Biogeographic venom variation in Russell's viper (Daboia russelii) and the preclinical inefficacy of antivenom therapy in snakebite hotspots

Background Snakebite in India results in over 58,000 fatalities and a vast number of morbidities annually. The majority of these clinically severe envenomings are attributed to Russell's viper (Daboia russelii), which has a near pan-India distribution. Unfortunately, despite its medical significance, the influence of biogeography on the composition and potency of venom from disparate D. russelii populations, and the repercussions of venom variation on the neutralisation efficacy of marketed Indian antivenoms, remain elusive. Methods Here, we employ an integrative approach comprising proteomic characterisation, biochemical analyses, pharmacological assessment, and venom toxicity profiling to elucidate the influence of varying ecology and environment on the pan-Indian populations of D. russelii. We then conducted in vitro venom recognition experiments and in vivo neutralisation assays to evaluate the efficacy of the commercial Indian antivenoms against the geographically disparate D. russelii populations. Findings We reveal significant intraspecific variation in the composition, biochemical and pharmacological activities and potencies of D. russelii venoms sourced from five distinct biogeographic zones across India. Contrary to our understanding of the consequences of venom variation on the effectiveness of snakebite therapy, commercial antivenom exhibited surprisingly similar neutralisation potencies against the majority of the investigated populations, with the exception of low preclinical efficacy against the semi-arid population from northern India. However, the ability of Indian antivenoms to counter the severe morbid effects of Daboia envenoming remains to be evaluated. Conclusion The concerning lack of antivenom efficacy against the north Indian population of D. russelii, as well as against two other 'big four' snake species in nearby locations, underscores the pressing need to develop pan-India effective antivenoms with improved efficacy in high snakebite burden locales. Author summary The Russell's viper (Daboia russelii), with a near-countrywide distribution, is arguably the deadliest snake species in India. Despite being responsible for the majority of snakebite deaths in the country, the influence of biogeography on its venom composition and potency, and the impact of this variation on snakebite therapy, is yet to be understood. Evaluation of the composition, biochemical activities, pharmacological implications and potencies of D. russelii venoms from five distinct biogeographic zones in India (>5,800 km) revealed remarkable intraspecific differences in venom profiles. Surprisingly, these observed differences did not seem to affect the marketed effectiveness of the commercial Indian antivenoms in countering the lethal effects of D. russelii venoms, with the exception of the North Indian semi-arid population. A similar lack of antivenom potency has also been documented in two other 'big four' snake species in these regions that suffer the brunt of snakebite. These alarming findings underscore the pressing need to develop pan-India efficacious antivenoms, especially for the treatment of snakebites in regions that are worst affected by this neglected tropical disease.

Automated summary

In India, snakebite results in a high number of fatalities and morbidities annually, with Russell's viper being a major contributor to these cases. Despite significant intraspecific variation in venom composition and potency across different biogeographic zones in India, commercial antivenoms have shown similar neutralisation potencies against most venom populations, except for low efficacy against the semi-arid population in northern India. There is a pressing need for the development of pan-India effective antivenoms, especially in regions heavily impacted by snakebites.