BACKGROUND AND INTRODUCTION Snakebite has been declared by the World Health Organization (WHO) as a neglected yet serious public health issue in many tropical and subtropical countries. Nearly 1.8–2.7 million cases of snake envenomation are reported worldwide, with data showing 81,410–137,880 deaths annually due to snakebites, and approximately three times as many amputations and other permanent disabilities occurring each year.1 Currently, the only effective treatment for snakebite envenomation is Anti-Snake Venom (ASV), which has been in use for the past 120 years and has been highly successful in reducing mortality and morbidity, saving countless lives.2,3 However, the limited availability of ASV and the significant risk of life-threatening hypersensitivity reactions have been the Achilles’ heel of effective venomous snakebite management. It is time for clinicians and toxicologists worldwide to explore alternatives to ASV. CLINICAL EFFICACY OF ANTI-SNAKE VENOM AND MECHANISM OF ACTION ASVs are immunoglobulin preparations made from equine (or ovine) plasma and can be either monospecific (targeting a single snake species) or polyspecific (polyvalent). The interaction between venom and anti-venom is primarily an immunological reaction involving the antigen, which is the venom, and the antibody, the anti-venom. This reaction results in the neutralisation of toxins in the snake venom. The formed immune complex is then either destroyed or deactivated by other immunological mechanisms.4,5 Numerous studies and animal experiments over the years have demonstrated the efficacy of ASV in reducing mortality and morbidity from venomous snakebites.6 DRAWBACKS OF EXISTING ANTI-SNAKE VENOMS Despite using conventional ASV, its limitations and drawbacks have kept the burden of snakebite-related death and morbidity high. Significant interspecies, intraspecies, and geographic variation in venom composition renders antivenom ineffective, and patients are being given higher doses of ASV with no assured clinical benefits. There is uncertainty about adequate therapeutic dosing strategies, especially without reliable bedside methods to determine the optimal dosage for the patient. ASV dosing is largely empirical, leading to both under-treatment and over-treatment, and increasing the dose does not necessarily improve outcomes, particularly in neurotoxic and myotoxic envenomation. Immediate hypersensitivity reactions, including anaphylactic reactions and pyrogenic reactions such as chills, rigour, headache, and tachycardia, as well as possible delayed reactions like serum sickness, can deter physicians – especially those in remote rural areas with limited medical infrastructure – from using conventional ASV generously. Non-availability and limited supply of quality ASV, due to manufacturing issues like high production costs, low profitability, supply and distribution problems, and limited shelf life, are driving manufacturers out of the anti-venom sector.1,3,7 ADEQUACY AND SPECIFICITY OF AVAILABLE ANTI-SNAKE VENOMS IN INDIA Currently, we have eight ASV manufacturers producing anti-venom in India, but they are effective only against the Big Four venomous snakes (Krait, Cobra, Russell’s viper, Saw scaled viper), and they are ineffective at neutralising the venom of other venomous snakes, especially different species of pit vipers. Large doses of polyvalent anti-venom have been used in these snake envenomations without much clinical benefit. The polyvalent anti-venom is prepared from the venom obtained by milking the big four snakes available in a particular geographical area. Hence, the adequacy and specificity of venom-neutralising ability are questionable when used across different geographical areas due to interspecific and intraspecific variability in venom antigens. This erratic clinical response to available ASVs raises significant doubts among clinicians about their efficacy.8 Senji Laxme et al. found identical results in their study, which showed vast inter- and intraspecific differences in venom composition, biochemical and toxicological profiles, and poor cross-neutralising capabilities of commercial Indian antivenoms, emphasising an urgent need to develop specific antivenoms against the many neglected species of venomous snakes.9 ALTERNATIVE THERAPEUTIC STRATEGIES TO CONVENTIONAL ANTI-SNAKE VENOMS The limitations and drawbacks of traditional ASVs have led clinicians to seek alternatives, though they remain indispensable for now. There is a growing need for a paradigm shift towards developing adjunctive and alternative therapeutic strategies that complement or extend beyond traditional anti-venom, while circumventing their limitations, and are outlined below: Small-molecule toxin inhibitors Small-molecule inhibitors (SMIs) target venom toxins by directly inhibiting their enzymatic activities, unlike ASV, which relies on antigen-antibody binding. These are therapeutic agents that are already licensed for other medical applications, repurposed for use in snake envenomation. Examples include phospholipase A2 inhibitors such as varespladib, and zinc metalloproteinase inhibitors such as marimastat and 2, 3-dimercapto-1-propane sulphonic acid. Other repurposed or investigational molecules in preclinical stages include batimastat, prinomastat, nafamostat, and dimercaprol, all targeting components of venom pathophysiology.2,10 Varespladib (LY315920), originally developed for cardiovascular indications, has emerged as a potent inhibitor of venom PLA2 enzymes. Preclinical studies have demonstrated the prospect of this molecule becoming a wonder drug against the lethality caused by venom from major vipers.10 Agents like marimastat (a matrix metalloproteinase inhibitor) and DMPS (Unithiol) (a zinc chelator) have demonstrated the ability to counter SVMP-mediated effects like hemorrhage, coagulopathy and tissue necrosis in vitro and in vivo11 Some of these molecules have also shown great promise with their potential to be effective as pre-hospital and on field therapeutics especially their ability to be effective as oral agents.10,11 Recombinant antibody-based anti-venoms The traditional ASVs, which are derived from hyperimmunizing large mammals such as horses and sheep and produced as polyclonal antibodies, are highly immunogenic and pose a significant risk of hypersensitivity reactions. Recombinant technologies tend to address these drawbacks and generate monoclonal antibodies (mAbs), nanobodies, or biosynthetic oligoclonal antibody cocktails. Human and humanised monoclonal antibodies mAbs can be engineered to bind specific toxins with high affinity and minimal immunogenicity. Recent research highlights the use of neutralising human mAbs that target conserved toxin epitopes, offering effective neutralisation across multiple snake venoms. These molecules hold promise for more consistent efficacy and reduced risk of allergic reactions.12 Nanobody-based antivenoms These tiny antibodies are produced by exposing camelids, such as alpacas and llamas, to potent venoms from African snakes, including cobras and mambas. Because of their small size, they can quickly diffuse through tissues and bind to venom toxins, reaching hard-to-access areas of the human body. Researchers have also combined eight of these engineered nanobodies into a powerful mixture to develop a new antivenom that can outperform traditional antivenom serum (ASV).13 These recombinant antibody formats can be manufactured on a large scale using microbial expression systems, potentially lowering production costs and enhancing accessibility compared to traditional ASV. Oligoclonal cocktails and toxin-targeted strategies The strategy of combining mAbs to create oligoclonal mixtures targeting all key venom toxins has been quite successful in producing a broadly neutralising mAb. This antibody has demonstrated the ability to neutralise an epitope widely conserved across long-chain α-neurotoxins (3FTx-L) in the venoms of neurotoxic elapid snakes.2 Combination therapies These are next-generation snakebite therapeutics, not just a single antitoxin formulation (e.g., antibodies or SMIs), but composite products that combine different modalities to provide a broad-spectrum snakebite treatment capable of neutralising numerous distinct snake venoms in one formulation. These composite therapeutics would maximise toxin neutralisation, addressing both systemic and local effects. Therefore, we benefit from a single formulation with broad therapeutic potential.14 This involves a therapeutic strategy that combines SMIs and recombinant antitoxins. SMIs could be administered immediately after a bite, before hospitalisation, similar to recombinant thrombolytics such as alteplase, used in acute myocardial infarction, to inhibit key venom enzymes. The definitive treatment would then begin in the hospital using recombinant antibodies or nanobodies to neutralise other toxin components of the venom. Diagnostic and supportive innovations Innovations and improvements in rapid venom-detection assays, point-of-care coagulation testing, and syndrome-based clinical protocols could enhance early, prompt diagnosis, which may aid targeted treatment. LIMITING FACTORS FOR THE DEVELOPMENT AND USE OF ALTERNATIVES TO ANTI-SNAKE VENOMS All are target-specific but not comprehensive, and have limited clinical trial data. High production costs, along with the risk of missing unrecognised toxin variants, are also of concern. Most of them are still in the experimental stage, requiring robust safety and efficacy trials in humans. Snake bites, as acute and emergency situations, pose significant ethical issues when conducting randomised trials. In the absence of data on superiority or non-inferiority relative to traditional ASV, and given the need for safety trials for regulatory approval for human use, this remains a significant challenge. CONCLUSION Despite promising new ideas and alternatives to traditional ASVs, their implementation and clinical use in humans must undergo rigorous testing through strict guidelines and clinical trials. Without such validation, they are often seen as merely theoretical concepts. Clinicians need to urge the WHO to adopt the Emergency Use of Unregistered and Experimental Interventions framework to facilitate the adoption of alternatives to ASV. Countries heavily affected by venomous snake bites need to invest sufficient resources in developing innovative snakebite treatments and conducting translational research as options beyond the conventional ASV. Until then, we may have to rely on our long-standing traditional ASVs. Author contributions SBN is the sole author of this article and contributed for the content, writing and revision of this article. Data availability statement No data was generated or analysed in this editorial.
Sadananda Bolar Naik (Tue,) studied this question.