Citation: Alirol E, Lechevalier P, Zamatto F, Chappuis F, Alcoba G, Potet J (2015) Antivenoms for Snakebite Envenoming: What Is in the Research Pipeline? PLoS Negl Trop Dis 9(9): e0003896. https://doi.org/10.1371/journal.pntd.0003896
Editor: H Janaka de Silva, University of Kelaniya, SRI LANKA
Published: September 10, 2015
Copyright: © 2015 Alirol et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Of the 24 neglected tropical diseases (NTDs) and conditions listed by WHO, snakebite is among the top killers . Tens of thousands of people die each year as a result of snakebite envenoming, with close to 50,000 deaths in India alone  and up to 32,000 in sub-Saharan Africa . Yet there are few sources of effective, safe, and affordable antivenoms. The regions that bear the highest snakebite burden are especially underserved .
The Fav-Afrique antivenom, produced by Sanofi Pasteur (France), is considered safe and effective and is one of the few antivenoms to be approved by a Stringent Regulatory Authority (French National Regulatory Authority), although limited formal evidence has been published [5,6]. It is polyvalent, targeting most of the medically important snake species in sub-Saharan Africa. In particular, it is highly effective in treating envenoming by Echis ocellatus, the West African saw-scaled viper [5–7] that causes great morbidity and mortality throughout the West and Central African savannah. The venom of E. ocellatus may induce systemic haemorrhage, coagulopathy, and shock, as well as extensive local tissue damage. In the absence of treatment, the case fatality rate is 10%–20% . Médecins Sans Frontières (MSF) uses Fav-Afrique in its projects in sub-Saharan Africa, notably in Paoua in Central African Republic (CAR), where E. ocellatus envenoming is frequent . Worryingly, MSF has been informed that the production of Fav-Afrique by Sanofi Aventis will be permanently discontinued. The last batch was released in January 2014, with an expiry date of June 2016. All the vials produced have already been sold by Sanofi Pasteur.
Although several alternative antivenom products target a similar list of species as Fav-Afrique, there is currently no evidence of their safety and effectiveness. We aimed to review the evidence for the efficacy and safety of existing and in-development snake antivenoms, and to list the alternatives to Fav-Afrique in sub-Saharan Africa.
We searched clinical trial registries (National Institutes of Health clinicaltrials.gov and WHO International Clinical Trial Registry Platform) and a publication database (EMBASE) to identify ongoing and completed clinical trials. The registries were searched by condition using the keywords “snakebite” OR “snake bite” OR “snake envenom*” OR “envenom*” OR “bite.” Publication database search strategy was based on the Medical Subject Heading (MeSH) terms “clinical trial” AND “snake bites” AND “polyclonal antiserum OR snake venom antiserum OR venom antiserum.” All terms were explored, and results were limited to studies conducted in humans. No time limits were imposed. Searches were conducted in September 2014 and included all records from the launch of the databases. Only those studies with a design compatible with that of a clinical trial (prospective, comparative, and interventional) and with the definition given by the CONSORT glossary were included. Prospective, single-arm cohorts were not considered as clinical trials.
The registry searches yielded 29 records, four of which were observational studies. Among the interventional studies, 12 investigated antivenom as an intervention (eight were retrieved out of 176,201 records in clinicaltrials.gov and 12 out of 254,285 in ICTRP). Table 1 summarises the characteristics of the 12 trials. Four trials were sponsored by pharmaceutical companies and the remainder, by an individual researcher or academic institution. Four trials were open for recruitment and five were completed or terminated. A total of 11 different antivenoms were being investigated, most in only one trial.
The publication database search yielded 97 results (Fig 1). After cleaning, 82 records were retained, of which 30 had a design consistent with clinical trials. The remainder included 26 reviews or commentaries, 18 cohorts or cases series, four retrospective analyses of medical records, two case studies, one diagnostic study, and one cross-sectional survey. A search of references yielded an additional 11 reports of clinical trials. Of the 41 clinical trials thus identified, 32 investigated antivenom as an intervention. The locations of the 32 studies were Latin America (Brazil n = 3, Columbia n = 5, Ecuador n = 1); Asia (India n = 4, Thailand n = 5, Sri Lanka n = 3, Myanmar n = 1, Malaysia n = 1); Africa (Nigeria n = 5), and US (n = 4). 27 were sponsored by a public organization (e.g., university or public hospital). Most trials (n = 20) were conducted before 2000, the oldest dated from 1960 . A total of 30 antivenoms were investigated; half were investigated in only one trial.
The search was conducted on 15 September 2014. Merging the search results gave a total of 41 clinical trials investigating the efficacy or safety of snake antivenoms, of which four were active. A total of 36 different antivenoms were investigated (see Table 2). Based on the trial design (Phase I to IV), ten products were considered still “under development,” although development appears to have stalled for most of them. Our search strategy appears robust; a report conducted in 2010 identified a total of 43 randomized controlled trials on snakebite envenoming, 28 of which investigated antivenom properties . We retrieved all except two of these trials [12,51]; the discrepancy could be due to differences in the criteria used to define clinical trials.
Urgent Need for More Research
Our results highlight the paucity of adequately conducted clinical trials and corroborate previous findings on the scarcity of safe, effective, and quality-assured snake antivenoms . Comparison with dengue fever, which has a similar burden (11.97 Disability-Adjusted Life Years (DALYs) per 100,000 [4.99–20.46] versus venomous animal contacts 39.62 DALYs per 100,000 [22.46–69.74]) , is particularly revealing. In 2011, of 79 identified trials on dengue fever, 27 were recruiting patients, with six new products in development . By contrast, the research pipeline for snakebite remains desperately dry, despite numerous calls for action [15–17].
Antivenoms in Sub-Saharan Africa
To determine how many antivenom products are currently available in sub-Saharan Africa, we searched WHO “Venomous snakes and antivenoms database” and held bilateral discussions with snakebite experts and pharmaceutical companies. We found that 12 antivenom products were commercially available in sub-Saharan countries as of September 2014 (Table 3), only three of which had been tested in at least one clinical trial, and many of which may lack efficacy .
Case study: The MSF experience in Central African Republic
The experience of MSF in CAR suggests that there are indeed significant variations in the efficacy of antivenoms against African snake venoms. MSF has been using Fav-Afrique to manage patients presenting with features of snakebite envenoming in Paoua, CAR, since 2008. In the first half of 2013, Fav-Afrique was temporarily unavailable, and an alternative product was identified, directed against the venoms of 11 species of African snakes, including E. ocellatus. This antivenom was used for six months, with the same criteria for therapy as for Fav-Afrique. Although a methodologically sound study could not be conducted, a retrospective analysis of MSF medical records showed that the case fatality rate increased from 0.47% (three of 644 treated patients) with Fav-Afrique  to 10% (five of 50 treated patients) with the alternative antivenom. While more than 80% of patients were successfully treated with only one dose of Fav-Afrique, more than 60% treated with the alternative antivenom (31 of 50) required more than one dose to control envenoming. Worryingly, the first dose of the alternative antivenom was not able to alleviate spontaneous bleeding at admission in ten of 13 patients, and the administration of additional doses was required. These field data need cautious interpretation. However, they echo findings on the availability of ineffective and potentially harmful antivenoms in sub-Saharan Africa and support the conclusion that post-marketing surveillance is crucial . They also call for a more robust and systematic evaluation of marketed products by regulatory authorities in the affected countries.
The Way Forward
Sanofi Pasteur urgently needs to disclose its plan to mitigate the negative impact of the decision to stop producing Fav-Afrique. Over the longer term, the multi-component strategy described by the Global Snakebite Initiative must be fully financed ; both innovations for better products and interventions and access to quality care need to be enhanced. The vast majority of the trials that we identified were sponsored by public organizations. The snakebite antivenom market so far appears poorly lucrative, unpredictable, and fragmented, hindering investment from pharmaceutical companies . A major donor needs to step in, provide support, and, importantly, encourage existing global health initiatives, such as Drugs for Neglected Diseases initiative (DNDi), the Global Alliance for Vaccine and Immunization (GAVI)-Alliance, or the European and Developing Countries Clinical Trials Partnership (EDCTP), to extend their remits to life-saving treatments for snakebites. Finally, WHO should fully include snakebite envenoming in its list and programme of NTDs, support national regulatory authorities in performing adequate evaluations of existing antivenom products, and establish partnerships for access to existing and future antivenoms. Snakebite envenoming has been a most neglected disease for far too long.
We would like to thank Sarah Venis for her thorough review of the manuscript and Elisabeth Baudin for performing the cleaning and analysis of the data from Paoua, Central African Republic.
- 1. WHO. The 17 Neglected Tropical Diseases. [cited 25 Jul 2014]. http://www.who.int/neglected_diseases/diseases/en/
- 2. Mohapatra B, Warrell DA, Suraweera W, Bhatia P, Dhingra N, Jotkar RM, et al. Snakebite mortality in India: a nationally representative mortality survey. PLoS Negl Trop Dis. 2011;5: e1018. pmid:21532748
- 3. Kasturiratne A, Wickremasinghe AR, de Silva N, Gunawardena NK, Pathmeswaran A, Premaratna R, et al. The global burden of snakebite: a literature analysis and modelling based on regional estimates of envenoming and deaths. PLoS Med. 2008;5: e218. pmid:18986210
- 4. Brown NI. Consequences of neglect: analysis of the sub-Saharan African snake antivenom market and the global context. PLoS Negl Trop Dis. 2012;6: e1670. pmid:22679521
- 5. Wolf A, Mazenot C, Spadoni S, Calvet F, Demoncheaux JP. [FAV-Africa: a polyvalent antivenom serum used in Africa and Europe]. Med Trop (Mars). 2011;71: 537–40.
- 6. Chippaux J-P, Lang J, Amadi-Eddine SM, Fagot P, Le Mener V. Short report: Treatment of snake envenomations by a new polyvalent antivenom composed of highly purified F(ab)2: results of clinical trial in Cameroon. Am J Trop Med Hyg. 1999;61: 1017–1018. pmid:10674688
- 7. Chippaux J-P, Lang J, Eddine SA, Fagot I, Rage V, Le Mener V. Clinical safety of a polyvalent F(ab’) equine antivenom envenomations : a field trial in Cameroon in 223 African snake. Trans R Soc Trop Med Hyg. 1998; 657–662. pmid:10326114
- 8. Pugh RNH, Theakston RDG. Incidence and mortality of snake bite in savanna Nigeria. Lancet 1980; 1181–1183. pmid:6107780
- 9. Gras S. Envenimations ophidiennes en Ouham-Pende [dissertation]. Paris, France: Université Paris-Diderot; 2011.
- 10. Reid HA, Thean PC, Martin WJ. Specific antivenene and prednisone in viper-bite poisoning. Controlled trial. Br Med J. 1963; 1378–1380. pmid:14063030
- 11. Chippaux J-P, Stock RP, Massougbodji A. Methodology of clinical studies dealing with the treatment of envenomation. Toxicon 2010;55: 1195–212. pmid:20219515
- 12. Karnchanachetanee C, Hanvivatvong O, Mahasandana S. Monospecific antivenin therapy in Russell’s viper bite. J Med Assoc Thai. 1994;77: 293–7. pmid:7869015
- 13. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380: 2095–128. pmid:23245604
- 14. Pedrique B, Strub-Wourgaft N, Some C, Olliaro P, Trouiller P, Ford N, Pecoul B, Bradol J-H. The drug and vaccine landscape for neglected diseases (2000–11): A systematic assessment. Lancet Glob Health 2013; e371–e379. pmid:25104602
- 15. Gutierrez JM, Warrell DA, Williams DJ, Jensen S, Brown N, Calvete JJ, Harrison RA. The need for full integration of snakebite envenoming within a global strategy to combat the Neglected Tropical Diseases: the way forward. PLoS Negl Trop Dis 2013;7(6):e2162. pmid:23785526
- 16. Cheng AC, Winkel K. Call for global snake-bite control and procurement funding. Lancet 2001;357: 1132.
- 17. Theakston R, Warrell D. Crisis in snake antivenom supply for Africa. Lancet 2000;356: 2104.
- 18. Visser LE, Kyei-Faried S, Belcher DW, Geelhoed DW, van Leeuwen JS, van Roosmalen J. Failure of a new antivenom to treat Echis ocellatus snake bite in rural Ghana: the importance of quality surveillance. Trans R Soc Trop Med Hyg 2008; 445–450. pmid:18190937
- 19. Williams D, Gutiérrez JM, Harrison R, Warrell DA, White J, Winkel KD, et al. The Global Snake Bite Initiative: an antidote for snake bite. Lancet 2010;375: 89–91. pmid:20109867
- 20. Hung HT, Hojer J, Kiem TX, Du NT. A controlled clinical trial of a novel antivenom in patients envenomed by Bungarus multicinctus. J Med Toxicol 2010; 393–397. pmid:20358414
- 21. Boyer LV, Chase PB, Degan JA, Figge G, Buelna-Romero A, Luchetti C, Alagón A. Subacute coagulopathy in a randomized, comparative trial of Fab and F(ab’)2 antivenoms. Toxicon 2013; 101–108.
- 22. Abubakar IS, Abubakar SB, Habib AG, Nasidi A, Durfa N, Yusuf PO, et al. Randomised controlled double-blind non-inferiority trial of two antivenoms for saw-scaled or carpet viper (Echis ocellatus) envenoming in Nigeria. PLoS Negl Trop Dis. 2010;4: e767. pmid:20668549
- 23. Dart RC, Seifert SA, Boyer LV, Clark RF, Hall E, McKinney P, McNally J, Kitchens CS, Curry SC, Bogdan GM, Ward SB, Porter RS. A randomized multicenter trial of Crotalinae polyvalent immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch Intern Med 2001; 2030–2036. pmid:11525706
- 24. Dart RC, Seifert SA, Carroll L, Clark RF, Hall E, Boyer-Hassen LV, Curry SC, Kitchens CS, Garcia RA. Affinity-purified, mixed monospecific crotalid antivenom ovine fab for the treatment of crotalid venom poisoning. Ann Emerg Med 1997; 33–39. pmid:9209222
- 25. Cardoso JLC, Fan HW, Franca FOS, Jorge MT, Leite RP, Nishioka SA, Avila A, Sano-Martins IS, Tomy SC, Santoro ML, Chudzinski AM, Castro SCB, Kamiguti AS, Kelen EMA, Hirata MH, Mirandola RMS, Theakston RDG, Warrell DA. Randomized comparative trial of three antivenoms in the treatment of envenoming by lance-headed vipers (Bothrops jararaca) in São Paulo, Brazil. Q J Med 1993; 315–325. pmid:8327649
- 26. Jorge MT, Cardoso JLC, Castro SCB, Ribeiro L, Franca FOS, Sbrogio de Almeida ME, Kamiguti AS, Santo-Martins IS, Santoro ML, Mancau JEC, Warrell DA, Theakston RDG, A randomized “blinded” comparison of two doses of antivenom in the treatment of Bothrops envenoming in São Paulo, Brazil. Trans R Soc Trop Med Hyg. 1995; 111–114. pmid:7747293
- 27. Smalligan R, Cole J, Brito N, Laing GD, Mertz BL, Manock S, Maudlin J, Quist B, Holland G, Nelson S, Lalloo DG, Rivadeneira G, Barragan ME, Dolley D, Eddleston M, Warrell DA, Theakston RDG, Crotaline snake bite in the Ecuadorian Amazon: randomised double blind comparative trial of three South American polyspecific antivenoms. Br Med J. 2004; 1129–1133.
- 28. Otero-Patino R, Cardoso JLC, Higashi HG, Nunez V, Diaz A, Toro MF, Garcia ME, Sierra A, Garcia LF, Moreno AM, Medina MC, Castaneda N, Silva-Diaz JF, Murcia M, Cardenas SY, Dias Da Silva WD, Quintero A, Yepes AC, Arboleda M, Blanco N, Brand BN, A randomized, blinded, comparative trial of one pepsin-digested and two whole IgG antivenoms for Bothrops snake bites in Uraba, Colombia. Am J Trop Med Hyg.; 1998; 183–189. pmid:9580075
- 29. De Oliveira Pardal PP, Souza SM, da Costa Monteiro MRC, Fan HW, Cardoso JLC, Franca FOS, Tomy SC, Sano-Martins IS, de Sousa-e-Silva MCC, Colombini M, Kodera NF, Moura-da-Silva AM, Cardoso DF, Velarde DT, Kamiguti AS, Theakston RDG, Clinical trial of two antivenoms for the treatment of Bothrops and Lachesis bites in the north eastern Amazon region of Brazil. Trans R Soc Trop Med Hyg. 2004; 28–42. pmid:14702836
- 30. Otero R, Gutierrez JM, Rojas G, Nunez V, Diaz A, Miranda E, Uribe AF, Silva JF, Ospina JG, Medina Y, Toro MF, Garcia ME, Leon G, Garcia M, Lizano S, De La Torre J, Marquez J, Mena Y, Gonzalez N, Arenas LC, Puzon A, Blanco N, Sierra A, Espinal ME,. A randomized blinded clinical trial of two antivenoms, prepared by caprylic acid or ammonium sulphate fractionation of IgG, in Bothrops and Porthidium snake bites in Colombia: Correlation between safety and biochemical characteristics of antivenoms. Toxicon. 1999; 895–908. pmid:10340829
- 31. Otero R, Gutierrez JM, Nunez V, Robles A, Estrada R, Segura E, Toro MF, Garcia ME, Diaz A, Ramirez EC, Gomez G, Castaneda J, Moreno ME, Canadas R, Bernal E, De Leon P, Vanegas I, Gonzalez G, Huertas M, Agudelo M, Davila ME, Lara M, Diaz LE, Giraldo. A randomized double-blind clinical trial of two antivenoms in patients bitten by Bothrops atrox in Colombia. Trans R Soc Trop Med Hyg. 1996; 696–700. pmid:9015522
- 32. Otero-Patino R, Segura A, Herrera M, Angulo Y, Leon G, Gutierrez JM, Barona J, Estrada S, Pereanez A, Quintana JC, Vargas LJ, Gomez JP, Diaz A, Suarez AM, Fernandez J, Ramirez P, Fabra P, Perea M, Fernandez D, Arroyo Y, Betancur D, Pupo L, Cordoba E, Comparative study of the efficacy and safety of two polyvalent, caprylic acid fractionated [IgG and F(ab’)2] antivenoms, in Bothrops asper bites in Colombia. Toxicon. 2012; 344–355. pmid:22146491
- 33. Otero R, Leon G, Gutierrez JM, Rojas G, Toro MF, Barona J, Rodriguez V, Diaz A, Nunez V, Quintana JC, Ayala S, Mosquera D, Conrado LL, Fernandez D, Arroyo Y, Paniagua CA, Lopez M, Ospina CE, Alzate C, Fernandez J, Meza JJ, Silva JF, Ramirez P. Efficacy and safety of two whole IgG polyvalent antivenoms, refined by caprylic acid fractionation with or without beta-propiolactone, in the treatment of Bothrops asper bites in Colombia. Trans R Soc Trop Med Hyg. Netherlands; 2006; 1173–1182.
- 34. Meyer WP, Habib AG, Onayade AA, Yakubu A, Smith DC, Nasidi A, Daudu IJ, Warrell DA, Theakston RDG, First clinical experiences with a new ovine fab Echis ocellatus snake bite antivenom in Nigeria: Randomized comparative trial with Institute Pasteur Serum (Ipser) Africa antivenom. Am J Trop Med Hyg. 1997; 291–300. pmid:9129531
- 35. Abubakar SB, Abubakar IS, Habib a G, Nasidi a, Durfa N, Yusuf PO, et al. Pre-clinical and preliminary dose-finding and safety studies to identify candidate antivenoms for treatment of envenoming by saw-scaled or carpet vipers (Echis ocellatus) in northern Nigeria. Toxicon. 2010;55: 719–23. pmid:19874841
- 36. Warrell DA, Warrell MJ, Edgar W. Comparison of Pasteur and Behringwerke antivenoms in envenoming by the carpet viper (Echis carinatus). Br Med J. 1980; 607–609. pmid:7370603
- 37. Warrell DA, Davidson McD, N. Omerod LD, Bites by the saw scaled or carpet viper (Echis carinatus): trial of two specific antivenoms. Br Med J. 1974; 437–440.
- 38. Warrell DA, Looareesuwan S, Theakston RDG, Randomized comparative trial of three monospecific antivenoms for bites by the Malayan pit viper (Calloselasma rhodostoma) in Southern Thailand: Clinical and laboratory correlations. Am J Trop Med Hyg. 1986; 1235–1247. pmid:3538922
- 39. Ho M, Silamut K, White NJ, Karbwang J, Looareesuwan S, Phillips RE, et al. Pharmacokinetics of three commercial antivenoms in patients envenomed by the Malayan pit viper, Calloselasma rhodostoma, in Thailand. Am J Trop Med Hyg. 1990;42: 260–266. pmid:2316795
- 40. Malasit P, Warrell DA, Chanthavanich P, Viravan C, Mongkolsapaya J, Singhthong B. Prediction, prevention, and mechanism of early (anaphylactic) antivenom reactions in victims of snake bite. Br Med J (Clin Res Ed). 1986;292: 17–20.
- 41. Pochanugool C, Limthongkul S, Wilde H. Management of Thai cobra bites with a single bolus of antivenin. Wilderness Environ Med. 1997; 20–23. pmid:11990132
- 42. Rojnuckarin P, Chanthawibun W, Noiphrom J, Pakmanee N, Intragumtornchai T. A randomized, double-blind, placebo-controlled trial of antivenom for local effects of green pit viper bites. Trans R Soc Trop Med Hyg. 2006; 879–884. pmid:16466758
- 43. Win-Aung , Tin-Tun , Khin-Maung-Maung , Aye-Kyaw , Hla-Pe , Tin-Nu-Swe , Saw-Naing . Clinical trial of intramuscular anti-snake venom administration as a first aid measure in the field in the management of Russell’s viper bite patients. Southeast Asian J Trop Med Public Health. 1996; 494–497. pmid:9185259
- 44. Ariaratnam CA, Sjostrom L, Raziek Z, Abeyasinghe S, Kularatne M, Arachchi RWKK, Sheriff MHR, Theakston RDG, Warrell DA. An open, randomized comparative trial of two antivenoms for the treatment of envenoming by Sri Lankan Russell’s viper (Daboia russelii russelii). Trans R Soc Trop Med Hyg. 2001; 74–80. pmid:11280073
- 45. Ariaratnam CA, Meyer WP, Perera G, Eddleston M, Kuleratne SAM, Attapattu W, Sheriff R, Richards AM, Theakston RDG, Warrell DA. A new monospecific ovine Fab fragment antivenom for treatment of envenoming by the Sri Lankan Russell’s viper (Daboia russelii russelii): A preliminary dose-finding and pharmacokinetic study. Am J Trop Med Hyg. 1999; 259–265. pmid:10463677
- 46. Paul V, Pratibha S, Prahlad KA, Earali J, Francis S, Lewis F. High-dose anti-snake venom versus low-dose anti-snake venom in the treatment of poisonous snake bites—a critical study. J Assoc Physicians India. 2004; 14–17. pmid:15633711
- 47. Tariang DD, Philip PJ, Alexander G, Macaden S, Jeyaseelan L, Peter JV, Cherian AM, Randomized controlled trial on the effective dose of anti-snake venom in cases of snake bite with systemic envenomation. J Assoc Physicians India. 1999; 369–371. pmid:10778516
- 48. Srimanarayana J, Dutta TK, Sahai A, Badrinath S. Rational use of Anti-snake Venom (ASVS): Trial of various regimens in hemotoxic snake envenomation. J Assoc Physicians India. 2004;52: 788–793. pmid:15909856
- 49. Thomas PP, Jacob J. Randomised trial of antivenom in snake envenomation with prolonged clotting time. Br Med J. 1985; 177–178.
- 50. Sellahewa KH, Gunawardena G, Kumararatne MP, Efficacy of antivenom in the treatment of severe local envenomation by the hump-nosed viper (Hypnale hypnale). Am J Trop Med Hyg. 1995; 260–262. pmid:7573709
- 51. Chippaux J-P, Massougbodji A, Stock RP, Alagon A. Clinical trial of an F(ab')2 polyvalent equine antivenom for African snake bites in Benin. Am J Trop Med Hyg; 2007; 538–46 pmid:17827375