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 [
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 [
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).
Trial ID number | Title | Sponsor | Type of funding | Location | Year of trial registration | Recruitment status | Results published |
---|---|---|---|---|---|---|---|
NCT00303303 | The Efficacy of Crotaline Fab Antivenom for Copperhead Snake Envenomations | Carolinas Healthcare System | Government | United States | 2006 | Terminated | No |
NCT00636116 | Phase 3 Multicenter Comparative Study to Confirm Safety and Effectiveness of the F(ab)2 Antivenom Anavip | Instituto Bioclon S.A. de C.V. | Industry | US | 2008 | Completed | No |
NCT00639951 | Study to Evaluate the Efficacy of Two Treatment Schemes With Antivipmyn for the Treatment of Snake Bite Envenomation | Instituto Bioclon S.A. de C.V. | Industry | Mexico | 2008 | Recruiting | NA |
NCT00811239 | A Controlled Clinical Trial on The Use of a Specific Antivenom Against Envenoming by |
Hanoi Medical University | Government | Vietnam | 2008 | Completed | Yes [ |
NCT00868309 | A Comparison of Crotalinae (Pit Viper) Equine Immune F(ab)2 Antivenom (Anavip) and Crotalidae Polyvalent Immune Fab, Ovine Antivenom (CroFab) in the Treatment of Pit Viper Envenomation | Instituto Bioclon S.A. de C.V. | Industry | US | 2008 | Completed | Yes [ |
ISRCTN01257358 | Clinical trial of two new anti-snake venoms for the treatment of patients bitten by poisonous snakes in Nigeria | Nigeria MoH | Unknown | Nigeria | 2009 | Completed | Yes [ |
SLCTR/2010/006 | Low dose versus high dose of Indian polyvalent snake antivenom in reversing neurotoxic paralysis in common krait ( |
Individual researcher | None | Sri Lanka | 2010 | Not recruiting | No |
ACTRN12611000588998 | A randomised controlled trial of antivenom and corticosteroids for red-bellied black snake envenoming | Individual researcher | Government | Australia | 2011 | Not recruiting | No |
NCT01284855 | Comparison of Two Dose Regimens of Snake Antivenom for the Treatment of Snake Bites Envenoming in Nepal | University of Geneva | Government | Nepal | 2011 | Not recruiting | No |
NCT01337245 | Emergency Treatment of Coral Snake Envenomation With Antivenom | University of Arizona | Government | US | 2011 | Recruiting | NA |
ACTRN12612001062819 | A randomized controlled trial (RCT) of a new monovalent antivenom (ICP Papuan taipan antivenom) for the treatment of Papuan taipan ( |
University of Melbourne | Government | Papua New Guinea | 2012 | Recruiting | NA |
NCT01864200 | A Randomized, Double-Blind, Placebo-Controlled Study Comparing CroFab Versus Placebo With Rescue Treatment for Copperhead Snake Envenomation (Copperhead RCT) | BTG International Inc. | Industry | US | 2013 | Recruiting | NA |
The publication database search yielded 97 results (
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
Product name | Other name/product specifications | Manufacturer | Development stage |
Target region | Publications | Clinical trials registry number |
---|---|---|---|---|---|---|
CroFab | Polyvalent ovine antivenom (Fab) against Crotalid | Protherics | Phase III–IV | North America | [ |
NCT00303303 NCT00636116 NCT00868309 NCT01864200 |
Anavip | Polyvalent equine antivenom (Fab2) against Crotalinae (pit viper) | Instituto Bioclon S.A. | Terminated after Phase III | North America | [ |
NCT00868309 NCT00636116 |
Antivypmin | Polyvalent equine antivenom (Fab2) against Crotalinae (pit viper) | Instituto Bioclon S.A. | Phase III | North America | None | NCT00639951 |
NA | Polyvalent equine antivenom (Fab2) against North American Coral snakes ( |
University of Arizona | Phase III | North America | None | NCT01337245 |
Tiger snake antivenom | Monovalent equine (Fab) against |
CSL | Phase III–IV | Australia | None | ACTRN12611000588998 |
Taipan antivenom | Monovalent equine (Fab) against |
CSL | Phase I–II | Australia | None | ACTRN12612001062819 |
Antibotropico IVB | Instituto Vital Brazil | Phase II | Latin America | [ |
None | |
Antibotropico Butantan | Polyvalent equine antivenom against |
Instituo Butantan | Phase II–III | Latin America | [ |
None |
Antibotropico FUNED | Fundação Ezequiel Dias | Terminated | Latin America | [ |
None | |
Antibotropico-laquetico Butantan | Bothrops-Lachesis polyvalent equine antivenom | Instituo Butantan | Phase II | Latin America | [ |
None |
Antiofiodico botropico polivalente | Polyvalent equine antivenom (IgG) against |
Instituto Nacional de Higiene y Medicina Tropical "Leopoldo Izquieta Pérez" | Phase II–III | Latin America | [ |
None |
Monovalent |
Instituto Clodomiro Picado | Terminated | Latin America | [ |
None | |
Monovalent |
Instituto Nacional de Salud | Terminated | Latin America | [ |
None | |
Polyvalent equine antivenom (IgG) against |
Fundação Ezequiel Dias | Terminated | Latin America | [ |
None | |
Polyvalent Antivenom | Polyvalent equine antivenom (IgG) against |
Instituto Nacional de Salud | ? | Latin America | [ |
None |
Polyvalent antivenom ICP | Polyvalent equine antivenom (IgG or Fab2) |
Instituto Clodomiro Picado (University of Costa Rica) | Phase II | Latin America | [ |
None |
EchiTab | Monovalent ovine antivenom (Fab) against |
Therapeutic Antibodies/Micropharm | ? | Sub-Saharan Africa | [ |
None |
EchiTab Plus | Polyvalent equine antivenom against |
Instituto Clodomiro Picado (University of Costa Rica) | Phase I–II | Sub-Saharan Africa | [ |
ISRCTN01257358 |
EchiTab G | Monovalent antivenom (IgG) against |
Micropharm | Phase I–II | Sub-Saharan Africa | [ |
ISRCTN01257358 |
EgyVac antivenom | Equine polivalent antivenom against |
Vacsera Ltd | Terminated after Phase I | Sub-Saharan Africa | [ |
None |
Ipser Africa Antivenom | Polyvalent equine (Fab2) antivenom against |
Institut Pasteur | ? | Sub-Saharan Africa | [ |
None |
Monospecific antivenom against |
Institut Pasteur | ? | Sub-Saharan Africa | [ |
None | |
SAIMR Echis antivenom | Monovalent equine antivenom (IgG or Fab2) against |
South African Vaccines Producer | ? | Sub-Saharan Africa | [ |
None |
North and West African polyvalent antivenom ( |
Behningwerke | ? | Sub-Saharan Africa | [ |
None | |
Malayan pit viper antivenom | Monovalent equine antivenom against |
Queen Saovabha Memorial Institute | Phase I–II | South East Asia | [ |
None |
Malayan pit viper antivenom | Monovalent caprine antivenom against |
Twyford Pharmaceutical | Phase I–II | South East Asia | [ |
None |
Malayan pit viper antivenom | Monovalent equine antivenom against |
Thai Government Pharmaceutical Organisation | Phase I–II | South East Asia | [ |
None |
Monocellate cobra antivenom | Monovalent equine antivenom against aja. |
Queen Saovabha Memorial Institute | ? | South East Asia | [ |
None |
Green pit viper antivenin (QSMI) | Polyvalent equine antivenom (Fab2) against green pit vipers | Queen Saovabha Memorial Institute | Phase I–II | South East Asia | [ |
None |
Polyvalent equine antivenom (Fab2) against |
Vietnam Poison Control Center, Hanoi Medical University | Phase I–II | South East Asia | [ |
NCT00811239 | |
Monospecific antivenom against |
Myanmar Pharmaceutical Factory | ? | South East Asia | [ |
None | |
ProlongaTab | Monovalent ovine antivenom (Fab) against |
Therapeutic Antibodies Inc | Terminated | South Asia | [ |
None |
SII Polyvalent ASV IP | Polyvalent equine antivenom (Fab2) against |
India Serum Institute | ? | South Asia | [ |
None |
Snake antivenin IP | Polyvalent equine antivenom (Fab2) against |
Haffkine Biopharmaceutical Corporation Ltd | Phase II | South Asia | [ |
None |
Snake venom anti-serum | Polyvalent equine F(ab)2 against |
VINS bioproducts | Phase II | South Asia | None | SLCTR/2010/006 NCT01284855 |
Snake venom antiserum | Polyvalent equine F(ab)2 against |
Bharat Serum and Vaccines Ltd | Phase II | South Asia | None | SLCTR/2010/006 |
1 Not all publications mentioned the trial phase, and development status was established based on trial design, primary objectives, and number of subjects. This classification, though, bears some limitations, especially with regards to snake antivenoms development, in which Phase I with healthy volunteers are generally not conducted.
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 [
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 (
Product | Company | Country of production |
---|---|---|
Antivipmyn-Africa | Instituto Bioclon/Silanes | Mexico |
ASNA-C | Bharat Serums and Vaccines | India |
ASNA-D | Bharat Serums and Vaccines | India |
EchiTabG | MicroPharm | United Kingdom |
EchiTabPlus | Instituto Clodomiro Picado | Costa Rica |
Fav-Afrique | Sanofi Pasteur | France |
Inoserp PanAfrica | Inosan | Spain |
SAIMR Boomslang antivenom | South African Vaccine Producers | South Africa |
SAIMR Echis antivenom | South African Vaccine Producers | South Africa |
SAIMR Polyvalent Snake antivenom | South African Vaccine Producers | South Africa |
Snake Venom Antiserum (Pan-African) | VINS Bioproducts | India |
Snake venom antiserum Echis ocellatus | VINS Bioproducts | India |
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
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 [
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.