ReviewEnding the drought: New strategies for improving the flow of affordable, effective antivenoms in Asia and Africa
Graphical abstract
An international, multidisciplinary collaboration provides a mechanism to fund evaluation of existing antivenoms and production of new antivenoms using improved antigens. This donorfunded, regulated process would deliver safe, effective free antivenoms to snakebite victims.
Research highlights
► Snakebite is arguably the most neglected of all the neglected tropical diseases. ► A global shortage of accessible, safe, effective antivenoms is a major barrier to improving snakebite treatment. ► Greater deployment of proteomic, and other techniques could produce improved antivenoms. ► A multi‐disciplinary, multi‐centre collaboration to improve access to safe, effective antivenoms is proposed.
Introduction
Throughout the last decade, modern proteomic investigational tools have given toxinologists the key to revealing a dazzling array of biotoxins in the venoms of snakes, spiders, scorpions, wasps, caterpillars and a vast treasure trove of marine organisms. Never before have we been able to grasp the true complexity and diversity of venom proteins and peptides with such clarity and precision. With the aid of 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE), high-performance liquid chromatography (HPLC), a variety of sophisticated mass spectrometry platforms, and the ability to unravel protein transcriptomes or probe complex solutions with well designed ligand libraries, we have entered a new world of discovery and understanding in our quest to penetrate fundamental biological processes at the microcellular level. In these few short years we have gone beyond the limits of basic protein separation and characterisation into the very foundations of the genes that are the design blueprints of protein structure and function and the scaffolds upon which we can build treatments for diseases of many causes.
Snake venoms are rich soups of protein and peptide diversity. Many authors have discussed means of deploying proteomic investigations to unravel the venomes of numerous species [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]. Proteomics has been used not only to explore individual species' proteomes [5], [10], [13], [16], [20], [23], [24], [29], [32], [33], [34] and sub-proteomes [19], [22], [25], [35], [36], [37], [38], but to compare and contrast differences at both intra- [17], [20], [30], [33], [39], [40] and inter-species levels [3], [9], [11], [14], [15], [17], [18], [36], [40], [41], [42], [43]. A number of excellent reviews are available [8], [44], [45], [46], [47], [48], [49], [50], [51]. Many of the recent papers have taken snake proteomics to its logical extension, antivenomics. Proteomic techniques are now being applied to the neglected field of immunotherapy for snake envenoming [8], [39], [40], [43], [47], [49], [51], [52], [53], [54], [55].This has been a most welcome development, perhaps one of the most important new avenues in antivenom research to have been explored in the post-World War II era. Whilst the origins of immunotherapy for envenoming stretch back more than 120 years, a lack of financial incentives, dwindling markets and stagnant leadership from global public health organisations have made this a field of modest improvements and very little innovation. Although antivenoms are the most effective treatment for snakebites, they are frequently inaccessible to the millions of rural poor most at risk from snakebites in low and middle-income countries [56]. This tragic reality belies the fact that, with modest investments in innovation, antivenoms are potentially one of the most cost-effective and affordable treatments [57].
As the 20th century drew to a close, the future of antivenom treatment for snakebites looked anything but certain, particularly in the developing world where these essential medicines are most needed. In Africa, where some of the most exciting developments in antivenom research have been directed, many governments, overwhelmed by the HIV/AIDS epidemic and with numerous other issues of governance to contend with, allowed many less compelling health issues to be ignored, de-prioritised or merely neglected. Snake antivenoms became scarce or non-existent as poor economic viability forced some manufacturers to leave the market, and others to downscale production [58], [59], [60]. Although an important humanitarian and social issue, death from snakebite lacks the profile, status and assistance associated with other international health crises in Africa, and reputable manufacturers have been left to carry the burden with only limited support.
Widespread shortages of antivenom in Africa opened doors to opportunists. Poorly manufactured, ineffective products and in some cases complete counterfeits emerged [59], [61], [62]. Poorly equipped National Regulatory Agencies (NRA) lack the resources and skills to detect and exclude deleterious products. Faced with the choice between an expensive but effective product or an affordable but unproven alternative, many agencies have simply opted for the latter, with disastrous results [63].
Chronic shortages of effective antivenom were not confined to Africa. In Sri Lanka, where the incidence and mortality associated with snakebites are amongst the highest in the world, dependence on poor quality, low potency antivenoms made in India resulted in many patients' not receiving effective treatment, whilst suffering adverse reaction rates as high as 80% [64], [65]. Shortages of antivenom have also become common elsewhere in Asia and Oceania, most notably in nations such as Cambodia, Laos, Malaysia and Papua New Guinea, which lack local producers. But deficiencies have also occurred in countries that do produce antivenom, such as Myanmar, where natural disasters have led to acute rises in demand [66], [67] and Viet Nam where antivenom was originally introduced by Albert Calmette in the 1890s. These inadequacies have led both to the legal sale of inappropriate products and to thriving black markets [62]. Despite initial promise and some constructive intermediate outcomes, efforts to engage the wider public health community in programmes to address these challenges have been largely unsuccessful [68]. A positive step forward was the publication, following a wide consultation process, of the WHO Guidelines for the Production, Regulation and Control of Snake Antivenom Immunoglobulins, which should be used by manufacturers and regulators for the improvement of antivenom quality [68]. However, WHO's promise to advise national producers and help them achieve prequalification of antivenoms failed to attract funding due to the Global Financial Crisis. It became apparent that the toxinology community itself must assume the responsibility for drawing international attention to the plight of snakebite victims, and developing pragmatic, lasting solutions. To this end, the Global Snakebite Initiative (GSI) was founded in collaboration with the International Society on Toxinology (IST) in 2008 [69], [70]. It is currently working towards the development of a strategic approach to improving access to antivenoms in sub-Saharan Africa and South and South-East Asia. In the 21st century, proteomics can play a vital role in the design, development and testing of antivenoms. This paper discusses some of the challenges, opportunities and practical considerations, and identifies broader issues that need to be addressed if the developing world's antivenom drought is to be ended.
Section snippets
A brief history of antivenoms
The first experimental snake antivenom was raised in pigeons against venom from a pit viper Sistrurus catenatus[71], but the pioneer of immunotherapy in the treatment of envenoming was Albert Calmette. In October 1891, whilst Calmette was foundation director of the Vaccine Institute of Viet Nam, flooding along the Mekong river led to 40 snakebites including fatalities at Bac-Liêu near the river mouth [72].The District Governor sent Calmette a barrel-full of 19 monocellate cobras (Naja kaouthia
Sub-Saharan Africa
The availability of antivenoms in Africa during the 1930s was associated with a decline in morbidity and mortality from snakebite envenoming which encouraged their widespread use. Sadly, the last 30 years have been marked by critical shortages of this life-saving medication. By 1994, it was estimated that 1.6 million vials of antivenom were required annually for the whole of Africa, yet only 100,000 vials were produced and distributed. It has been suggested that the demise of the antivenom market
How can we best contribute to sustainable improvements?
The reality of the current antivenom situations in Africa, South and South-East Asia, and Papua New Guinea is such that many obstacles stand in the path of sustainable solutions. Many of the broader issues of governance, poor medicines regulation, corruption and social inequity apply generally to the societies in which these problems have become endemic, and will perhaps take many decades to resolve. By far the most surmountable challenges are those where we can deploy considerable experience;
So what does proteomics and biotechnology have to do with all of this?
A great deal of the interest in subjecting snake venoms to rigorous proteomic investigation has its foundations in the quest to discover, characterise and harness their bioactive constituent toxins in the fields of drug discovery and design [8], [49]. But researchers have not ignored the fact that these venoms are principally diverse offensive weapons systems, and that humans are all too often the subject of their onslaughts. Many of these victims are amongst the most impoverished inhabitants
A new approach
Despite strident efforts to engage the broader public health community in seeking long-term sustainable solutions to the perennial problems facing the victims of snakebites in the developing world, success remains elusive and antivenom scarcity persists in many regions as a result of many of the factors outlined in this review. The toxinology community is now taking a much more active role in advocacy about these issues [57], [59], [62], [69], [70], [234]. Efforts are also being made to develop
Summary
This paper looks pragmatically at the problems associated with obtaining adequate supplies of safe, affordable, effective antivenoms for communities in Africa and Asia. Many of these problems are complex political, good-governance and policy-related issues that are beyond easy resolution. This review acknowledges those obstacles and considers what can and cannot be achieved. It explores in detail how some of the technological problems associated with producing effective antivenoms can and are
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