METHODS: This study examined the immunological binding and neutralization capacity of PCAV against the two cobra venoms using WHO-recommended protocols.
RESULTS: In mice, both venoms were highly neurotoxic and lethal with a median lethal dose of 0.18 and 0.20 µg/g, respectively. PCAV exhibited strong and comparable immunoreactivity toward the venoms, indicating conserved venom antigenicity between the two allopatric species. In in vivo assay, PCAV was only moderately effective in neutralizing the toxicity of both venoms. Its potency was even lower against the hetero-specific N. samarensis venom by approximately two-fold compared with its potency against N. philippinensis venom.
CONCLUSION: The results indicated that PCAV could be used to treat N. samarensis envenomation but at a higher dose, which might increase the risk of hypersensitivity and worsen the shortage of antivenom supply in the field. Antivenom manufacturing should be improved by developing a low-dose, high-efficacy product against cobra envenomation.
METHODOLOGY/PRINCIPLE FINDINGS: In this systematic review, we searched for articles published until May 30, 2022, in PubMed, Scopus, Web of Science, and Embase. Preclinical studies that reported the available antivenoms' neutralizing ability against Asian snake lethality were included. Quality assessment was performed using the Systematic Review Centre for Laboratory animal Experimentation's risk of bias tool and the adapted the Animal Research Reporting In Vivo Experiments guidelines. The availability of effective antivenoms against Asian snakes was analyzed by comparing data from included studies with snakebite-information and data platforms developed by the World Health Organization. Fifty-two studies were included. Most studies assessed the antivenom efficacy against snakes from Southeast Asia (58%), followed by South Asia (35%) and East Asia (19%). Twenty-two (49%) medically important snakes had antivenom(s) with confirmed neutralizing ability. Situation analyses of the availability of effective antivenoms in Asia demonstrated that locally produced antivenoms did not cover all medically important snakes in each country. Among countries without local antivenom production, preclinical studies were conducted only in Bangladesh, Sri Lanka, and Malaysia. Risk of bias assessment was limited in some domains because of unreported data.
CONCLUSIONS/SIGNIFICANCE: Cross-neutralizing of antivenoms against some medically important snakes in Asia was confirmed. This strategy may improve access to geographically effective antivenoms and bypass investment in novel antivenom development, especially in countries without local antivenom production. A database should be developed to aid the development of a snakebite-information system.
BIOLOGICAL SIGNIFICANCE: The Indian krait or blue krait, Bungarus caeruleus, is a highly venomous snake that contributes to the snakebite envenoming problem in South Asia. This is a less aggressive snake species but its accidental bite can cause rapid and severe neurotoxicity, in which the patient may succumb to paralysis, respiratory failure and death within a short frame of time. The proteomic analysis of its venom (sourced from Sri Lanka) unveils its content that well correlates to its envenoming pathophysiology, driven primarily by the abundant presynaptic and postsynaptic neurotoxins (β-bungarotoxins and κ-neurotoxins, respectively). The absence of cytotoxins in the venom proteome also correlates with the lack of local envenoming sign (pain, swelling), and explains why the bite may be insidious until later stage when paralysis sets in. The muscarinic toxin-like proteins in the venom may be the cause of severe abdominal pain that precedes paralysis in many cases, and justifies the need of closely monitoring this symptom in suspected cases. Venom samples from Sri Lanka, India and Pakistan exhibited no remarkable variation in protein profiling and reacted immunologically toward the VINS Indian Polyvalent Antivenom, though to a varying extent. The antivenom is effective in neutralizing the Sri Lankan and Indian venoms, confirming its clinical use in the countries. The antivenom efficacy against the Pakistani venom, however, may be further optimized by incorporating the Pakistani venom in the antivenom production.
PRINCIPAL FINDINGS: In vitro neutralization study using mice showed that NPAV was able to neutralize effectively the lethality of venoms of most common Asiatic cobras (Naja spp.), Ophiophagus hannah and kraits (Bungarus spp.) from Southeast Asia, but only moderately to weakly effective against venoms of Naja from India subcontinent and Africa. Studies with several venoms showed that the in vivo neutralization potency of the NPAV was comparable to the in vitro neutralization potency. NPAV could also fully protect against N. sputatrix venom-induced cardio-respiratory depressant and neuromuscular blocking effects in anesthetized rats, demonstrating that the NPAV could neutralize most of the major lethal toxins in the Naja venom.
CONCLUSIONS/SIGNIFICANCE: The newly developed polyvalent antivenom NPAV may find potential application in the treatment of elapid bites in Southeast Asia, especially Malaysia, a neighboring nation of Thailand. Nevertheless, the applicability of NPAV in the treatment of cobra and krait envenomations in Southeast Asian victims needs to be confirmed by clinical trials. The cross-neutralization results may contribute to the design of broad-spectrum polyvalent antivenom.