Therapeutic research

The ARVRU has been heavily involved in undertaking and publishing research on the development, testing and delivery of snakebite therapies known as antivenoms. These antibody-based therapeutics are the cornerstone of snakebite treatment, although their method of production has changed little over the past century:  horses or sheep are hyper-immunised with harmless amounts of venom, and antivenom is prepared from the IgG antibodies isolated from the animals’ blood.

Polyspecific antivenoms are required for regions like sub-Saharan Africa because of the diversity of venomous snakes, and are prepared by immunising horses with venoms from multiple snakes. This however creates a therapeutic paradox because the proportion of IgG in a vial that targets the venom of any one species is small, necessitating the administration of multiple vials to achieve cure. However, each extra vial of polyspecific antivenom increases both the risk of severe antivenom-induced adverse effects (anaphylactic shock and serum sickness) and the cost to the patient. The focus of our therapeutic research is to dislocate the various factors causing this polyspecific antivenom efficacy paradox by developing next-generation of antivenoms designed to have unparalleled snake species efficacy, affordability and safety.

 

 

 

Next-generation antivenoms

Toxin-specific antivenoms

Using a genetic engineering approach, we are currently pioneering the development of toxin-specific antivenoms to treat envenoming by multiple snake species. By characterising the toxin genes expressed in the venom glands of different snakes, we can identify which venom proteins are common to all snake species and distinguish those that are (toxins), and are not, likely to be responsible for causing life-threatening pathology during snakebite. We interrogate these toxin DNA datasets to identify regions of these genes that are cross-species conserved and likely to generate an immune response, and then assemble these ‘domains’ into synthetic proteins for immunisation. The resulting antibodies are thus specific only to the pathological toxins in the venoms of multiple snake species. The improved toxin-specificity of these experimental antivenoms should confer greater dose efficacy over conventional antivenoms and thus greatly reduce both the risks of adverse effects and costs to the victim.

Geographical antivenoms

Part of the reason that antivenoms are unaffordable to the rural poor is that each antivenom is specific to treating snakebite by relatively few snake species, and therefore sales and profit for the antivenom manufacturer are low. Producing a single antivenom for use in an entire geographical region should provide economies of scale to make antivenom manufacturing more amenable to commercial entities. To this end we are using “antivenomic” approaches to improve the geographical cover of existing antivenoms. By first using proteomic technologies to identify which snake venom toxins are not neutralised by an existing antivenom, we can then isolate those toxins and add these to the immunising mixture. By doing so, the new version of the antivenom should show greater efficacy to additional snake species found in the region of interest. We are currently using this approach to develop a new antivenom for the whole of sub-Saharan Africa.

Antivenom for treating local tissue pathology

Envenoming by many snakes causes extensive tissue death (necrosis). Antivenom IgG is administered intravenously to treat systemic envenoming, but is too large (150 kDa) to rapidly cross the blood/tissue barrier to neutralise the venom toxins responsible for causing necrosis. Surgical debridement or amputation of the affected tissue is therefore performed to prevent spread of life-threatening gangrene. This problem is so commonplace that 8,000 amputations are performed on snakebite victims every year in Africa alone. We were the first to demonstrate that the uniquely small parts of camelid IgG (VHH) provide the most dose-effective immunotherapy ever developed against the local tissue-destructive and systemic effects of snake venom. The research challenge is to modify this novel experimental result into a venom-necrosis therapy for Africa that is affordable, effective at ambient temperatures and easily applied as an immediate First Aid tool.