New Strategies for Improving the Flow of Affordable, Effective Antivenoms in Asia and Africa
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JOURNAL OF PROTEOMICS 74 (2011) 1735– 1767 available at www.sciencedirect.com www.elsevier.com/locate/jprot Review Ending the drought: New strategies for improving the flow of affordable, effective antivenoms in Asia and Africa David J. Williamsa,b,c,⁎, José-María Gutiérrezd, Juan J. Calvetee, Wolfgang Wüster f, Kavi Ratanabanangkoong, Owen Paivaa,b, Nicholas I. Browna, Nicholas R. Casewellh, Robert A. Harrisonh, Paul D. Rowleyh, Mark O'Sheaa,i, Simon D. Jensena,b, Kenneth D. Winkela, David A. Warrella,j a Australian Venom Research Unit, Department of Pharmacology, University of Melbourne, Parkville, Vic, 3010, Australia b School of Medicine & Health Sciences, University of Papua New Guinea, Boroko, NCD, Papua New Guinea c Nossal Institute for Global Health, University of Melbourne, Parkville, Vic, 3010, Australia d Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica, San José, Costa Rica e Laboratorio de Proteinomíca Estructural, Instituto de Biomedicina de Valencia, CSIC, Jaime Roig 11, 46010 Valencia, Spain f School of Biological Sciences, Bangor University, Environment Centre Wales, Bangor, UK g Laboratory of Immunology, Chulabhorn Research Institute and Chulabhorn Graduate Institute, Laksi, Bangkok, 10210, Thailand h Alistair Reid Venom Research Unit, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK i West Midland Safari Park, Bewdley, Worcestershire, UK j Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK ARTICLE INFO ABSTRACT Available online 19 May 2011 The development of snake antivenoms more than a century ago should have heralded effective treatment of the scourge of snakebite envenoming in impoverished, mostly rural Keywords: populations around the world. That snakebite still exists today, as a widely untreated illness Snakebite that maims, kills and terrifies men, women and children in vulnerable communities, is a Venomics and antivenomics cruel anachronism. Antivenom can be an effective, safe and affordable treatment for Antivenoms snakebites, but apathy, inaction and the politicisation of public health have marginalised Proteomics both the problem (making snakebite arguably the most neglected of all neglected tropical Neglected tropical diseases diseases) and its solution. For lack of any coordinated approach, provision of antivenoms has Global Snakebite Initiative been pushed off the public health agenda, leading to an incongruous decline in demand for these crucial antidotes, excused and fed by new priorities, an absence of epidemiological data, and a poor regulatory framework. These factors facilitated the infiltration of poor quality products that degrade user confidence and undermine legitimate producers. The result is that tens of thousands are denied an essential life-saving medicine, allowing a toll of human suffering that is a summation of many individual catastrophes. No strategy has been developed to address this problem and to overcome the intransigence and inaction responsible for the global tragedy of snakebite. Attempts to engage with the broader public health community through the World Health Organisation (WHO), GAVI, and other agencies ⁎ Corresponding author at: Australian Venom Research Unit, Department of Pharmacology, University of Melbourne, Parkville, Vic, 3010, Australia. Tel.: +675 76719476; fax: +613 93482048. E-mail address: [email protected] (D.J. Williams). 1874-3919/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jprot.2011.05.027 1736 JOURNAL OF PROTEOMICS 74 (2011) 1735– 1767 have failed. Consequently, the toxinology community has taken on a leadership role in a new approach, the Global Snakebite Initiative, which seeks to mobilise the resources, skills and experience of scientists and clinicians for whom venoms, toxins, antivenoms, snakes and snakebites are already fields of interest. Proteomics is one such discipline, which has embraced the potential of using venoms in bio-discovery and systems biology. The fields of venomics and antivenomics have recently evolved from this discipline, offering fresh hope for the victims of snakebites by providing an exciting insight into the complexities, nature, fundamental properties and significance of venom constituents. Such a rational approach brings with it the potential to design new immunising mixtures from which to raise potent antivenoms with wider therapeutic ranges. This addresses a major practical limitation in antivenom use recognised since the beginning of the 20th century: the restriction of therapeutic effectiveness to the specific venom immunogen used in production. Antivenomic techniques enable the interactions between venoms and antivenoms to be examined in detail, and if combined with functional assays of specific activity and followed up by clinical trials of effectiveness and safety, can be powerful tools with which to evaluate the suitability of current and new antivenoms for meeting urgent regional needs. We propose two mechanisms through which the Global Snakebite Initiative might seek to end the antivenom drought in Africa and Asia: first by establishing a multidisciplinary, multicentre, international collaboration to evaluate currently available antivenoms against the venoms of medically important snakes from specific nations in Africa and Asia using a combination of proteomic, antivenomic and WHO-endorsed preclinical assessment protocols, to provide a validated evidence base for either recommending or rejecting individual products; and secondly by bringing the power of proteomics to bear on the design of new immunising mixtures to raise Pan-African and Pan-Asian polyvalent antivenoms of improved potency and quality. These products will be subject to rigorous clinical assessment. We propose radically to change the basis upon which antivenoms are produced and supplied for the developing world. Donor funding and strategic public health alliances will be sought to make it possible not only to sustain the financial viability of antivenom production partnerships, but also to ensure that patients are relieved of the costs of antivenom so that poverty is no longer a barrier to the treatment of this important, but grossly neglected public health emergency. © 2011 Elsevier B.V. All rights reserved. Contents 1. Introduction .........................................................1737 2. A brief history of antivenoms ...............................................1737 3. The current global situation ................................................1738 3.1. Sub-Saharan Africa .................................................1738 3.2. South and Southeast Asia ..............................................1739 3.3. Papua New Guinea .................................................1740 3.4. Latin America ....................................................1741 4. How can we best contribute to sustainable improvements? ...............................1741 5. So what does proteomics and biotechnology have to do with all of this? ........................1742 5.1. Proteomic tools for studying venoms .......................................1742 5.1.1.Snake venomics ............................................1742 5.1.2.Antivenomics ..............................................1744 5.2. Getting the names and places right: systematics, phylogenetics and snake distributions .............1746 5.3. The use of proteomics in the design of venom mixtures for immunisation and in the preclinical assessment of antivenoms ....................................................1748 5.4. The quest for ‘universal’ antidotestoelapidpostsynapticneurotoxins(PSNTs)..................1752 5.4.1.The active site of PSNTs in the binding to nAChR ..........................1752 5.4.2.Strategies for finding a ‘universal’ inhibitor/antibody against elapid PSNTs ............1752 5.5. Another big challenge: the neutralisation of toxins responsible for local tissue damage ...........1754 6. A new approach .......................................................1754 7. Summary ...........................................................1759 References .............................................................1760 JOURNAL OF PROTEOMICS 74 (2011) 1735– 1767 1737 ated with other international health crises in Africa, and 1. Introduction reputable manufacturers have been left to carry the burden with only limited support. Throughout the last decade, modern proteomic investigational Widespread shortages of antivenom in Africa opened doors tools have given toxinologists the key to revealing a dazzling to opportunists. Poorly manufactured, ineffective products and array of biotoxins in the venoms of snakes, spiders, scorpions, in some cases complete counterfeits emerged [59,61,62]. Poorly wasps, caterpillars and a vast treasure trove of marine organisms. equipped National Regulatory Agencies (NRA) lack the resources Never before have we been able to grasp the true complexity and and skills to detect and exclude deleterious products. Faced with diversity of venom proteins and peptides with such clarity and the choice between an expensive but effective product or an precision. With the aid of 2-dimensional polyacrylamide gel affordable but unproven alternative, many agencies have electrophoresis (2D-PAGE), high-performance liquid chromatog- simply opted for the latter, with disastrous results [63]. raphy (HPLC), a variety of sophisticated mass spectrometry Chronic shortages of effective antivenom were not con- platforms, and the ability to unravel protein