Home to more than 60 species of venomous snakes, India bears the world's largest burden of death and disability caused by snakebites. The gold-standard treatment is an antivenom raised against the combined venom of four widespread species that are responsible for most attacks, collectively referred to as the "big four." Although this critical treatment routinely saves lives, a new study published in early December in PLOS Neglected Tropical Diseases shows that it comes up short against the venoms of other Indian snakes whose bites can be deadly.
Kartik Sunagar, an evolutionary biologist at the Indian Institute of Science in Bangalore, co-authored the study. It examined the venom compositions of Sochurek's saw-scaled viper, two populations of monocled cobras, the banded krait and the Sind krait—perhaps the most toxic snake in India—and three of their closest big-four cousins. Working with herpetologists Romulus Whitaker of the Madras Crocodile Bank Trust and Center for Herpetology in Chennai, and Gerard Martin, founder of a conservation organization called the Gerry Martin Project in the Mysore District, the researchers identified 45 snakes and extracted their venom. Once they identified the proteins and toxins in the samples, they used mouse models to test their toxicity and the efficacy of existing antivenoms. Alarmingly, the team found that the most widely marketed antivenom failed against venoms from both populations of the monocled cobra, the Sind krait and northern populations of the common krait.
Conventional antivenoms are produced by immunizing animals such as horses or sheep with venom and collecting the antibodies they produce, a protocol that has remained unchanged for more than a century. In India, horses are injected with a cocktail of venoms from Russell's viper, the saw-scaled viper, the spectacled cobra and the common krait, sourced exclusively from snakes in the southern state of Tamil Nadu. This is a problem.
Studies have shown that snake species' venom compositions can differ dramatically. "We treat snakebites as one medical emergency. But the reality is, if you're bitten by a snake like a cobra, then you might suffer neurotoxic effects that lead to respiratory paralysis, [and] if you're bitten by the Russell's viper, you may have a completely different variety of syndromes such as hemorrhage or bleeding disorders," says Nick Casewell, who works on animal venoms at the Liverpool School of Tropical Medicine in England and was not part of this study.
The venom of the same species can even vary among different geographical populations. In India, species are distributed widely across the vast subcontinent. Sunagar and his colleagues found that whereas the venom of one monocled cobra population targets the nervous system, the other population's venom is rich in toxins that cause cell and tissue damage. "The venoms of local, medically relevant snakes must be used to produce antivenoms that will work more effectively in that region," Sunagar says, adding that more government funding and attention would go a long way. Sunagar and his colleagues are now working with antivenom manufacturers to develop and test such region-specific formulations.
Several global efforts are underway to upgrade existing snakebite treatments and discover novel therapies. Sunagar and Casewell, along with scientists from Kenya and Nigeria, are part of a year-old consortium that aims to develop a new type of antivenom to counteract venoms from Africa and India. The idea is to design treatments that will specifically target the toxins in venom. At the moment, only 15 percent of antibodies in an antivenom are specific to toxins, Casewell says; the rest are directed toward parasites or germs in the involved animal's environment. Instead of just collecting antibodies from the animals' blood, he and his colleagues will gather the cells that produce them and grow these in the lab, using them to generate a synthetic "library" of antibodies. "We can then choose just those few antibodies that neutralize lots of different toxins and use that as a treatment moving forward," he explains. This cocktail of select antibodies will likely also be safer for patients, many of whom suffer adverse reactions to the numerous foreign proteins from other animals that make up the conventional antivenom, he says.
Another promising treatment approach involves a small molecule called varespladib, identified by Matthew Lewin, founder of Bay Area startup Ophirex. Lewin and his colleagues have shown that the compound is very potent against a virulent component of venom called sPLA2, found in abundance in many of the world's venomous snakes. Varespladib is also small enough to penetrate brain tissue, which conventional antivenoms fail to reach. The team is preparing to perform clinical trials of the compound soon.
Researchers expect that collectively, their research will yield multi-pronged solutions that can be used in isolation or in tandem to combat snakebites worldwide. "However," Sunagar says, "with 200,000 people affected by snakebites annually, we cannot wait for the next-generation antivenoms. What India needs immediately are antivenoms that are effective against local snake populations in different regions."