India. In spite 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 endeavor is highly appreciated and remains essential for our country to overcome this debilitating disease. Rapid fire: 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 Another vaccine formulation against P. falciparum, JAIVAC-2 has been developed by ICGEB along with Zydus Cadlia Through DBT support, SBT, JNU and ICGEB have discovered a novel multi-protein adhesion complex, which is essential for the malaria parasite P. falciparum to invade human erythrocytes This complex comprises of three proteins (RH5, CyRPA, Ripr), which form the basis of the new generation candidate vaccine , JAIVAC-3 Development of curcumin as an antimalarial supported by DBT. In another DBT project. JNU & NII are working on producing nanoparticle based formulations of the drug acriflavin and targeting it to the parasite through specific antibodies. DBT’s support has produced a critical mass of Indian scientists involved in malaria research.
Dr Gaur has discovered a novel multiprotein adhesion complex on the surface of Plasmodium falciparum that is essential for erythrocyte invasion and a highly potent target of strain-transcending parasite neutralization.
Author is Professor at School of Biotechnology, Jawaharlal Nehru University, New Delhi.
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