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.

Biogeographical venom variation in the Indian spectacled cobra (Naja naja) underscores the pressing need for pan-India efficacious snakebite therapy.

BACKGROUND: Snake venom composition is dictated by various ecological and environmental factors, and can exhibit dramatic variation across geographically disparate populations of the same species. This molecular diversity can undermine the efficacy of snakebite treatments, as antivenoms produced against venom from one population may fail to neutralise others. India is the world's snakebite hotspot, with 58,000 fatalities and 140,000 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. METHODS: Here, we used a multi-disciplinary approach consisting of venom proteomics, biochemical and pharmacological analyses, and in vivo research to comparatively analyse N. naja venoms across a broad region (>6000 km; seven populations) covering India's six distinct biogeographical zones. FINDINGS: By generating the most comprehensive pan-Indian proteomic and toxicity profiles to date, we unveil considerable differences in the composition, pharmacological effects and potencies of geographically-distinct venoms from this species and, through the use of immunological assays and preclinical experiments, demonstrate alarming repercussions on antivenom therapy. We find that commercially-available antivenom fails to effectively neutralise envenomations by the pan-Indian populations of N. naja, including a complete lack of neutralisation against the desert Naja population. CONCLUSION: Our findings highlight the significant influence of ecology and environment on snake venom composition and potency, and stress the pressing need to innovate pan-India effective antivenoms to safeguard the lives, limbs and livelihoods of the country's 200,000 annual snakebite victims.

Trends in snakebite deaths in India from 2000 to 2019 in a nationally representative mortality study.

The World Health Organization call to halve global snakebite deaths by 2030 will require substantial progress in India. We analyzed 2833 snakebite deaths from 611,483 verbal autopsies in the nationally representative Indian Million Death Study from 2001 to 2014, and conducted a systematic literature review from 2000 to 2019 covering 87,590 snakebites. We estimate that India had 1.2 million snakebite deaths (average 58,000/year) from 2000 to 2019. Nearly half occurred at ages 30-69 years and over a quarter in children < 15 years. Most occurred at home in the rural areas. About 70% occurred in eight higher burden states and half during the rainy season and at low altitude. The risk of an Indian dying from snakebite before age 70 is about 1 in 250, but notably higher in some areas. More crudely, we estimate 1.11-1.77 million bites in 2015, of which 70% showed symptoms of envenomation. Prevention and treatment strategies might substantially reduce snakebite mortality in India.

Beyond the 'big four': Venom profiling of the medically important yet neglected Indian snakes reveals disturbing antivenom deficiencies.

BACKGROUND: Snakebite in India causes the highest annual rates of death (46,000) and disability (140,000) than any other country. Antivenom is the mainstay treatment of snakebite, whose manufacturing protocols, in essence, have remained unchanged for over a century. In India, a polyvalent antivenom is produced for the treatment of envenomations from the so called 'big four' snakes: the spectacled cobra (Naja naja), common krait (Bungarus caeruleus), Russell's viper (Daboia russelii), and saw-scaled viper (Echis carinatus). In addition to the 'big four', India is abode to many other species of venomous snakes that have the potential to inflict severe clinical or, even, lethal envenomations in their human bite victims. Unfortunately, specific antivenoms are not produced against these species and, instead, the 'big four' antivenom is routinely used for the treatment. METHODS: We characterized the venom compositions, biochemical and pharmacological activities and toxicity profiles (mouse model) of the major neglected yet medically important Indian snakes (E. c. sochureki, B. sindanus, B. fasciatus, and two populations of N. kaouthia) and their closest 'big four' congeners. By performing WHO recommended in vitro and in vivo preclinical assays, we evaluated the efficiencies of the commercially marketed Indian antivenoms in recognizing venoms and neutralizing envenomations by these neglected species. FINDINGS: As a consequence of dissimilar ecologies and diet, the medically important snakes investigated exhibited dramatic inter- and intraspecific differences in their venom profiles. Currently marketed antivenoms were found to exhibit poor dose efficacy and venom recognition potential against the 'neglected many'. Premium Serums antivenom failed to neutralise bites from many of the neglected species and one of the 'big four' snakes (North Indian population of B. caeruleus). CONCLUSIONS: This study unravels disturbing deficiencies in dose efficacy and neutralisation capabilities of the currently marketed Indian antivenoms, and emphasises the pressing need to develop region-specific snakebite therapy for the 'neglected many'.

Snakebite Mitigation Project of the Madras Crocodile Bank/Centre for Herpetology, India: background and a brief summary of activities.

Snakebite is a serious problem in rural India where several highly venomous species are commonly found in and around agricultural areas where prey such as rodents and amphibians are abundant. Four snake species, referred to as the Big Four, are responsible for the most serious and fatal bites: spectacled cobra (Naja naja), Russell's viper (Daboia russelii), common krait (Bungarus caeruleus) and saw-scaled viper (Echis carinatus). A polyvalent antivenom is made to treat these bites but public awareness and distribution of this life-saving drug is inadequate. The Madras Crocodile Bank and its partners are conducting a snakebite project which includes venom sampling and research, snake and snakebite treatment centre mapping, and a nationwide awareness campaign for snakebite mitigation.

Venomous Snake Bite in India - Why do 50,000 Indians Die Every Year?

Snakebite is an occupational hazard causing considerable morbidity and mortality worldwide, particularly so in tropical countries like India. An estimated 50,000 Indians die due to venomous snakebite every year, seventy percent of whom are males between the ages of 20 to 50 years. Along with the associated morbidity and mortality, snakebite leads to a significant financial burden on the victim, both by way of hospital bills and labour hours lost. Snakebite is also a cause for considerable psychological stress among survivors. Most snakebites are eminently treatable and curable. Given a concerted thrust from all concerned , this menace could surely be curtailed considerably over the next few years.

Snakebite mortality in India: a nationally representative mortality survey.

BACKGROUND: India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey. METHODS AND FINDINGS: We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001-03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication. A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15-29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6-4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8-6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). CONCLUSIONS: Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India.