ReviewResearch strategies to improve snakebite treatment: Challenges and progress
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
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2020, Toxicon: XCitation Excerpt :Genomics (A) can enable identification of possible toxins in an unknown venom based on tissue samples of the animal in question, and hence provide some basis for treatment options in case of future envenomations. Transcriptomics (B) and proteomics (C) provide a clearer picture of what toxins are actually present in the venom and also provide resources for development of new (and in some cases synthetic) antivenom treatments (Calvete, 2010; Williams et al., 2011; Harrison et al., 2011). An understanding of whole venoms (D), including venom/toxin yields and synergistic effects of toxins, will inform predictions of the likely severity of envenomations (Mirtschin et al., 2002) and a fuller range of expected symptoms beyond simple lists of toxins present.