Comparison of Preclinical Properties of Several Available Antivenoms in the Search for Effective Treatment of Vipera ammodytes and Vipera berus Envenoming

Abstract

Snakebites are a relatively rare medical emergency in Europe. In more than half of the annual cases caused by Vipera ammodytes, Vipera berus, and Vipera aspis, immunotherapy with animal-derived antivenom is indicated. Among eight products recently identified as available against European medically relevant species, only Zagreb antivenom, Viperfav, and ViperaTAb have been used almost exclusively for decades. Zagreb antivenom comprises V. ammodytes-specific F(ab′)2 fragments. Viperfav is a polyspecific preparation based on F(ab′)2 fragments against V. aspis, V. berus, and V. ammodytes venoms. ViperaTAb contains Fab fragments against the venom of V. berus. In 2014 the production of Zagreb antivenom was discontinued. Additionally, in the period of 2017 to 2018 a shortage of Viperfav occurred. Due to a lack of the product indicated for the treatment of V. ammodytes bites, other antivenoms were implemented into clinical practice without comparative assessment of their eligibility. The aim of our work was to identify a high-quality antivenom that might ensure the successful treatment of V. ammodytes and V. berus bites at the preclinical level. Differentiation between bites from these two species is difficult and unreliable in clinical practice, so the availability of a unique antivenom applicable in the treatment of envenoming caused by both species would be the most advantageous for Southeastern Europe. Zagreb antivenom, Viperfav, and ViperaTAb, as well as Viper venom antitoxin for V. berus envenoming and the in-development Inoserp Europe, which was designed to treat envenoming caused by all medically important European snakes, were comparatively tested for the first time. Emphasis was placed on their physicochemical properties, primarily purity and aggregate content, as well as their in vivo protective efficacies. As Zagreb antivenom is no longer available on the European market, Viperfav is the highest-quality product currently available and the only antivenom whose neutralisation potency against V. ammodytes and V. berus venoms was above regulatory requirements.

Acute Exposure to European Viper Bite in Children: Advocating for a Pediatric Approach

“…Given the large time span of the study, it should not surprise the reader that the use of obsolete yet effective sera such as the ‘Zagreb’ antivenom, which is not produced anymore. However, while polyvalent sera (that is, derived from multiple viper species) are effective antivenoms for the management of the main European viper species [ 21 ], other monovalent antivenoms may also be administered on the grounds of their cross-reactivity [ 23 ]. That being said, the ‘Viperfav’ (manufacturer: Sanofi-Pasteur MSD, France) antivenom, which is derived from V. ammodytes , V. berus , and V. aspis venom, seems to be the best choice for the treatment of viper bites in Italy, as in Europe, where these viper species reside.…”

Biochemistry and toxicology of proteins and peptides purified from the venom of Vipera berus berus

“…The potency of the anti- V. b. berus antivenom could be improved 11.5 to 23 times by affinity chromatographic purification of its F(ab') 2 antibodies. Recently Kurtovič et al (2021) performed comparative analysis of the safety-related properties and efficacy of a panel of antivenoms against V. ammodytes and/or V. berus envenoming that are currently available, or in development for the European market. They revealed that Viperfav (Sanofi Pasteur SA, Lyon, France) had the best protection against lethal toxicity induced by the venoms of both V. ammodytes and V. berus .…”

“…In comparison to Zagreb antivenom Viperfav showed 4- to 5-fold weaker protective efficacy. Renewal of Zagreb antivenom production would be of great value ( Kurtovič et al 2021 ).…”

Patofiziološki mehanizmi djelovanja životinjskih i biljnih toksina

“…Također važno je spomenuti i zagrebački protuotrov koji se prestao proizvoditi 2014., a pokazao je najveću specifičnu aktivnost te bi njegova ponovna proizvodnja omogućila svim javnozdravstvenim ustanovama dostupnost protuotrova čija je sigurnost i učinkovitost ispitana. 26…”