Elsevier

Journal of Proteomics

Volume 74, Issue 9, 24 August 2011, Pages 1768-1780
Journal of Proteomics

Review
Research strategies to improve snakebite treatment: Challenges and progress

https://doi.org/10.1016/j.jprot.2011.06.019Get rights and content

Abstract

Antivenom is an effective treatment of snakebite but, because of the complex interplay of fiscal, epidemiological, therapeutic efficacy and safety issues, the mortality of snakebite remains unacceptably high. Efficiently combating this high level of preventable death amongst the world's most disadvantaged communities requires the globally-coordinated action of multiple intervention programmes. This is the overall objective of the Global Snakebite Initiative. This paper describes the challenges facing the research community to develop snakebite treatments that are more efficacious, safe and affordable than current therapy.

Graphical Abstract

Highlights

► Improve dose-efficacy: monoclonal and short chain variable fragment antibodies. ► Expand geographic & snake-species efficacy: antivenomics and epitope-string immunogens. ► Improve safety of therapy: manufacturing techniques and camelid IgG antivenoms. ► Identify a therapy for effects of local envenoming: MMP peptide inhibitors; camild VHH. ► Improve affordability: increase governmental demand; acquire fiscal support.

Section snippets

The challenge to improve the clinical efficacy of antivenom

Adult horses or sheep are immunised with snake venom/s over a period of months/years and their immunoglobulin is purified to manufacture antivenom. These animals have mature immune systems and during their grazing in open fields are reacting to daily antigenic stimuli. It is therefore not surprising that only 10% of the immunoglobulin in antivenom binds to snake venom proteins [12]. Furthermore, venom-immunisation protocols have changed little over the last century and make no attempt to direct

The challenge to reduce adverse effects of antivenom treatment

Antivenom therapy of snakebite has long been associated with adverse effects that range from early pruritic, urticarial and anaphylactic reactions to later onset of serum-sickness-like reactions. These reactions were particularly frequent and severe in the early 1900s following therapy with antivenoms that were serum based.

Modification of antivenom manufacturing processes to improve IgG purity

To address this deficiency, manufacturers used ammonium sulphate to precipitate IgG from serum/plasma to produce a profoundly improved therapy. Subsequently, because the Fc

The challenge

Bites by many vipers, pit vipers and some elapid species can cause a rapid onset of oedema, blistering, haemorrhage and irreversible necrosis that can culminate in permanent disability or surgical intervention in the form of debridement and amputation [2], [78], [79]. It has been estimated that approximately 400,000 amputations are conducted each year [80] and that the long term sequelae of snakebite affect 500,000 people worldwide [7]. Victims are often young and perform economically

Modifications to reduce manufacturing costs

Manufacturers have already explored several modifications to reduce the cost/vial of antivenom manufacture. Venom immunisation protocols involving a low dose, low volume, multi-site protocol have improved the dose efficacy of antivenoms for treatment of snakebite in SE Asia [71], [111]. In an effort to improve IgG yield from venom-immunised animals and to reduce the number of ‘non-responders,’ antivenom producers are examining the use of modern adjuvants [112], [113]. As discussed above, the

Conclusion

A great deal has been achieved by manufacturers and the toxinological research community to improve the efficacy, safety and affordability of conventionally manufactured antivenoms. The rapid development and improved access to the new proteomic, gene sequencing and bioinformatic technologies has been embraced by the toxinology researchers to identify what appear to be promising leads to further improve snakebite treatment. It becomes apparent however that much of this research is funded through

Acknowledgements

We wish to thank all present and previous staff and student members of the Alistair Reid Venom Research Unit whose research has contributed to this work. We also wish to thank our collaborating colleagues, and particularly in Costa Rica (Instituto Clodomiro Picado), Wales (University of Bangor, MicroPharm), Valencia (Instituto de Biomedicina de Valencia), Dubai (Central Veterinary Research Laboratory) and the many members of the EchiTAb Study Group in Nigeria and UK. We wish to acknowledge

References (120)

  • L. Pillet

    Anti-idiotypic and anti-anti-idiotypic responses to a monoclonal antibody directed to the acetylcholine receptor binding site of curaremimetic toxins

    Biochim Biophys Acta

    (1992)
  • O. Clot-Faybesse

    Monoclonal antibodies against the Androctonus australis hector scorpion neurotoxin I: characterisation and use for venom neutralisation

    FEBS Lett

    (1999)
  • V.R. Juarez-Gonzalez

    Directed evolution, phage display and combination of evolved mutants: a strategy to recover the neutralization properties of the scFv version of BCF2 a neutralizing monoclonal antibody specific to scorpion toxin Cn2

    J Mol Biol

    (2005)
  • M. Mousli

    A recombinant single-chain antibody fragment that neutralizes toxin II from the venom of the scorpion Androctonus australis hector

    FEBS Lett

    (1999)
  • G.P. Espino-Solis

    Antidotes against venomous animals: state of the art and prospectives

    J Proteomics

    (2009)
  • S.B. Abubakar

    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)
  • J.J. Calvete

    Venoms, venomics, antivenomics

    FEBS Lett

    (2009)
  • S.C. Wagstaff et al.

    Venom gland EST analysis of the saw-scaled viper, Echis ocellatus, reveals novel alpha9beta1 integrin-binding motifs in venom metalloproteinases and a new group of putative toxins, renin-like aspartic proteases

    Gene

    (2006)
  • R.A. Harrison

    The conserved structure of snake venom toxins confers extensive immunological cross-reactivity to toxin-specific antibody

    Toxicon

    (2003)
  • R.A. Harrison

    Development of venom toxin-specific antibodies by DNA immunisation: rationale and strategies to improve therapy of viper envenoming

    Vaccine

    (2004)
  • L.M. Alvarenga

    Molecular characterization of a neutralizing murine monoclonal antibody against Tityus serrulatus scorpion venom

    Toxicon

    (2005)
  • K.G. Gazarian

    Immunology of scorpion toxins and perspectives for generation of anti-venom vaccines

    Vaccine

    (2005)
  • A.F. Licea

    Fab fragments of the monoclonal antibody BCF2 are capable of neutralizing the whole soluble venom from the scorpion Centruroides noxius Hoffmann

    Toxicon

    (1996)
  • L.M. Alvarenga

    Production of monoclonal antibodies capable of neutralizing dermonecrotic activity of Loxosceles intermedia spider venom and their use in a specific immunometric assay

    Toxicon

    (2003)
  • P. Guilherme

    Neutralization of dermonecrotic and lethal activities and differences among 32–35 kDa toxins of medically important Loxosceles spider venoms in Brazil revealed by monoclonal antibodies

    Toxicon

    (2001)
  • Q. Li

    Cross-reactivities of monoclonal antibodies to a myotoxin from the venom of the broad-banded copperhead (Agkistrodon contortrix laticinctus)

    Toxicon

    (1993)
  • M.I. Estevao-Costa

    Neutralization of the hemorrhagic activity of Bothrops and Lachesis snake venoms by a monoclonal antibody against mutalysin-II

    Toxicon

    (2000)
  • D.A. Cidade

    Bothrops jararaca venom gland transcriptome: analysis of the gene expression pattern

    Toxicon

    (2006)
  • S. Kashima

    Analysis of Bothrops jararacussu venomous gland transcriptome focusing on structural and functional aspects: I — gene expression profile of highly expressed phospholipases A2

    Biochimie

    (2004)
  • J. Boldrini-Franca

    Crotalus durissus collilineatus venom gland transcriptome: analysis of gene expression profile

    Biochimie

    (2009)
  • Y. Jiang

    Venom gland transcriptomes of two elapid snakes (Bungarus multicinctus and Naja atra) and evolution of toxin genes

    BMC Genomics

    (2011)
  • S.C. Wagstaff

    Combined snake venomics and venom gland transcriptomic analysis of the ocellated carpet viper, Echis ocellatus

    J Proteomics

    (2009)
  • L. Alvarenga

    Design of antibody-reactive peptides from discontinuous parts of scorpion toxins

    Vaccine

    (2010)
  • V. Arce-Estrada

    Neutralization of venom-induced hemorrhage by equine antibodies raised by immunization with a plasmid encoding a novel P-II metalloproteinase from the lancehead pitviper Bothrops asper

    Vaccine

    (2009)
  • G. Azofeifa-Cordero

    Immunization with cDNA of a novel P-III type metalloproteinase from the rattlesnake Crotalus durissus durissus elicits antibodies which neutralize 69% of the hemorrhage induced by the whole venom

    Toxicon

    (2008)
  • M.C. dos Santos

    Purification of F(ab′)2 anti-snake venom by caprylic acid: a fast method for obtaining IgG fragments with high neutralization activity, purity and yield

    Toxicon

    (1989)
  • G. Rojas

    Caprylic acid fractionation of hyperimmune horse plasma: description of a simple procedure for antivenom production

    Toxicon

    (1994)
  • T. Burnouf et al.

    Reducing the risk of infection from plasma products: specific preventative strategies

    Blood Rev

    (2000)
  • M. Herrera

    Factors associated with adverse reactions induced by caprylic acid-fractionated whole IgG preparations: comparison between horse, sheep and camel IgGs

    Toxicon

    (2005)
  • F. Meddeb-Mouelhi

    Immunized camel sera and derived immunoglobulin subclasses neutralizing Androctonus australis hector scorpion toxins

    Toxicon

    (2003)
  • R.A. Harrison

    Neutralisation of venom-induced haemorrhage by IgG from camels and llamas immunised with viper venom and also by endogenous, non-IgG components in camelid sera

    Toxicon

    (2006)
  • R. Pratanaphon

    Production of highly potent horse antivenom against the Thai cobra (Naja kaouthia)

    Vaccine

    (1997)
  • L. Chinonavanig

    Antigenic relationships and relative immunogenicities of venom proteins from six poisonous snakes of Thailand

    Toxicon

    (1988)
  • D.A. Cook

    Analysis of camelid IgG for antivenom development: serological responses of venom-immunised camels to prepare either monospecific or polyspecific antivenoms for West Africa

    Toxicon

    (2010)
  • D.A. Cook

    Analysis of camelid IgG for antivenom development: immunoreactivity and preclinical neutralisation of venom-induced pathology by IgG subclasses, and the effect of heat treatment

    Toxicon

    (2010)
  • D.A. Cook

    Analysis of camelid antibodies for antivenom development: neutralisation of venom-induced pathology

    Toxicon

    (2010)
  • G.P. Fernandez

    Neutralization of Bothrops mattogrossensis snake venom from Bolivia: experimental evaluation of llama and donkey antivenoms produced by caprylic acid precipitation

    Toxicon

    (2010)
  • E.M. Einterz et al.

    Snakebite in northern Cameroon: 134 victims of bites by the saw-scaled or carpet viper, Echis ocellatus

    Trans R Soc Trop Med Hyg

    (2003)
  • J.F. Trape

    High mortality from snakebite in south-eastern Senegal

    Trans R Soc Trop Med Hyg

    (2001)
  • J.M. Gutierrez et al.

    Snake venom metalloproteinases: their role in the pathogenesis of local tissue damage

    Biochimie

    (2000)
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