Rodent Lethality Models Are Problematic for Evaluating Antivenoms for Human Envenoming

Silva, Anjana; Hodgson, Wayne C.; Tasoulis, Theo; Isbister, Geoffrey K.

doi:10.3389/fphar.2022.830384

Cited by 15 publications

(10 citation statements)

References 30 publications

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“…An important note, however, is that this study was undertaken using human plasma and; thus, while in vitro, it may produce results more suggestive of potential human envenomation effects than in vivo animal-model studies, if the venoms have a differential effect between humans and animal-models. This is, indeed, recognised as a critical issue and a limitation of the applicability of animal-based research for human medicine [ 93 ]. Regardless, future in vivo work should be conducted before making any therapeutic recommendations regarding clinical care.…”

Section: Discussionmentioning

confidence: 99%

Clinical and Evolutionary Implications of Dynamic Coagulotoxicity Divergences in Bothrops (Lancehead Pit Viper) Venoms

Bourke

Zdenek

Tanaka-Azevedo

et al. 2022

Toxins

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Despite coagulotoxicity being a primary weapon for prey capture by Bothrops species (lancehead pit vipers) and coagulopathy being a major lethal clinical effect, a genus-wide comparison has not been undertaken. To fill this knowledge gap, we used thromboelastography to compare 37 venoms, from across the full range of geography, taxonomy, and ecology, for their action upon whole plasma and isolated fibrinogen. Potent procoagulant toxicity was shown to be the main venom effect of most of the species tested. However, the most basal species (B. pictus) was strongly anticoagulant; this is consistent with procoagulant toxicity being a novel trait that evolved within Bothrops subsequent to their split from anticoagulant American pit vipers. Intriguingly, two of the arboreal species studied (B. bilineatus and B. taeniatus) lacked procoagulant venom, suggesting differential evolutionary selection pressures. Notably, some terrestrial species have secondarily lost the procoagulant venom trait: the Mogi Mirim, Brazil locality of B. alternatus; San Andres, Mexico locality of B. asper; B. diporus; and the São Roque of B. jararaca. Direct action on fibrinogen was extremely variable; this is consistent with previous hypotheses regarding it being evolutionary decoupled due to procoagulant toxicity being the primary prey-capture weapon. However, human patients live long enough for fibrinogen depletion to be clinically significant. The extreme variability may be reflective of antivenom variability, with these results thereby providing a foundation for such future work of clinical relevance. Similarly, the venom diversification trends relative to ecological niche will also be useful for integration with natural history data, to reconstruct the evolutionary pressures shaping the venoms of these fascinating snakes.

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Section: Discussionmentioning

confidence: 99%

Clinical and Evolutionary Implications of Dynamic Coagulotoxicity Divergences in Bothrops (Lancehead Pit Viper) Venoms

Bourke

Zdenek

Tanaka-Azevedo

et al. 2022

Toxins

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“…The most important of these is that, due to the restricted blood sample volumes collected post-immunisation (which were due to the relatively small sample size per immunogen group ( n = 5) and ethical constraints), our analyses of the binding and functional neutralisation of SVSP toxins and crude venoms were limited to in vitro experiments. While there remain considerable issues associated with current preclinical models used to assess antivenom efficacy, including their questionable relevance for modelling VICC [ 59 ], these in vivo models remain the gold standard for efficacy testing. Thus, important next steps with recombinant toxin-specific antivenoms, such as those generated here, would be to test whether their functional inhibitory profiles are capable of conferring preclinical protection against venom-induced pathologies in appropriate in vivo models.…”

Section: Discussionmentioning

confidence: 99%

Exploring the Utility of Recombinant Snake Venom Serine Protease Toxins as Immunogens for Generating Experimental Snakebite Antivenoms

Alomran

Blundell

Alsolaiss

et al. 2022

Toxins

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Snakebite is a neglected tropical disease that causes high rates of global mortality and morbidity. Although snakebite can cause a variety of pathologies in victims, haemotoxic effects are particularly common and are typically characterised by haemorrhage and/or venom-induced consumption coagulopathy. Despite polyclonal antibody-based antivenoms being the mainstay life-saving therapy for snakebite, they are associated with limited cross-snake species efficacy, as there is often extensive toxin variation between snake venoms, including those used as immunogens for antivenom production. This restricts the therapeutic utility of any antivenom to certain geographical regions. In this study, we explored the feasibility of using recombinantly expressed toxins as immunogens to stimulate focused, pathology-specific, antibodies in order to broadly counteract specific toxins associated with snakebite envenoming. Three snake venom serine proteases (SVSP) toxins, sourced from geographically diverse and medically important viper snake venoms, were successfully expressed in HEK293F mammalian cells and used for murine immunisation. Analyses of the resulting antibody responses revealed that ancrod and RVV-V stimulated the strongest immune responses, and that experimental antivenoms directed against these recombinant SVSP toxins, and a mixture of the three different immunogens, extensively recognised and exhibited immunological binding towards a variety of native snake venoms. While the experimental antivenoms showed some reduction in abnormal clotting parameters stimulated by the toxin immunogens and crude venom, specifically reducing the depletion of fibrinogen levels and prolongation of prothrombin times, fibrinogen degradation experiments revealed that they broadly protected against venom- and toxin-induced fibrinogenolytic functional activities. Overall, our findings further strengthen the case for the use of recombinant venom toxins as supplemental immunogens to stimulate focused and desirable antibody responses capable of neutralising venom-induced pathological effects, and therefore potentially circumventing some of the limitations associated with current snakebite therapies.

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“…The most important of these is that, due to the restricted blood sample volumes collected post-immunsiation (which were due to the relatively small sample size per immunogen group (n=5) and ethical constraints), our analyses of the binding and functional neutralisation of SVSP toxins and crude venoms were limited to in vitro experiments. While there remain considerable issues associated with current preclinical models used to assess antivenom efficacy, including their questionable relevance for modelling VICC (60), these in vivo models remain the gold standard for efficacy testing. Thus, important next steps with recombinant toxin-specific antivenoms, such as those generated here, would be to test whether their functional inhibitory profiles are capable of conferring preclinical protection against venom-induced pathologies in appropriate in vivo models.…”

Section: Discussionmentioning

confidence: 99%

Exploring the utility of recombinantly expressed snake venom serine protease toxins as immunogens for generating experimental snakebite antivenoms

Alomran

Blundell

Alsolaiss

et al. 2022

Preprint

View full text Add to dashboard Cite

Snakebite is a neglected tropical disease that causes high rates of global mortality and morbidity. Although snakebite can cause a variety of pathologies in victims, haemotoxic effects are particularly common and are typically characterised by haemorrhage and/or venom-induced consumption coagulopathy. Despite polyclonal antibody-based antivenoms being the mainstay life-saving therapy for snakebite, they are associated with limited cross-snake species efficacy, as there is often extensive toxin variation between snake venoms, including those used as immunogens for antivenom production. This restricts the therapeutic utility of any antivenom to certain geographical regions. In this study, we explored the feasibility of using recombinantly expressed toxins as immunogens to stimulate focused, pathology-specific, antibodies to broadly counteract specific toxins associated with snakebite envenoming. Three snake venom serine proteases (SVSP) toxins, sourced from geographically diverse and medically important viper snake venoms were successfully expressed in HEK293F mammalian cells and used for murine immunisation. Analyses of the resulting antibody responses revealed that ancrod and RVV-V stimulated the strongest immune responses, and that experimental antivenoms directed against these recombinant SVSP toxins, and a mixture of the three different immunogens, extensively recognised and exhibited immunological binding towards a variety of native snake venoms. While the experimental antivenoms showed some reduction in abnormal clotting parameters stimulated by the toxin immunogens and crude venom, specifically reducing the depletion of fibrinogen levels and prolongation of prothrombin times, fibrinogen degradation experiments revealed they broadly protected against venom- and toxin-induced fibrinogenolytic functional activities. Overall, our findings further strengthen the case for the use of recombinant venom toxins as supplemental immunogens to stimulate focused and desirable antibody responses capable of neutralising venom-induced pathological effects, and therefore potentially circumventing some of the limitations associated with current snakebite therapies.

show abstract

Rodent Lethality Models Are Problematic for Evaluating Antivenoms for Human Envenoming

Cited by 15 publications

References 30 publications

Clinical and Evolutionary Implications of Dynamic Coagulotoxicity Divergences in Bothrops (Lancehead Pit Viper) Venoms

Clinical and Evolutionary Implications of Dynamic Coagulotoxicity Divergences in Bothrops (Lancehead Pit Viper) Venoms

Exploring the Utility of Recombinant Snake Venom Serine Protease Toxins as Immunogens for Generating Experimental Snakebite Antivenoms

Exploring the utility of recombinantly expressed snake venom serine protease toxins as immunogens for generating experimental snakebite antivenoms

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