IISc efforts to save country’s 2L annual snakebite victims

A detailed study on snakebites carried out by the Centre for Ecological Sciences (CES) of the Indian Institute of Sciences (IISc) along with other collaborators stresses the importance of developing recombinant antivenoms which can be produced in cells on culture plates.

India is the world’s snakebite hotspot, with 58,000 fatalities and 1,40,000 morbidities occurring annually. Spectacled cobra (Naja naja) and Russell’s viper (Daboia russelii) are known to cause the majority of these envenomations, in part due to their near country-wide distributions. However, the impact of differing ecologies and environment on their venom compositions has not been comprehensively studied.

Majority of snakebites that lead to death or disability are attributed to the ‘big four’ of Indian snakes — the Russell’s viper (Daboia russelii), one of the deadliest snake species in the world, the spectacled cobra (Naja naja), the common krait (Bungarus caeruleus) and the saw-scaled viper (Echis carinatus).

Kartik Sunagar, Assistant Professor at the IISc’s CES and the corresponding author of this study stated that there is an urgent need for immediate production of region-specific antivenoms for deadly snakes in snakebite hotspots of the country in order to ensure that antivenoms are more effective against variants of snake venom.

“At least developing region-specific antivenoms for deadly snakes in snakebite hotspots of the country can safeguard the lives, limbs and livelihoods of the country’s 2,00,000 annual snakebite victims,” he said.

He stated that as a long-term strategy the country needs to focus on developing recombinant antivenoms to bring down death and morbidity due to snakebites.

Sunagar also stresses the importance of developing recombinant antivenoms (which can be produced in cells on culture plates instead of the current method of using horse antibodies) for increased efficacy, specificity, and safety — an area that his lab is working on as well.

He claims that recombinant antibodies could be developed by various approaches and in different formats (e.g., monoclonal, oligoclonal, intact IgG, nanobodies, etc.), and could be human-derived or humanised, and engineered to specifically target clinically important toxins detected across distinct snake populations and species.

“Thus, recombinant therapy has the potential to deliver many advantages over conventional antivenom therapy, including high dose efficacy, pan-Indian efficacy, and improved safety profiles. The cost of production is the only current limitation of recombinant therapy as this entirely depends on the number of neutralising antibodies in the commercial antivenom concoction,” Sunagar argues.

He, however, added that the cost of production could be overcome by discovering and engineering broadly effective/paraspecific antibodies.

“The recombinant expression of such broadly neutralising antibodies should therefore be strongly pursued as long-term replacements of conventional antivenoms to enable rural Indian communities to access safe and efficacious life-saving snakebite therapies,” Sunagar said.

In a study published in PLoS Neglected Tropical Diseases, researchers at IISc’s Centre for Ecological Sciences (CES) and collaborators demonstrated that the venom of Russell’s vipers shows dramatic differences in composition and toxicity based on geographical location.

“Snake venom is known to be an adaptive trait that can vary depending on the environment. To demonstrate this in Russell’s vipers, the researchers used analytical techniques such as SDS-PAGE and reversed-phase HPLC, which reveal variations in composition and abundance of venom components. Mass spectrometry helped to identify the constituents of the venoms,” the study pointed out.

“An immediate solution to this problem could be the identification of medically important snakes by regions, i.e., consideration of both the ‘big four’ and the ‘neglected many’ (medically important yet neglected lineages of snakes), and the inclusion of their venoms in the immunisation mixture for formulating regionally-effective antivenoms,” he recommends.

He said that given the considerable biotic and abiotic diversity in India, and the remarkable geographic venom variability among snakes, the conventional antivenom is doomed to failure in regions with disparate populations of ‘big four’ and/or other distinct venomous snake species.

The study adds that since Indian antivenoms have never undergone clinical validation through formal clinical trials, robust data on their efficacy and safety is currently unavailable. “Given the potential for significant batch-to-batch variation and treatment failure due to venom variation, stringent evaluation of the preclinical efficacy of antivenoms, ideally by an independent external laboratory or at the very least the publication of manufacturer-generated data for independent assessment, should be mandatory prior to marketing,” the paper stated.

Pointing out at the inherent flaws of antivenom procuring systems by various governments, the paper stated that the license to sell commercial antivenoms in various Indian states is currently based on a tender system.

“Instead, licensure should be strictly based on the outcomes of such rigorous preclinical evaluation. In addition, the procurement and qualification guidelines for venoms used for immunisation during the manufacturing process should take into account the influence of various ecological and environmental factors on venom variability,” the paper recommended.

“Commercial antivenom treatment for snakebite does not always prove effective, and despite the severity of the problem in India, few efforts have been made to understand why this is so,” the study observed.

According to the paper, antivenoms are cocktails of antibodies that bind to the toxins in the venom and neutralise them.

“Commercial antivenoms are often deployed in the market without preclinical assessments, which are typically done using animals, or clinical studies, which involve testing on humans. To understand the actual efficacy of antivenom against Russell’s viper venom, the researchers collected venom from 48 individual vipers in five biogeographical regions of India, as well as tested how well the antivenom neutralised the different types of venoms in mice,” the paper observes.