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Global Availability of Antivenoms: The Relevance of Public Manufacturing Laboratories
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Abstract
Snakebite envenoming is a serious global public health problem, and international initiatives, under the coordination of the World Health Organization and its regional offices, are being developed to reduce the impact of this neglected tropical disease. The global availability of safe and effective antivenoms is one of the key aspects in this global strategy. This review discusses the role of public antivenom manufacturing laboratories for ensuring the supply of antivenoms. The difficulties faced by public laboratories are discussed, together with some tasks that need to be implemented for strengthening them. In addition, the concept of ‘redundancy’ in the supply of antivenoms is emphasized, as a way to cope with the risks associated with the provision of antivenoms by few manufacturers. In general, the public sector should play a leading role, in antivenom availability and other aspects as well, within the global struggle to reduce the mortality and morbidity caused by snakebite envenoming.
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Confronting the Neglected Problem of Snake Bite Envenoming: The Need for a Global Partnership
Envenoming resulting from snake bites is an important public health hazard in many regions of the world, yet public health authorities have given little attention to the problem.
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Consequences of Neglect: Analysis of the Sub-Saharan African Snake Antivenom Market and the Global Context
Nicholas Brown (2012)
Introduction Snakebite is a significant social and economic problem in many developing countries, however its victims rank among those most neglected by global health campaigns. Snakebite was recognised by the WHO as a Neglected Tropical Diseases in 2007, and antivenom – the only specific treatment for systemic envenoming - remains largely inaccessible to hundreds of thousands of snakebite victims around the world. Since its introduction and continued refinement throughout the twentieth century, antivenoms have saved countless lives [1]. Although readily available in wealthy countries and able to reduce mortality rates to less than 1% [1]–[3], sources of effective, safe and affordable antivenom in low-income countries, where the incidence of snakebite is greatest, are highly variable. Whilst good quality products do exist in some developing countries its procurement is often inadequate, leaving snakebite victims without access to proper treatment. Quantifying the gap between what is currently available and what is needed is a critical step towards developing effective solutions to this problem. This study provides a contemporary overview of global antivenom production, focusing particularly on the antivenom market in sub-Saharan Africa. 1. The rise and fall of antivenom Since Edward Jenner's controversial inoculation of James Phipps with cowpox in 1796, immunotherapy has developed into a diverse industry [4]. Calmette's groundbreaking work with equine antiserum resulted in the first, unrefined antivenom in 1894. Pope's improvements to antivenom refinement in the 1930s were another major step forward in safety and potency of antivenom. Unfortunately, further advances since then have been limited. Despite snakebite being over-represented in morbidity and mortality tables [5], investment in this type of immunotherapy has not been characterised by the same level of publicity or resolve that has characterised vaccine production or monoclonal antibody research. This under-recognition of bites and stings as major medical and social problems, and snakebite's association with poverty, have contributed to the current antivenom crisis [6]. The introduction of antivenom to Africa in the 1950s heralded a decline in morbidity and mortality from snakebites that led to its widespread use and production. Sadly, over the last 30 years, production of this life-saving medication has been neglected by governments and non-government organisations, and abandoned by some manufacturers [7]. The 1970s and 1980s were characterised by a decline in the sale of antivenom in Africa due to growing neglect and prohibitive costs [8]. By 1998, it was estimated that fewer than 100,000 vials of antivenom were available across Africa, constituting less than 25% of the amount needed [9]. A number of recent publications state the availability of antivenom in Africa has reduced to 20–25 LD50 Naja melanoleuca, N. nigricollis, N. haje, Dendroaspis polylepis, D. viridis, D. jamesoni, Bitis gabonica, B. arietans, Echis leucogaster, E. carinatus#; Daboia russelli#, Kenya, Nigeria, Ghana, Burkina Faso, Angola, Mozambique, Sudan Bharat Serums and Vaccines, India Poly; F(ab)′2 equine; lyophilised or liquid (10 ml); Bitis gabonica, B. arietans, B. nasicornis, Dendroaspis jamesonii, D. polylepis, D. angusticeps, Echis carinatus#,Naja nivea, N. nigricollis, N. haje, N. Melanoleuca Ghana, Nigeria, Kenya, Benin, Burkina Faso, Sudan Serum Institute of India, India* (now discontinued) Poly; equine; lyophilised (10 ml) Bitis, Echis, Dendroaspis, Daboia russelli# Ghana, Tanzania, Ethiopia, Kenya, Sudan Instituto Bioclon, Mexico, N/A Poly; equine; F(ab)′2; lyophilised Bitis arietans, B. gabonica, Echis ocellatus, E. Pyramidum, E. leucogaster, Naja naja, N. haje, N. nigricollis, N. pallida, Dendroaspis polylepis, D. Viridis West Africa; Post clinical trials; [44] Instituto Clodomiro Picado, Costa Rica, N/A Poly; equine; liquid; intact IgG Echis ocellatus, Bitis arietans, Naja nigricollis West Africa; Post clinical trials; [2] Instituto Butantan, Brazil, N/A Poly; Equine, F(ab)′2, liquid. Bitis arietans, B. nasicornis, B. rhinoceros, Naja malanoleuca, N. Mossambica Mozambique; in clinical trials [41] (* manufacturer has now ceased antivenom production; # not an African species; poly = polyspecific; mono = monospecific; N/A = not yet available). Between 2007 and 2010/11, six manufacturers sold antivenom for use in sub-Saharan Africa, although one has now ceased producing African antivenom indefinitely and another now only manufacturers antivenom to order after a lack of demand forced a temporarily hiatus of production in 2010. Three other institutions are developing antivenom against African snake species that have either recently been licensed or are in the final stages of development. Data on the planned output of antivenoms for Africa from these organisations is either not yet available or for experimental purposes only. Companies are based in the United Kingdom, France, South Africa, India, Mexico, Costa Rica and Brazil, with only one classified as “big pharma”. A further three groups based in Egypt, Saudia Arabia and Iran produce antivenom against snake species found in West Asia and the Arabian peninsula, which may have efficacy against some North African snake species. Owing to their “off-label” nature for use against continental African snake species, these were not included in the final analysis. Another organisation, based in Colombia, appears to have suspended development of a pan-African antivenom after conducting preclinical work in 2003. b. Antivenom output and capacity Producers of sub-Saharan African antivenom had a combined annual output of at least 377,500 vials in 2010/2011, equating to approximately 83,000 complete treatments for moderate envenoming, based on manufacturers' recommended doses (table 2). By comparison, 227,400 vials of sub-Saharan African antivenom were marketed to African countries in 2007, providing just over 54,000 average treatments (table 3). In 2007, manufacturers reported a combined excess supply of more than 26,000 vials of unsold African antivenom. By 2010 no manufactured antivenom was unsold, however significant unutilised production capacity was reported by 5 of the 8 current producers, including two with manufacturing facilities and quality control procedures regulated by the European Medical Agency (EMEA). If utilised, this combined capacity could produce enough antivenom to treat 600,000 patients and save thousands of lives. 10.1371/journal.pntd.0001670.t002 Table 2 2007sub-Saharan African antivenom output and market. Company Vials produced per year No. of vials (treatments) unsold in 2007 Wholesale cost per vial (US$) Vials per average treatment Complete treatments (average) Cost of AVERAGE treatment Value of African AV A 10,000 5,000 (3,570) $40 1–2 (Avg 1.4) 7,200 $56 $400,000 B 1,000 (>125) $80 (poly) $200 (mono) 6–10 (poly) 2 (mono) 1250 (poly) 200 (mono) $640 (poly) $400 (mono) $880,000 D 5,000 0 $18 4–9 770 $117 $90,000 E 100,000 >20,000 (>6,667) $32 2–4 33,300 $96 $3,200,000 F 100,000 0 $18 6–12 11,111 $162 $1,800,000 TOTAL 227,400 >26,000 (>10,362) ∼$32 (average) ∼4.2 vials (average) 54,371 ∼$133 (average) $6,640,000 10.1371/journal.pntd.0001670.t003 Table 3 2010/11 sub-Saharan African antivenom output and market. Company Vials produced per year Vials unsold in 2010 Wholesale cost per vial (US$) Vials per average treatment Complete treatments (average) Cost of AVERAGE treatment Value of African AV A 12,000 0 $40 1–2 (mean 1.4) 8,500 $55 $480,000 B 2000† 0 $135 3–4 (mean 3.7); ≥25 LD50 20–25 LD50 22,222 $162 $3,600,000 G N/A 2–6 vials (mean 3.8) H N/A (projected 20,000) 3–6 vials (mean 3.8) I N/A TOTAL 377,500 0 ∼$28∧ ∼4.5 vials∧ 83,072 ∼$124∧ $10,290,000 (†based on 2007 company projections;∧ average;N/A = not yet available). c. Antivenom quality It is evident from product inserts and literature reviews that the potency of antivenom sold in sub-Saharan Africa varies widely. The average number of antivenom vials required to achieve effective neutralisation of a moderate envenoming, based on manufacturers' recommended doses, is 4.5 vials (range 1 to 12 vials). Doses for severe envenomings can be several times greater. Whilst proven effective antivenom products against African snake species do exist, it is highly concerning to note that recent peer-reviewed evaluations and published personal reports have indicated that two dominant products in the African market, which account for up to 90% of the total output, lack efficacy against some snake species to which they are targetted [2], [12], [33]–[35]. The actual number of effective antivenom treatments available in Africa, therefore, is potentially only a fraction of the 83,000 stated above, and may cover as little as 2.5% of the estimated need. d. Antivenom cost The wholesale cost of antivenoms for sub-Saharan Africa ranged from $18 to $200 per vial. The corresponding cost per effective treatment, using recommended doses, was $55 to $640, with an average cost of $124. Total company revenues from these products increased from $6.6 million in 2007 to approximately $10.3 million in 2010/11. The two largest manufacturers accounted for almost $8.4 million (81.5%) of revenues, despite recent concerns about the suitability of their products for use in some African markets. e. Antivenom formulation Of the 8 current and pending producers of sub-Saharan African antivenoms, 6 manufacture solely polyspecific products, one produces only monospecific, and one produces both polyspecific and monospecific antivenoms. One currently marketed and one future product consists of whole IgG antibodies purified with caprylic acid, while the remainder manufacture F(ab)′2 products. One company utilises ovine antisera instead of equine, and 6 offer lyophilised products. 3. Global antivenom market a. Manufacturers In 2007, 46 one-time antivenom manufacturers across 28 countries were surveyed and 35 reported current production of at least one type of snake antivenom for commercial, government or research purposes. Eleven organisations listed in various media as antivenom manufacturers either no longer produce snake antivenom or did not respond to the survey. Twenty-four of the 35 organisations producing antivenom operate on a commercial basis; 6 were purely government facilities manufacturing non-commercial antivenom for domestic purposes; and 5 companies did not provide financial data. b. Antivenom output and capacity Total global snake antivenom output by surveyed companies exceeded 4 million vials, although this equated to fewer than 600,000 effective treatments. This is well below the WHO's worldwide estimated requirement of at least 2 million treatments per year. Globally, twelve manufacturers reported having capacity to increase volume, which if realised could potentially double the current output. c. Antivenom quality and formulation As with the antivenoms in Africa, many commercially available antivenoms are associated with highly variable potency, ranging from 1 to >30 vials required to complete an effective treatment. A majority of products were produced using F(ab)′2, and only 3 manufacturers reported using Fab or intact IgG. d. Antivenom cost In 2007 wholesale prices for individual antivenoms across the global range of products ranged from $8 to $1338. The cost of treatment based on manufacturer recommended doses was calculated to be between $40 and $24,000. However case reports indicate that the number of vials required to successfully treat severe envenoming with some products may exceed the recommended amount [36], [37], with associated wholesale costs of over $35,000 per treatment [38] and even higher retail costs. Total company income from worldwide antivenom sales amounted to more than $60 million, and only two groups had annual antivenom sales exceeding $10 million. There is a clear relationship between wholesale cost of antivenom and throughput (Figure 1), which has important implications for strategies seeking to increase the amount of antivenom produced globally. It was estimated by one company that costs could be reduced 5-fold from an 8-fold increase in output. Another company reported that doubling production would only increase costs by 10% and could potentially halve antivenom price. However, the retail price of antivenom is also heavily influenced by the market's ability to pay for it. On a per vial basis, antivenom developed for use in high-income countries is disproportionately more expensive, represented by the two out-lying plot points in Figure 1. 10.1371/journal.pntd.0001670.g001 Figure 1 Antivenom price v output. Economies of scale mean that the cost per ampoule decreases as throughput increases. 4. Attitudes to future antivenom production All companies currently producing antivenom for sub-Saharn Africa indicated a willingness to increase output should market demand improve. Manufacturers identified factors that prevented them from raising production, despite a willingness to do so. Whilst not all manufacturers listed the same reasons, there was some concordance and the responses below have been listed in descending order of frequency: Lack of consistent market demand for antivenom products; Inconsistencies with manufacturers receiving payment. Corruption within some global markets and government agencies; Threats from black market re-sale of antivenom products; Lack of appropriate venom for immunogen preparation, A lack of certainty regarding appropriate distribution of their products; Inappropriate clinical use of antivenom products; Lack of adequate animals for raising antisera; and High costs of maintaining livestock for antivenom production; Discussion This survey of antivenom manufacturers highlights the paucity of antivenom products for sub-Saharan Africa and the unhelpful variability that exists within the current industry. It also illustrates that despite the exodus of manufacturers in the 1970s and 1980s, willing producers do exist and they possess substantial unutilised production capacity. Unfortunately, inadequate government and non-government funding for procurement and regulatory oversight restrains production of commercial antivenom. This lack of investment is not only the reason for the current crisis in antivenom availability, but also represents the greatest challenge to future improvements in quantity and quality. Although inexpensive and efficacious antivenoms do exist, and compelling moral and legal arguments advocate increased purchase and distribution [39], [40], a lack of funding for antivenom acquisition and regulation of quality standards has catalysed the vicious cycle responsible for the decline in production and use over the last 30 years (figure 2). This cycle has also contributed to conditions that have allowed lesser quality products and inappropriate marketing to emerge. The arrival of new manufacturers and the presence of spare capacity within some current facilities provide hope, but uncertain market conditions and inadequate financial support will continue to restrict growth of trustworthy antivenoms. 10.1371/journal.pntd.0001670.g002 Figure 2 The self-perpetuating cycle responsible for the decline in antivenom production in sub-Saharan Africa. Inadequate financial support for antivenom production and variable quality have catalysed the collapse of the antivenom market, which is now characterised by deficient supply, deficient quality control, rising prices and poor profitability. This cycle is a variation on that proposed by Stock et al in 2007 [9], and demonstrates the importance of future financial stimulus in reinvigorating competition and viability of the antivenom market. Inadequate financing within the antivenom industry is the major factor underpinning its decline over the last 40 years, and strategies to solve this crisis must recognise and unwind the economic and commercial drivers on both sides of the supply and demand equation. It is unrealistic to expect that pharmaceutical companies will commit to long-term production of antivenom for an inconsistent and unreliable market that is starved of investment. Even if greater volumes of appropriate antivenom could be produced, without adequate subsidisation it will be priced out of range for most snakebite victims living in underprivileged rural and remote areas. Similarly, corporate executives and regulatory bodies must also accept that there exists a moral imperative for them to contribute their expertise and capabilities, and that existing business models and production frameworks may be inappropriate for the supply of humanitarian products to developing countries. Encouragingly, there has been a small increase in financial support for the development and procurement of new African antivenoms between 2007 and 2010. Whilst the >$60 million in global antivenom revenue and $10.3 million from African antivenom sales are small by pharmaceutical standards, this represents valuable investment and an encouraging base from which the industry can grow. Better utilisation of spare production capacity and improved economies of scale will produce greater yields, reduce costs, increase revenues and further enhance the commercial viability of antivenoms. The second major problem eroding the antivenom market is the lack of accountability in quality standards. Possessing the capacity to produce vast amounts of antivenom for sub-Saharan African communities is meaningless if the products are poorly made and ineffective against the snakes in those regions. A current lack of interest, insufficient investment and poor competition are allowing unscrupulous behaviours within the marketplace to go unchecked. Given the ongoing severe shortage of antivenom and the continuing high incidence of envenoming, it is not surprising that opportunistic manufacturers seek to fill the void. The advent of seemingly inexpensive, but low quality or inappropriate antivenoms with poor neutralising ability, not only compromises the reputation of antivenoms in general but also drains important financial resources away from proven snakebite treatment programs and products. Some manufacturers have cited this uneven playing field as a key impediment to future innovation and productivity. Nevertheless, the very high volume output by some manufacturers of alleged inappropriate products still make them key players in the antivenom industry, and potentially integral to future strategies for increasing output of higher quality products. Improving standards and maximising efficiencies ought to be the common goal for all manufacturers. The three groups with emerging new African antivenoms provide hope for the future [41]–[44], however ensuring that these products, as well as existing antivenoms, are of sufficient quality to be incorporated into a properly funded and sustainable market is paramount [8]. The final quality control checkpoint for all antivenoms entering a country should be the national regulatory authorities. It is essential that NRAs are adequately resourced and transparent to ensure the integrity and robustness of their mechanisms are above reproach. Linking funds for antivenom procurement to improved quality control and assurance measures would enhance the crucial role of local regulatory bodies and incentivise the maintenance of minimum standards. Antivenom's usually rapid and curative effects make it a highly cost-effective intervention [40], and together with snakebite's surpassing morbidity and mortality [6], ought to attract attention from global health funding bodies. If improved efficiencies, technical support and collaboration within the antivenom industry were achieved, the cost of an effective antivenom treatment would fall below the current average of $124, and may ultimately be significantly less than $100. Supplying sufficient quantities of antivenom to the whole of Africa at that price would require an annual input of less than $30–$50 million, which is considerably lower than the budgets for many other global health programs. Leadership and support from groups such as the Global Snakebite Initiative and the World Health Organisation may help to secure essential funds from donors and provide important coordination, transparency and accountability. It will also help to recruit and reform manufacturers capable of contributing a greater supply of effective and appropriate antivenoms. The declining availability of high quality antivenom in sub-Saharan Africa is a real and unnecessary tragedy, and constitutes a major neglected global health concern. The amount of suitable antivenom marketed in these countries has fallen to crisis levels, representing only a fraction of the amount required. Although recent output of antivenom for Africa has increased, and the number of manufacturers able to boost production is growing, inadequate financial support and market uncertainty continue to suppress growth and compromise quality standards. The provision of sufficient funds to identify satisfactory antivenoms, maintain quality control, maximise efficiencies and increase procurement is desperately needed to break the vicious cycle that currently constrains the antivenom industry. The mechanisms to achieve this are realistic and available; science, business and government must collaborate to secure a brighter future for snakebite victims in developing countries. Only then will the goal of providing effective, safe and affordable antivenoms to all who need them, be realised.
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Snake venomics of the Central American rattlesnake Crotalus simus and the South American Crotalus durissus complex points to neurotoxicity as an adaptive paedomorphic trend along Crotalus dispersal in South America.
Alberto Alape-Giron, Libia Sanz, Juan Calvete … (2009)
We report a comparative venomic and antivenomic characterization of the venoms of newborn and adult specimens of the Central American rattlesnake, Crotalus simus, and of the subspecies cumanensis, durissus, ruruima, and terrificus of South American Crotalus durissus. Neonate and adult C. simus share about 50% of their venom proteome. The venom proteome of 6-week-old C. simus is predominantly made of the neurotoxic heterodimeric phospholipase A(2) (PLA(2) crotoxin) (55.9%) and serine proteinases (36%), whereas snake venom Zn(2+)-metalloproteinases (SVMPs), exclusively of class PIII, represent only 2% of the total venom proteins. In marked contrast, venom from adult C. simus comprises toxins from 7 protein families. A large proportion (71.7%) of these toxins are SVMPs, two-thirds of which belong to the PIII class. These toxin profiles correlate well with the overall biochemical and pharmacological features of venoms from adult (hemorrhagic) and newborn (neurotoxic) C. simus specimens. The venoms of the South American Crotalus subspecies belong to one of two distinct phenotypes. C. d. cumanensis exhibits high levels of SVMPs and low lethal potency (LD(50)), whereas C. d. subspecies terrificus, ruruima, and durissus have low SVMP activity and high neurotoxicity to mice. Their overall toxin compositions explain the outcome of envenomation by these species. Further, in all C. simus and C. durissus venoms, the concentration of neurotoxins (crotoxin and crotamine) is directly related with lethal activity, whereas lethality and metalloproteinase activity show an inverse relationship. The similar venom toxin profiles of newborn C. simus and adult C. durissus terrificus, ruruima, and durissus subspecies strongly suggests that the South American taxa have retained juvenile venom characteristics in the adult form (paedomorphism) along their North-South stepping-stone dispersal. The driving force behind paedomorphism is often competition or predation pressure. The increased concentration of the neurotoxins crotoxin and crotamine in South American rattlesnake venoms strongly argues that the gain of neurotoxicity and lethal venom activities to mammals may have represented the key axis along which overall venom toxicity has evolved during Crotalus durissus invasion of South America. The paedomorphic trend is supported by a decreasing LNC (lethal neurotoxicity coefficient, defined as the ratio between the average LD(50) of the venom and the crotoxin + crotamine concentration) along the North-South axis, coincident with the evolutionary dispersal pattern of the Neotropical rattlesnakes. The indistinguisable immunoreactivity patterns of Costa Rican and Venezuelan polyvalent antivenoms toward C. simus and C. durissus venoms strongly suggest the possibility of using these antivenoms indistinctly for the management of snakebites by adult C. simus and by certain C. d. cumanensis populations exhibiting a hemorrhagic venom phenotype. The antivenomic results also explain why the antivenoms effectively neutralize the hemorrhagic activity of adult C. simus venoms but does not protect against adult C. durissus sp. and newborn C. simus envenomations. The identification of evolutionary trends among tropical Crotalus, as reported here, may have an impact in defining the mixture of venoms for immunization to produce an effective pan-American anti-Crotalus antivenom.
Author and article information
Journal
Journal ID (nlm-ta): Toxins (Basel)
Journal ID (iso-abbrev): Toxins (Basel)
Journal ID (publisher-id): toxins
Title:
Toxins
Publisher:
MDPI
ISSN
(Electronic):
2072-6651
Publication date
(Electronic):
24
December
2018
Publication date Collection:
January
2019
Volume: 11
Issue: 1
Electronic Location Identifier: 5
Affiliations
Instituto Clodomiro Picado, Facultad de Microbiología, Universidad de Costa Rica,
San José 11501-2060, Costa Rica;
jose.gutierrez@
123456ucr.ac.cr
; Tel.: +506-2511-7865
Author information
José María Gutiérrez
https://orcid.org/0000-0001-8385-3081
Article
Publisher ID: toxins-11-00005DOI: 10.3390/toxins11010005
PMC ID: 6356591
PubMed ID: 30586868
SO-VID: 26cb9e52-8886-4c37-9f2f-77625ce497f0
Copyright © © 2018 by the author.
License:
Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).
History
Date
received
: 16
November
2018
Date
accepted
: 20
December
2018
Categories
Subject:
Review
ScienceOpen disciplines: Molecular medicine
Data availability:
ScienceOpen disciplines: Molecular medicine