Pathology-specific experimental antivenoms for haemotoxic snakebite: The impact of immunogen diversity on the in vitro cross-reactivity and in vivo neutralisation of geographically diverse snake venoms.
Pathology-specific experimental antivenoms for haemotoxic snakebite: The impact of immunogen diversity on the in vitro cross-reactivity and in vivo neutralisation of geographically diverse snake venoms.
复制标题
DOI：
10.1371/journal.pntd.0009659
复制
发表时间：
2021-08
影响因子：
3.8
通讯作者：
Casewell NR
中科院分区：
文献类型：
--
作者：
Alomran N;Alsolaiss J;Albulescu LO;Crittenden E;Harrison RA;Ainsworth S;Casewell NR
蛇咬伤是一种被忽视的热带疾病，导致全球高死亡率和高发病率。尽管蛇咬伤可导致受害者多种病理变化，但血液毒性效应尤其常见，其典型特征是出血和/或毒液引起的消耗性凝血障碍。抗蛇毒血清是治疗蛇咬伤毒性效应的主要治疗方法，但尽管每年挽救数千人的生命，但由于毒液变化，这些疗法的跨蛇种疗效有限，这最终限制了它们对特定地理区域的治疗作用。在这项研究中，我们探索了产生全球有效的病理特异性抗蛇毒血清来对抗蛇咬伤蛇毒的血液毒性迹象的可行性。两种不同的免疫原混合物，由来自不同地理位置和/或医学上重要的蛇的7种和12种血液毒液组成，用于培养绵羊多克隆抗体，然后对它们的免疫结合特性和体外中和特性进行表征。尽管免疫原混合物不同，但在免疫学和功能分析中，两种实验性抗蛇毒血清在体外对单个毒液免疫原的毒液结合和中和情况大体相似。然而，使用小鼠抗蛇毒血清疗效的临床前模型进行的体内评估显示，在毒液中和方面存在显著差异。从七种蛇毒免疫原混合物中产生的实验性抗蛇毒液性能优于参照物，因为它对所测试的八种地理上不同的毒液中的七种所引起的毒液致死性提供了保护作用，其中包括三种不同的毒液，它们没有被用作产生这种抗蛇毒毒素的免疫原。这些发现表明，一套核心的毒液免疫原可能足以激发能够广泛中和地理上不同的血液毒性蛇毒阵列的抗体，而添加额外的毒液免疫原可能会对所产生的抗蛇毒血清的剂量效率产生负面影响。尽管选择合适的免疫原在不稀释抗蛇毒效力的情况下包裹蛇毒毒素多样性仍然具有挑战性，需要进一步优化，但这项试点研究的结果表明，产生具有全球实用性的病理特异性抗蛇毒血清很可能是可行的，从而突显了它们作为未来模块治疗世界热带蛇咬伤受害者的前景。蛇咬伤是一个主要的公共卫生问题，在热带世界造成广泛的死亡和残疾。毒液成分的变化给蛇咬伤治疗带来了重大挑战，通常将抗蛇毒效果限制在每种产品设计针对的少数几种蛇品种上，这意味着许多受地理限制的治疗药物是为世界不同地区生产的。在这项研究中，我们探索了用两组不同的血液毒性毒液作为免疫原，其中一组包括7种毒液和另外12种毒液来产生绵羊多克隆抗体，以产生一种全球病理特异性的抗蛇毒血清的可行性。我们的体外免疫交叉反应和毒液功能中和结果显示，无论它们是否包括在免疫混合物中，对各种毒液免疫原的毒液识别和抑制作用大致相似。然而，对小鼠体内对毒液诱导的致死性的保护评估表明，用较少的免疫原产生的抗蛇毒血清表现优于对照组，并提供了更广泛的临床前效力，甚至对一些不用来提高抗体的毒液也是如此。这些发现表明，仔细选择用作免疫原的毒液对于维持抗蛇毒效果至关重要，一小部分毒液可能能够产生一种具有潜在全球疗效的抗蛇毒血清，以对抗蛇咬伤后常见的一种特定病理。
Snakebite is a neglected tropical disease that causes high global rates of 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. Antivenoms are the mainstay therapeutic for treating the toxic effects of snakebite, but despite saving thousands of lives annually, these therapies are associated with limited cross-snake species efficacy due to venom variation, which ultimately restricts their therapeutic utility to particular geographical regions. In this study we explored the feasibility of generating globally effective pathology-specific antivenoms to counteract the haemotoxic signs of snakebite envenoming. Two different immunogen mixtures, consisting of seven and twelve haemotoxic venoms sourced from geographically diverse and/or medically important snakes, were used to raise ovine polyclonal antibodies, prior to characterisation of their immunological binding characteristics and in vitro neutralisation profiles against each of the venoms. Despite variability of the immunogen mixtures, both experimental antivenoms exhibited broadly comparable in vitro venom binding and neutralisation profiles against the individual venom immunogens in immunological and functional assays. However, in vivo assessments using a murine preclinical model of antivenom efficacy revealed substantial differences in venom neutralisation. The experimental antivenom generated from the seven venom immunogen mixture outperformed the comparator, by providing protective effects against venom lethality caused by seven of the eight geographically diverse venoms tested, including three distinct venoms that were not used as immunogens to generate this antivenom. These findings suggest that a core set of venom immunogens may be sufficient to stimulate antibodies capable of broadly neutralising a geographically diverse array of haemotoxic snake venoms, and that adding additional venom immunogens may impact negatively on the dose efficacy of the resulting antivenom. Although selection of appropriate immunogens that encapsulate venom toxin diversity without diluting antivenom potency remains challenging and further optimisation is required, the findings from this pilot study suggest that the generation of pathology-specific antivenoms with global utility is likely to feasible, thereby highlighting their promise as future modular treatments for the world’s tropical snakebite victims. Snakebite is a major public health concern that causes extensive death and disability in the tropical world. Variation in venom composition causes major challenges for snakebite therapy by typically restricting antivenom efficacy to only the few snake species that each product was designed against, meaning that many geographically restricted therapeutics are manufactured for different parts of the world. In this study, we explored the feasibility of generating a global pathology-specific antivenom by using two different sets of haemotoxic venoms as immunogens, one including seven venoms and the other twelve venoms, to generate ovine polyclonal antibodies. Our in vitro immunological cross-reactivity and venom functional-neutralisation findings demonstrated broadly comparable venom recognition and inhibition against the various venom immunogens, irrespective of whether they were included in the immunising mixture. However, assessments of murine in vivo protection against venom-induced lethality revealed that the antivenom generated with fewer immunogens outperformed the comparator, and provided broader preclinical efficacy, even against some venoms not used to raise the antibodies. These findings suggest that careful selection of venoms used as immunogens is crucial for maintaining antivenom potency, and that a small subset of venoms may be capable of generating an antivenom with potential global efficacy against a specific pathology commonly observed after snakebite.
登录
查看更多内容
两种小分子毒素抑制剂的治疗组合提供了针对蝰蛇咬伤的广泛临床前疗效。
影响因子：
16.6
作者：
Albulescu LO;Xie C;Ainsworth S;Alsolaiss J;Crittenden E;Dawson CA;Softley R;Bartlett KE;Harrison RA;Kool J;Casewell NR
通讯作者：
Casewell NR
影响因子：
2.8
作者：
Calvete, Juan J.
通讯作者：
Calvete, Juan J.
影响因子：
4.2
作者：
Bermúdez-Méndez E;Fuglsang-Madsen A;Føns S;Lomonte B;Gutiérrez JM;Laustsen AH
通讯作者：
Laustsen AH
影响因子：
13.3
作者：
Isbister, G. K.;Maduwage, K.;Buckley, N. A.
通讯作者：
Buckley, N. A.
影响因子：
2.8
作者：
DOSSANTOS, MC;LIMA, MRD;DASILVA, WD
通讯作者：
DASILVA, WD