Abstract
This review describes the research aimed at the development of universal antivenom against elapid neurotoxic snake venoms. The antivenoms produced in Thailand in the 1980s were of low potency, especially against the elapid venoms. This was thought to be due to the low immunogenicity of the α-neurotoxins, which are the most lethal toxins in these venoms. Comparisons of various α-neurotoxin conjugates and polymers, and also different immunological adjuvants, showed that the adjuvant used is the major determinant in the antibody response in horses. The potent Freund’s adjuvant was not used due to its severe local side-effect in horses. Therefore, a novel immunization protocol termed ‘low dose, low volume multi-site’ was developed for use in horses. This immunization protocol has led to the production of highly potent monospecific antivenoms against several elapid and viperid venoms, and two potent polyspecific antivenoms, one against 4 neurotoxic and another against 3 hematotoxic venoms. The immunization protocol has also led to other improvements in antivenom production including: several fold increases in antiserum potency, a reduction in the time required to reach therapeutically useful antibody titers, a 90% reduction in the amount of venom used, and 100% of the horses responding to the immunization program. This development is partly responsible for significant decrease in the Thailand’s annual snakebite death toll from a few dozens to mostly nil in recent years. Finally, a simple and novel immunization strategy, using a ‘diverse toxin repertoire’ composed of numerous elapid toxin fractions as immunogen, was proposed and tested. This immunization procedure has resulted in the successful production of a widely paraspecific antiserum against at least 36 neurotoxic venoms of 28 species encompassing 10 genera and from 20 countries on four continents, and possibly against all elapid venoms with α-neurotoxins as the lethal toxins. These results indicate that, with optimizations of the composition of the ‘diverse toxin repertoire’, the immunization scheme and antibody fractionation to increase the antivenom neutralizing potency, an effective universal antivenom against the neurotoxic elapid snakes of the world can be produced.
Highlights
Snakebite envenomation is an important medical problem in many tropical countries [1]
It was shown that the pan-specific Plasma-derived antivenom (PDAV) could effectively neutralize at least 36 neurotoxic venoms of 10 genera and from 4 continents including sea snakes from both Australia and the Arabian Sea [83]. These results suggest that universal antivenom against all elapid snakes is possible if the ‘diverse toxin repertoire’ is modified to include a few more neurotoxic venoms
There are some drawbacks to PDAV and this has led to attempts to produce ‘new generation’ antivenoms
Summary
Snakebite envenomation is an important medical problem in many tropical countries [1]. It should be noted that the very low venom/toxin dose used for the immunization reduces the cost because of the lower amount of venom used but, more importantly, stimulates the production of high affinity antitoxin antibody increasing PDAV potency [67,68,69]. This novel immunization protocol has resulted in the production of highly potent antiserum (2-4 fold increase in potency) against N. kaouthia venom [63] It reduces the time required for a horse to reach maximum antibody titers to about 6 to 8 weeks instead of several months. It indicates that it should be possible to produce a universal PDAV against the elapid snakes of the world
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