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Dawson, Charlotte (2021) Development of a Novel Therapeutic for the Treatment of Snakebite Induced Necrosis in Sub-Saharan Africa, Thesis (Doctoral), Liverpool School of Tropical Medicine.
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C Dawson - Final Thesis.pdf - Accepted Version Download (4MB) | Preview |
Abstract
Every year 1.8 - 2.7 million people suffer snakebite envenoming, of these, an estimated 81,000 - 138,000 die and 400’000 are left disfigured or disabled. The disfigurement and disability caused by snakebite induced necrosis leaves significant physical and psychological damage, and places already impoverished people under further economic pressures through the loss of income. Although antivenom represents the only currently approved therapeutics for the treatment of snakebite, its efficacy in the treatment of snakebite necrosis is highly debated. There is a clear clinical need for an antivenom that is safe, affordable, and effective in the treatment of snakebite necrosis.
A challenge to the efficacy of current antivenoms is the extensive intra-specific variation seen between different geographic populations within a species. The African Puff adder, Bitis arietans, is one of the most medically important snakes in sub-Saharan African but the extent of this variation is still being elucidated. Through the application of venom gland transcriptomics and in vitro functional assays to B. arietans specimens from Nigeria, Tanzanian and South Africa, I was able to demonstrate that there is considerable variation between these different populations. Extensive venom variation can have a deleterious impact on the efficacy of antivenoms, but this has not yet been explored in the context of B. arietans. Through the application of immunological assays and further in vitro testing I was able to show that for two antivenoms, EchiTAb-Plus and SAIMR Polyvalent, that the extensive variation in B. arietans does not appear to hamper antivenom activity. These findings are an encouraging finding for the efficacy of these antivenom therapies even when treating highly variable venom compositions.
Improving the efficacy of antivenoms in the treatment of snakebite-induced necrosis is a key criterion for the next-generation of snakebite therapeutics. Linear B-cells epitopes are short peptides displayed by antigen presenting cells to elicit an immune response and this approach has been shown effective in prior studies. Rationally designed epitopes represent a promising avenue for developing a sub-Saharan antivenom for the treatment of snakebite necrosis. By bioinformatically examining toxin sequences from the most medically important necrotic species from sub-Saharan Africa (Echis ocellatus, Bitis arietans and Naja nigriciollis) Through the bioinformatic interrogation of sequences of the most pathologically relevant necrosis-inducing toxins (snake venom metalloproteinases, hyaluronidases, and three-finger toxins) I was able to generate a panel of B-cell epitopes to be used as immunogens. In additional to the adoption, and expansion of the B-cell epitope response, there is also significant scope to improve the immunisation strategy to produce toxin-specific antibodies are raised. A prime example is the use of hepatitis B virus-like particles (HBcVLP) for the display and delivery of heterologous epitopes, an approach which has shown immense promise within the field of vaccinology.
The data here show that through the delivery of toxin-specific B-cell immunogens it is possible to raise a toxin-specific response for a sub-set of the necrosis toxins of interest (specifically PLA2 and SVMPs). Furthermore, through the application of in vitro functional assays, it was possible to demonstrate that experimental anti-SVMP IgG were able to neutralise toxin activity in a manner comparable to current antivenoms. These findings represent a stepping-stone in the progression towards the development of a safe, affordable, and effective anti-necrotic therapeutic with pan-African capabilities, the development of which would represent a significant shift in the ability to care for snakebite patients.
| Item Type: | Thesis (Doctoral) |
|---|---|
| Subjects: | QV Pharmacology > Toxicology > General Toxicology > QV 601 Antidotes and other therapeutic measures WD Disorders of Systemic, Metabolic or Environmental Origin, etc > Animal Poisons > WD 410 Reptiles |
| Faculty: Department: | Biological Sciences > Department of Tropical Disease Biology |
| Depositing User: | Lynn Roberts-Maloney |
| Date Deposited: | 11 Nov 2021 10:03 |
| Last Modified: | 11 Feb 2022 02:02 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/19403 |
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