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.
The Andaman and Nicobar Islands are an abode to a diversity of flora and fauna, including the many endemic species of snakes, such as the elusive Andaman cobra (Naja sagittifera). However, the ecology and evolution of venomous snakes inhabiting these islands have remained entirely uninvestigated. This study aims to bridge this knowledge gap by investigating the evolutionary history of N. sagittifera and its venom proteomic, biochemical and toxicity profile. Phylogenetic reconstructions confirmed the close relationship between N. sagittifera and the Southeast Asian monocellate cobra (N. kaouthia). Overlooking this evolutionary history, a polyvalent antivenom manufactured using the venom of the spectacled cobra (N. naja) from mainland India is used for treating N. sagittifera envenomations. Comparative evaluation of venoms of these congeners revealed significant differences in their composition, functions and potencies. Given the close phylogenetic relatedness between N. sagittifera and N. kaouthia, we further assessed the cross-neutralising efficacy of Thai monovalent N. kaouthia antivenom against N. sagittifera venoms. Our findings revealed the inadequate preclinical performance of the Indian polyvalent and Thai monovalent antivenoms in neutralising N. sagittifera venoms. Moreover, the poor efficacy of the polyvalent antivenom against N. naja venom from southern India further revealed the critical need to manufacture region-specific Indian antivenoms.
Snake envenoming afflicts the Indian subcontinent with the highest rates of mortality (47,000) and morbidity globally. The only effective treatment for snakebites is the administration of antivenom, which is produced by the hyperimmunisation of equines. Commercial Indian antivenoms, however, have been shown to exhibit a poor preclinical performance in neutralising venom, as a result of inter- and intrapopulation snake venom variation. Additionally, their poor dose effectiveness necessitates the administration of larger volumes of antivenom for treatment, leading to several harmful side effects in snakebite victims, including serum sickness and fatal anaphylaxis. In this study, we employed chromatographic purification to enhance the dose efficacy of commercial Indian antivenoms. The efficacy of this ‘second-generation’ antivenom was comparatively evaluated against six other marketed antivenoms using a number of in vitro and in vivo preclinical assays, which revealed its superior venom recognition capability. Enhanced purity also resulted in significant improvements in dose effectiveness, as the ‘second-generation’ antivenom exhibited a 3 to 4.5 times increased venom neutralisation potential. Furthermore, preclinical assays revealed the increased effectiveness of the ‘second-generation’ antivenom in countering morbid effects inflicted by the ‘big four’ Indian snakes. Thus, we demonstrate the role of simpler purification steps in significantly enhancing the effectiveness of snakebite therapy in regions that are most affected by snakebites.
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