Using the unique immune system of a self-immunized human, researchers engineered a three-part antivenom that neutralizes the world’s deadliest snakes, offering hope for a universal, safer, and more accessible treatment against snakebites. Death Adder snake (Acanthophis antarticus) native to Australia. Image Credit: Lauren Suryanata / Shutterstock By using antibodies from a human donor with a self-induced hyper-immunity to snake venom, scientists have developed the most broadly effective antivenom to date. In mouse trials, it is protective against the black mamba, king cobra, and tiger snakes, as well as several other medically significant snakes across the Elapidae family. Described May 2 in the Cell Press journal Cell, the antivenom combines protective antibodies and a small-molecule inhibitor and opens a path toward a universal antiserum. How we make antivenom has not changed much over the past century. Typically, it involves immunizing horses or sheep with venom from a single snake species and collecting the antibodies produced. While effective, this process could result in adverse reactions to the non-human antibodies, and treatments tend to be species and region-specific. Australia's Inland taipan (Oxyuranus microlepidotus) — World’s most venomous snake by LD₅₀; "fierce snake" or "small-scaled snake". Image Credit: Ken Griffiths While exploring ways to improve this process, scientists stumbled upon someone hyper-immune to the effects of snake neurotoxins. "The donor, for a period of nearly 18 years, had undertaken hundreds of bites and self-immunizations with escalating doses from 16 species of very lethal snakes that would normally a kill a horse," says first author Jacob Glanville, CEO of Centivax, Inc. After the donor, Tim Friede, agreed to participate in the study, researchers found that he had generated antibodies that were effective against several snake neurotoxins at once by exposing himself to the venom of various snakes over several years. "What was exciting about the donor was his once-in-a-lifetime unique immune history," says Glanville. "Not only did he potentially create these broadly neutralizing antibodies, in this case, it could give rise to a broad-spectrum or universal antivenom." Study design The team first created a testing panel to build the antivenom with 19 of the World Health Organization's category 1 and 2 deadliest snakes across the elapid family. This group contains roughly half of all venomous species, including coral snakes, mambas, cobras, taipans, and kraits. Next, researchers isolated target antibodies from the donor's blood that reacted with neurotoxins found within the snake species tested. One by one, the antibodies were tested in mice envenomated from each species included in the panel. In this way, scientists could systematically build a cocktail comprising a minimum but sufficient number of components to render all the venoms ineffective. The team formulated a mixture comprising three major components: two antibodies isolated from the donor and a small molecule. The first donor antibody, called LNX-D09, protected mice from a lethal dose of whole venom from six of the snake species present in the panel. To strengthen the antiserum further, the team added the small molecule varespladib, a known toxin inhibitor, which granted protection against an additional three species. Finally, they added a second antibody isolated from the donor, called SNX-B03, which extended protection across the full panel. Structural studies showed these antibodies bind to conserved sites on the neurotoxins, directly blocking the toxin’s interaction with its target in the nervous system, a key reason for their broad activity. "By the time we reached 3 components, we had a dramatically unparalleled breadth of full protection for 13 of the 19 species and then partial protection for the remaining that we looked at," says Glanville. "We were looking down at our list and thought, 'what's that fourth agent'? And if we could neutralize that, do we get further protection?" Even without a fourth agent, their results suggest that the three-part cocktail could be effective against many other, if not most, elapid snakes not tested in this study. The researchers noted that in some cases, not all mice survived beyond 24 hours, sometimes due to the short half-life of the small-molecule inhibitor varespladib, which may require redosing or longer-acting alternatives for complete protection. This underlines that while the cocktail provided robust and often complete protection, further optimization may improve its efficacy, especially for the most challenging venoms. The coastal taipan (Oxyuranus scutellatus), or common taipan, is a species of extremely venomous snake in the family Elapidae. Described by Wilhelm Peters in 1867, the species is native to the coastal regions of northern and eastern Australia and the island of New Guinea. Image Credit: Danny Ye / Shutterstock Next steps With the antivenom cocktail proving effective in mouse models, the team now looks to test its efficacy out in the field, beginning by providing the antivenom to dogs brought into veterinary clinics for snake bites in Australia. Further, they wish to develop an antivenom targeting the other major snake family, the vipers. "We're turning the crank now, setting up reagents to go through this iterative process of saying what's the minimum sufficient cocktail to provide broad protection against venom from the viperids," says lead author Peter Kwong, Richard J. Stock professor of medical sciences at Columbia University Vagelos College of Physicians and Surgeons and formerly of the National Institutes of Health. "The final contemplated product would be a single, pan-antivenom cocktail or we potentially would make two: one that is for the elapids and another that is for the viperids because some areas of the world only have one or the other." At present, the newly developed cocktail is effective across the Elapidae family, but not yet against viperid snakes; work is ongoing to extend this approach. The other primary goal is to approach philanthropic foundations, governments, and pharmaceutical companies to support the manufacturing and clinical development of the broad-spectrum antivenom. "This is critical, because although there are millions of snake envenomations per year, the majority of those are in the developing world, disproportionately affecting rural communities," Glanville says. This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the National Institutes of Health Small Business Innovation Research program, and the US Department of Energy.