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Jose Maria Gutierrez - One of the best experts on this subject based on the ideXlab platform.

  • A pan-specific antiserum produced by a novel immunization strategy shows a high spectrum of neutralization against neurotoxic snake venoms
    Scientific Reports, 2020
    Co-Authors: Kavi Ratanabanangkoon, Jose Maria Gutierrez, Kritsada Pruksaphon, Chaiya Klinpayom, Naeem H. Quraishi
    Abstract:

    Snakebite envenomation is a neglected tropical disease of high mortality and morbidity largely due to insufficient supply of effective and affordable Antivenoms. Snake Antivenoms are mostly effective against the venoms used in their production. It is thus crucial that effective and affordable Antivenom(s) with wide para-specificity, capable of neutralizing the venoms of a large number of snakes, be produced. Here we studied the pan-specific antiserum prepared previously by a novel immunization strategy involving the exposure of horses to a ‘diverse toxin repertoire’ consisting of 12 neurotoxic Asian snake toxin fractions/ venoms from six species. This antiserum was previously shown to exhibit wide para-specificity by neutralizing 11 homologous and 16 heterologous venoms from Asia and Africa. We now show that the antiserum can neutralize 9 out of 10 additional neurotoxic venoms. Altogether, 36 snake venoms belonging to 10 genera from 4 continents were neutralized by the antiserum. Toxin profiles previously generated using proteomic techniques of these 36 venoms identified α-neurotoxins, β-neurotoxins, and cytotoxins as predominant toxins presumably neutralized by the antiserum. The bases for the wide para-specificity of the antiserum are discussed. These findings indicate that it is feasible to generate Antivenoms of wide para-specificity against elapid neurotoxic venoms from different regions in the world and raises the possibility of a universal neurotoxic Antivenom. This should reduce the mortality resulting from neurotoxic snakebite envenomation.

  • coagulotoxic effects by brown snake pseudonaja and taipan oxyuranus venoms and the efficacy of a new Antivenom
    Toxicology in Vitro, 2019
    Co-Authors: Christina N Zdenek, Terry Morley, Nathan Dunstan, Luke Allen, Bianca Op Den Brouw, Maria Herrera, Kevin Arbuckle, Jordan Debono, Timothy N. W. Jackson, Jose Maria Gutierrez
    Abstract:

    Abstract Snakebite is a neglected tropical disease that disproportionately affects the poor. Antivenom is the only specific and effective treatment for snakebite, but its distribution is severely limited by several factors, including the prohibitive cost of some products. Papua New Guinea (PNG) is a snakebite hotspot but the high costs of Australian Antivenoms (thousands of dollars per treatment) makes it unaffordable in PNG. A more economical taipan Antivenom has recently been developed at the Instituto Clodomiro Picado (ICP) in Costa Rica for PNG and is currently undergoing clinical trials for the treatment of envenomations by coastal taipans (Oxyuranus scutellatus). In addition to potentially having the capacity to neutralise the effects of envenomations of non-PNG taipans, this Antivenom may have the capacity to neutralise coagulotoxins in venom from closely related brown snakes (Pseudonaja spp.) also found in PNG. Consequently, we investigated the cross-reactivity of taipan Antivenom across the venoms of all Oxyuranus and Pseudonaja species. In addition, to ascertain differences in venom biochemistry that influence variation in Antivenom efficacy, we tested for relative cofactor dependence. We found that the new ICP taipan Antivenom exhibited high selectivity for Oxyuranus venoms and only low to moderate cross-reactivity with any Pseudonaja venoms. Consistent with this genus level distinction in Antivenom efficacy were fundamental differences in the venom biochemistry. Not only were the Pseudonaja venoms significantly more procoagulant, but they were also much less dependent upon the cofactors calcium and phospholipid. There was a strong correlation between Antivenom efficacy, clotting time and cofactor dependence. This study sheds light on the structure-function relationships of the procoagulant toxins within these venoms and may have important clinical implications including for the design of next-generation Antivenoms.

  • Global Availability of Antivenoms: The Relevance of Public Manufacturing Laboratories.
    Toxins, 2018
    Co-Authors: Jose Maria Gutierrez
    Abstract:

    : Snakebite envenoming is a serious global public health problem, and international initiatives, under the coordination of the World Health Organization and its regional offices, are being developed to reduce the impact of this neglected tropical disease. The global availability of safe and effective Antivenoms is one of the key aspects in this global strategy. This review discusses the role of public Antivenom manufacturing laboratories for ensuring the supply of Antivenoms. The difficulties faced by public laboratories are discussed, together with some tasks that need to be implemented for strengthening them. In addition, the concept of 'redundancy' in the supply of Antivenoms is emphasized, as a way to cope with the risks associated with the provision of Antivenoms by few manufacturers. In general, the public sector should play a leading role, in Antivenom availability and other aspects as well, within the global struggle to reduce the mortality and morbidity caused by snakebite envenoming.

  • innovative immunization strategies for Antivenom development
    Toxins, 2018
    Co-Authors: Erick Bermudezmendez, Jose Maria Gutierrez, Bruno Lomonte, Albert Fuglsangmadsen, Sofie Fons, Andreas Hougaard Laustsen
    Abstract:

    Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with Antivenom. Current Antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of Antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating Antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of Antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing Antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for Antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation Antivenoms.

  • preclinical Antivenom efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in east africa
    PLOS Neglected Tropical Diseases, 2017
    Co-Authors: Robert A. Harrison, Jose Maria Gutierrez, George O Oluoch, Stuart Ainsworth, Jaffer Alsolaiss, Fiona M S Bolton, Anasilvia Arias, Paul D Rowley, Stephen Kalya, Hastings Ozwara
    Abstract:

    Background Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective Antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive Antivenoms, many of which are of untested efficacy. Some of these successfully marketed Antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available Antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of Antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa. Methods We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a ‘gold standard’ comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four Antivenoms available in Kenya with two Antivenoms of clinically-proven efficacy. To explain the variant efficacies of these Antivenoms we tested the IgG-venom binding characteristics of each Antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each Antivenom. Findings None of the six Antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available Antivenoms is of concern. In vitro assays of the abilities of ‘test’ Antivenom IgGs to bind venom proteins were not substantially different from that of the ‘gold standard’ Antivenoms. The least effective Antivenoms had the lowest IgG content/vial. Conclusions Manufacture-stated preclinical efficacy statements guide decision making by physicians and Antivenom purchasers in sub-Saharan Africa. This is because of the lack of both clinical data on the efficacy of most of the many Antivenoms used to treat patients and independent preclinical assessment. Our preclinical efficacy assessment of Antivenoms available in Kenya identifies important limitations for two of the most commonly-used Antivenoms, and that no Antivenom is preclinically effective against all the regionally important snakes. The potential implication to snakebite treatment is of serious concern in Kenya and elsewhere in sub-Saharan Africa, and underscores the dilemma physicians face, the need for clinical data on Antivenom efficacy and the medical and societal value of establishing independent preclinical Antivenom-efficacy testing facilities throughout the continent.

Geoffrey K Isbister - One of the best experts on this subject based on the ideXlab platform.

  • Current research into snake Antivenoms, their mechanisms of action and applications.
    Biochemical Society Transactions, 2020
    Co-Authors: Anjana Silva, Geoffrey K Isbister
    Abstract:

    Snakebite is a major public health issue in the rural tropics. Antivenom is the only specific treatment currently available. We review the history, mechanism of action and current developments in snake Antivenoms. In the late nineteenth century, snake Antivenoms were first developed by raising hyperimmune serum in animals, such as horses, against snake venoms. Hyperimmune serum was then purified to produce whole immunoglobulin G (IgG) Antivenoms. IgG was then fractionated to produce F(ab) and F(ab')2 Antivenoms to reduce adverse reactions and increase efficacy. Current commercial Antivenoms are polyclonal mixtures of antibodies or their fractions raised against all toxin antigens in a venom(s), irrespective of clinical importance. Over the last few decades there have been small incremental improvements in Antivenoms, to make them safer and more effective. A number of recent developments in biotechnology and toxinology have contributed to this. Proteomics and transcriptomics have been applied to venom toxin composition (venomics), improving our understanding of medically important toxins. In addition, it has become possible to identify toxins that contain epitopes recognized by Antivenom molecules (Antivenomics). Integration of the toxinological profile of a venom and its composition to identify medically relevant toxins improved this. Furthermore, camelid, humanized and fully human monoclonal antibodies and their fractions, as well as enzyme inhibitors have been experimentally developed against venom toxins. Translation of such technology into commercial Antivenoms requires overcoming the high costs, limited knowledge of venom and Antivenom pharmacology, and lack of reliable animal models. Addressing such should be the focus of Antivenom research.

  • Antivenom cross neutralisation in a suspected asian pit viper envenoming causing severe coagulopathy
    Toxicon, 2014
    Co-Authors: Geoffrey K Isbister, Kalana Maduwage, Colin B. Page
    Abstract:

    There is evidence of cross-neutralisation between common toxin groups in snake venoms and therefore the potential for Antivenoms to be effective against species they are not raised against. Here we present a 49 year old female bitten by an unknown pit-viper in Nepal. She developed a venom induced consumption coagulopathy with an unrecordable international normalised ratio and undetectable fibrinogen. On return to Australia 5 days post-bite she was treated successfully with one Antivenom raised against Malayan pit viper and green pit viper venoms (Haemato-polvalent Antivenom from Thailand) and then subsequently with another Antivenom raised against American pit-viper venoms (Antivipmyn). Presumed pit viper venom was detected in patient sera with an enzyme immunoassay against Hypnale hypnale venom. There was increased absorbance before Antivenom compared to non-envenomed control samples, which then decreased after the administration of each Antivenom. The recurrence of venom detected by enzyme immunoassay between Antivenom doses was accompanied by a recurrence of the coagulopathy. Cross reactivity between the unknown venom and both Antivenoms was supported by the fact that no venom was detected in the pre-Antivenom samples after they were incubated in vitro with both Antivenoms. This case and investigation of the venom and Antivenoms suggest cross-neutralisation between pit vipers, including pit vipers from different continents. Crown

  • current treatment for venom induced consumption coagulopathy resulting from snakebite
    PLOS Neglected Tropical Diseases, 2014
    Co-Authors: Kalana Maduwage, Geoffrey K Isbister
    Abstract:

    Venomous snakebite is considered the single most important cause of human injury from venomous animals worldwide. Coagulopathy is one of the commonest important systemic clinical syndromes and can be complicated by serious and life-threatening haemorrhage. Venom-induced consumption coagulopathy (VICC) is the commonest coagulopathy resulting from snakebite and occurs in envenoming by Viperid snakes, certain elapids, including Australian elapids, and a few Colubrid (rear fang) snakes. Procoagulant toxins activate the clotting pathway, causing a broad range of factor deficiencies depending on the particular procoagulant toxin in the snake venom. Diagnosis and monitoring of coagulopathy is problematic, particularly in resource-poor countries where further research is required to develop more reliable, cheap clotting tests. MEDLINE and EMBASE up to September 2013 were searched to identify clinical studies of snake envenoming with VICC. The UniPort database was searched for coagulant snake toxins. Despite preclinical studies demonstrating Antivenom binding toxins (efficacy), there was less evidence to support clinical effectiveness of Antivenom for VICC. There were no placebo-controlled trials of Antivenom for VICC. There were 25 randomised comparative trials of Antivenom for VICC, which compared two different Antivenoms (ten studies), three different Antivenoms (four), two or three different doses or repeat doses of Antivenom (five), heparin treatment and Antivenom (five), and intravenous immunoglobulin treatment and Antivenom (one). There were 13 studies that compared two groups in which there was no randomisation, including studies with historical controls. There have been numerous observational studies of Antivenom in VICC but with no comparison group. Most of the controlled trials were small, did not use the same method for assessing coagulopathy, varied the dose of Antivenom, and did not provide complete details of the study design (primary outcomes, randomisation, and allocation concealment). Non-randomised trials including comparison groups without Antivenom showed that Antivenom was effective for some snakes (e.g., Echis), but not others (e.g., Australasian elapids). Antivenom is the major treatment for VICC, but there is currently little high-quality evidence to support effectiveness. Antivenom is not risk free, and adverse reactions can be quite common and potentially severe. Studies of heparin did not demonstrate it improved outcomes in VICC. Fresh frozen plasma appeared to speed the recovery of coagulopathy and should be considered in bleeding patients.

  • snakebite in australia a practical approach to diagnosis and treatment
    The Medical Journal of Australia, 2013
    Co-Authors: Geoffrey K Isbister, David Mccoubrie, Shaun L Greene, Colin B. Page, Nicholas A Buckley, Simon G A Brown
    Abstract:

    Snakebite is a potential medical emergency and must receive high-priority assessment and treatment, even in patients who initially appear well. Patients should be treated in hospitals with onsite laboratory facilities, appropriate Antivenom stocks and a clinician capable of treating complications such as anaphylaxis. All patients with suspected snakebite should be admitted to a suitable clinical unit, such as an emergency short-stay unit, for at least 12 hours after the bite. Serial blood testing (activated partial thromboplastin time, international normalised ratio and creatine kinase level) and neurological examinations should be done for all patients. Most snakebites will not result in significant envenoming and do not require Antivenom. Antivenom should be administered as soon as there is evidence of envenoming. Evidence of systemic envenoming includes venom-induced consumption coagulopathy, sudden collapse, myotoxicity, neurotoxicity, thrombotic microangiopathy and renal impairment. Venomous snake groups each cause a characteristic clinical syndrome, which can be used in combination with local geographical distribution information to determine the probable snake involved and appropriate Antivenom to use. The Snake Venom Detection Kit may assist in regions where the range of possible snakes is too broad to allow the use of monovalent Antivenoms. When the snake identification remains unclear, two monovalent Antivenoms (eg, brown snake and tiger snake Antivenom) that cover possible snakes, or a polyvalent Antivenom, can be used. One vial of the relevant Antivenom is sufficient to bind all circulating venom. However, recovery may be delayed as many clinical and laboratory effects of venom are not immediately reversible. For expert advice on envenoming, contact the National Poisons Information Centre on 13 11 26. Language: en

  • Detection of venom-Antivenom (VAV) immunocomplexes in vitro as a measure of Antivenom efficacy.
    Toxicon, 2013
    Co-Authors: Margaret A. O'leary, Geoffrey K Isbister
    Abstract:

    The measurement of free venom with enzyme immunoassay in serum of patients with snake envenoming is used to confirm snake identification and to determine if sufficient Antivenom has been given. Recent studies with Russell’s viper (RV; Daboia russelii) envenoming have detected free venom post-Antivenom despite recovery of coagulopathy. This raises the question as to whether this assay also measures venom–Antivenom (VAV) complexes. In this study we developed an assay to measure VAV complexes and investigate the binding of venom and Antivenom in vitro. The assay consisted of rabbit anti-snake venom IgG attached to a microplate which binds the venom component of VAV and anti-horse IgG antibodies conjugated to horseradish peroxidase to detect the Antivenom portion of VAV. A known amount of venom or toxin was incubated with increasing Antivenom concentrations and VAV was detected as absorbance at 450 nm and plotted against AV concentration. Pseudonaja textilis (brown snake), Notechis scutatus (tiger snake), Oxyuranus scutellatus (taipan), Tropidechis carinatus (rough-scaled snake), Pseudechis porphyriacus (red-bellied black snake) and D. russelii mixtures with appropriate Antivenoms were assayed. Measured VAV initially increased with increasing Antivenom concentration until it reached a maximum after which the VAV concentration decreased with further increasing Antivenom concentrations. The VAV curves for two Australian snake venom–Antivenom mixtures, Hoplocephalus stephensii and Ancanthophis antarcticus, had broad VAV peaks with two maxima. Two fractions isolated from N. scutatus venom and Russell’s viper factor X activator toxin produced similar VAV curves to their whole venoms. The Antivenom concentration for which the maximum VAV occurred was linearly related to the venom concentration, and this slope or ratio was consistent with that used to define the neutralisation units for Australian Antivenoms. The maximal VAV point appears to represent the Antivenom concentration where every venom molecule (toxin) is attached to at least one Antivenom molecule (antibody) on average and may be a useful measure of Antivenom efficacy. In vivo this would mean that for a defined Antivenom concentration, venom components will be eliminated and are trapped in the central compartment. 2013 Published by Elsevier Ltd.

David A Warrell - One of the best experts on this subject based on the ideXlab platform.

  • a multicomponent strategy to improve the availability of Antivenom for treating snakebite envenoming
    Bulletin of The World Health Organization, 2014
    Co-Authors: Jose Maria Gutierrez, Robert A. Harrison, David A Warrell, Juan J. Calvete, Thierry Burnouf, Ulrich Kuch, David J Williams
    Abstract:

    Snakebite envenoming is a common but neglected public health problem, particularly in impoverished rural regions of sub-Saharan Africa, Asia and Latin America. The only validated treatment for this condition is passive immunotherapy with safe and effective animal-derived Antivenoms. However, there is a long-lasting crisis in the availability of these life-saving medications, particularly in sub-Saharan Africa and parts of Asia. We herein advocate a multicomponent strategy to substantially improve the availability of safe and effective Antivenoms at the global level. This strategy is based on: (i) preparing validated collections of representative venom pools from the most medically dangerous snakes in high-risk regions of the world; (ii) strengthening the capacity of national Antivenom manufacturing and quality control laboratories and their regulatory authorities and establishing new facilities in developing countries through technology transfer, as an integral part of efforts to develop their biological products industry; (iii) getting established laboratories to generate Antivenoms for various regions of the world; and (iv) getting governments and relevant organizations to give snakebite envenoming due recognition within national and international public health policy frameworks. These ways of making Antivenom available should be complemented by actions to improve health information systems, the accessibility of Antivenoms, the training of medical and nursing staff, and community-based education. Such a multicomponent strategy involving stakeholders on many levels could help consolidate sustainable improvements in Antivenom availability worldwide.

  • Antivenom therapy of carpet viper echis ocellatus envenoming effectiveness and strategies for delivery in west africa
    Toxicon, 2013
    Co-Authors: Abdulrazaq G Habib, David A Warrell
    Abstract:

    Abstract In West Africa, response to specific, geographically appropriate, Antivenom is often dramatic following carpet viper ( Echis ocellatus ) envenoming with rapid restoration of blood coagulability and resolution of spontaneous haemorrhage. Envenoming from Australasian snakes causing similar coagulopathies may respond less dramatically and the effectiveness of Antivenom is being questioned. Here we have reviewed and re-analysed all published preclinical and clinical studies on envenoming and Antivenom therapy conducted in West Africa to determine the effectiveness of Antivenom. 22 studies provided relevant information: 12 observational studies, 4 RCTs and 6 preclinical studies. Four comparative studies confirmed statistically significant protection against mortality ranging from 57 to 87% using specific Antivenoms compared to non-specific or no Antivenoms. Meta-analysis estimated combined Odds Ratio (95% CI) of 0.25 (0.14–0.45) of dying among those treated with specific Antivenom or 75% (95% CI: 55–86%) protection against death. Mortality more than doubled during times when stocks of reliable Antivenoms ran out, with Relative Risk (95% CI)] of 2.33 (1.26–4.06). Serum kinetics of venom antigen/Antivenom levels also confirmed that decline of venom antigen levels coincided with resolution of coagulopathy while decline of Antivenom levels was associated with venom antigen reappearance and recurrence of coagulopathy. Preclinical and Antivenomics analysis confirmed efficacy of regionally appropriate Antivenoms against E. ocellatus and related species' venoms in Sub-Saharan Africa but not against Asian Echis carinatus venom. Antivenoms raised against E. carinatus were ineffective in human studies. In West Africa, specific Antivenom is effective in managing carpet viper envenoming. A centralized hub-and-spoke strategy is suggested for broadening Antivenom access to endemic rural areas together with instituting quality assurance, standardization and manpower training. Benefits, risks, cost-effectiveness and feasibility of the approach should be formally assessed.

  • pan african polyspecific Antivenom produced by caprylic acid purification of horse igg an alternative to the Antivenom crisis in africa
    Transactions of The Royal Society of Tropical Medicine and Hygiene, 2005
    Co-Authors: Jose Maria Gutierrez, Guillermo Leon, Ermila Rojas, Lil Quesada, Javier Nunez, G D Laing, Mahmood Sasa, J M Renjifo, A Nasidi, David A Warrell
    Abstract:

    A polyspecific Pan-African Antivenom has been produced from the plasma of horses immunized with a mixture of the venoms of Echis ocellatus, Bitis arietans and Naja nigricollis, the three most medically important snakes in sub-Saharan Africa. The Antivenom is a whole IgG preparation, obtained by caprylic acid precipitation of non-IgG plasma proteins. The Antivenom effectively neutralizes the most important toxic activities of the three venoms used in the immunization in standard assays involving preincubation of venom and Antivenom before testing. This Antivenom compares favourably with other Antivenoms designed for use in Africa with respect to neutralization of the toxins present in the venom of E. ocellatus. Caprylic acid fractionation of horse hyperimmune plasma is a simple, convenient and cheap protocol for the manufacture of high quality whole IgG Antivenoms. It constitutes a potentially valuable technology for the alleviation of the critical shortage of Antivenom in Africa.

  • A new Pan African polyspecific Antivenom developed in response to the Antivenom crisis in Africa
    Toxicon, 2003
    Co-Authors: G D Laing, Robert A. Harrison, Jose Maria Gutierrez, Paul D Rowley, David A Warrell, J M Renjifo, A Nasidi, F Ruiz, R.d.g. Theakston
    Abstract:

    Abstract Currently there is a crisis in the supply of Antivenom for treatment of snake bite in sub-Saharan Africa. Commercial pressures have resulted in the reduction or even cessation of production of Antivenom by European manufacturers while continued production of Antivenom in Africa has been threatened by the privatisation of the only remaining company based in Africa. As a consequence, there has been an increase in snake bite morbidity and mortality in many African countries. Two Latin American Antivenom manufacturers have agreed to produce Antivenom suitable for Africa, using venoms from the species which are of the greatest medical importance in sub-Saharan Africa. Preclinical in vivo assays of neutralising potency demonstrated that a new Pan African Antivenom produced in Colombia compared favourably with the existing commercial monospecific and polyspecific Antivenoms. This new Antivenom, and a similar product being manufactured in Costa Rica, are now candidates for clinical testing at an appropriate site in Africa.

  • Report of a WHO workshop on the standardization and control of Antivenoms.
    Toxicon, 2003
    Co-Authors: R.d.g. Theakston, David A Warrell, E Griffiths
    Abstract:

    Abstract A workshop to discuss progress in the standardization and control of Antivenoms, organized by the Quality Assurance and Safety of Biologicals Unit of WHO, was held at the National Institute for Biological Standards and Control, Potters Bar, England, 7–9 February 2001. This was the first meeting convened by the WHO on this subject since 1979 and it brought together experts from academic institutions, Antivenom manufacturers and national regulatory authorities from 21 countries. The meeting reviewed Antivenom production and quality control measures and special consideration was given to the current crisis in Antivenom production and supply in sub-Saharan Africa. The importance of snake bite and scorpion stings as public health issues was re-emphasised. The majority of commercial Antivenoms are raised against snake or scorpion venoms. The review of Antivenom production methods indicated that the vast majority of commercial Antivenoms were still produced by traditional technology in horses, although some antisera were raised in sheep and rabbits. Methods used for plasma fractionation included salt and heat coagulation, caprylic acid stabilization or ion exchange chromatography, as well as immunoglobulin digestion with pepsin to produce F(ab′) 2 or with papain to produce Fab fragments. The meeting agreed that there was much room for improving the production, quality control and safety profile of these products and that lessons could be learnt from the experience gained with the preparation of human immunoglobulins. Many basic assumptions, such as the need to remove Fc fragments by enzyme digestion and to freeze–dry Antivenom preparations, required critical re-examination and more attention should be given to clinical trials as a means of assessing efficacy and safety and of defining the average initial dose. The Workshop also discussed concerns about the risks of transmitting infectious agents to humans via animal blood products, especially those posed by viruses or prions and it was agreed that this aspect needed attention. However, there was no documented or even suspected example of this ever having occurred in the case of Antivenom treatment. Current WHO Requirements for the production and control of Antivenoms and for immune sera of animal origin date from the late 1960s. The Workshop recommended that these be updated to take account of the progress that had taken place in the production and quality control of biologicals in recent years. In addition, the Workshop discussed the need for better standardization of both the venoms and Antivenoms, but concluded that international standards and reference materials were not appropriate in the Antivenom field due to the considerable variation in venom characteristics from the same species from region to region. Instead, it was recommended that national or regional standards be prepared and used.

S Jensen - One of the best experts on this subject based on the ideXlab platform.

  • neutralization of the neuromuscular inhibition of venom and taipoxin from the taipan oxyuranus scutellatus by f ab 2 and whole igg Antivenoms
    Toxicology Letters, 2016
    Co-Authors: Maria Herrera, Rita De Cassia O Collaco, Mauren Villalta, Alvaro Segura, Mariangela Vargas, Christine E Wright, Owen Paiva, Teatulohi Matainaho, S Jensen
    Abstract:

    Abstract The neuromuscular junction activity of Oxyuranus scutellatus venom and its presynaptic neurotoxin, taipoxin, and their neutralization by two Antivenoms were examined in mouse phrenic nerve-diaphragm preparations. The action of taipoxin was also studied at 21 °C. The efficacy of the Antivenoms was also assessed in an in vivo mouse model. Both Antivenoms were effective in neutralizing the neuromuscular blocking activity in preincubation-type experiments. In experiments involving independent addition of venom and Antivenoms, neutralization depended on the time interval between venom addition and Antivenom application. When taipoxin was incubated for 5, 10 or 20 min at 21 °C, and Antivenom added and temperature increased to 37 °C, neutralization was achieved only when the toxin was incubated for 5 or 10 min. The neutralization by the two Antivenoms in an in vivo model showed that both whole IgG and F(ab′)2 Antivenoms were effective in neutralizing lethality. Our findings highlight the very rapid action of taipan venom at the nerve terminal, and the poor capacity of Antivenoms to revert neurotoxicity as the time interval between venom or taipoxin application and Antivenom addition increased. Additionally the disparity between molecular masses of the active substances of the two Antivenoms did not result in differences in neutralization.

  • Antivenomic characterization of two Antivenoms against the venom of the taipan oxyuranus scutellatus from papua new guinea and australia
    American Journal of Tropical Medicine and Hygiene, 2014
    Co-Authors: Maria Herrera, Guillermo Leon, Mauren Villalta, Alvaro Segura, Mariangela Vargas, Owen Paiva, S Jensen, Ana Helena Pagotto, Solange M T Serrano, David J Williams
    Abstract:

    Antivenoms manufactured by bioCSL Limited (Australia) and Instituto Clodomiro Picado (Costa Rica) against the venom of the taipan snakes (Oxyuranus scutellatus) from Australia and Papua New Guinea (PNG), respec- tively, were compared using Antivenomics, an analytical approach that combines proteomics with immunoaffinity chro- matography. Both Antivenoms recognized all venom proteins present in venom from PNG O. scutellatus, although a pattern of partial recognition was observed for some components. In the case of the Australian O. scutellatus venom, both Antivenoms immunorecognized the majority of the components, but the CSL Antivenom showed a stronger pattern of immunoreactivity, which was revealed by the percentage of retained proteins in the immunoaffinity column. Antivenoms interacted with taipoxin in surface plasmon resonance. These observations on Antivenomics agree with previous neutralization studies. are responsible for the majority of cases: Acanthophis laevis (smooth-scaleddeathadder),Micropechisikaheka(NewGuinea small-eyed snake), and Oxyuranus scutellatus (Papuan taipan). Lower numbers of cases are induced by other Acanthophis species, Pseudechis papuanus (Papuan blacksnake), and Pseudonaja textilis (New Guinea brownsnake). 3 In southern PNG and southern Papua, the vast majority of snakebites are inflicted by O. scutellatus. 3 Envenomings by this large elapid snake are characterized by minor local effects and severe sys- temic manifestations, including irreversible flaccid paralysis, coagulopathy associated with systemic spontaneous bleeding, myotoxicity, acute kidney injury, and cardiac damage. 2-6 The therapy for envenomings by O. scutellatus in PNG is based on the intravenous administration of either CSL Poly- valent Antivenom or CSL Taipan Antivenom (both manufac- tured by bioCSL Limited in Melbourne, Victoria, Australia; CSL). They are F(ab')2 Antivenoms generated by pepsin diges- tion and ammonium sulphate precipitation of plasma of hyperimmunized horses. 3 Both of these Antivenoms, when administered early, have been shown to be effective in halting coagulopathy and bleeding and reduce the incidence of respi- ratory paralysis. CSL Polyvalent Antivenom is a polyspecific mixture of immunoglobulins (Igs) raised against the venom of Australian elapid species from five genera (Acanthophis, Notechis, Oxyuranus, Pseudechis ,a ndPseudonaja). Although CSL Taipan Antivenom is therapeutically indicated only for treating envenoming by snakes of the genus Oxyuranus ,t his Antivenom is also the result of hyperimmunizing horses with venom from the same five genera of Australian elapid snakes used in production of CSL Polyvalent Antivenom. 7 Recently, a

  • preclinical evaluation of caprylic acid fractionated igg Antivenom for the treatment of taipan oxyuranus scutellatus envenoming in papua new guinea
    PLOS Neglected Tropical Diseases, 2011
    Co-Authors: Mariangela Vargas, Maria Herrera, Ricardo Estrada, Mauren Villalta, Alvaro Segura, Owen Paiva, Teatulohi Matainaho, S Jensen, Maykel Cerdas
    Abstract:

    BACKGROUND: Snake bite is a common medical emergency in Papua New Guinea (PNG). The taipan, Oxyuranus scutellatus, inflicts a large number of bites that, in the absence of Antivenom therapy, result in high mortality. Parenteral administration of Antivenoms manufactured in Australia is the current treatment of choice for these envenomings. However, the price of these products is high and has increased over the last 25 years; consequently the country can no longer afford all the Antivenom it needs. This situation prompted an international collaborative project aimed at generating a new, low-cost Antivenom against O. scutellatus for PNG. METHODOLOGY/PRINCIPAL FINDINGS: A new monospecific equine whole IgG Antivenom, obtained by caprylic acid fractionation of plasma, was prepared by immunising horses with the venom of O. scutellatus from PNG. This Antivenom was compared with the currently used F(ab')(2) monospecific taipan Antivenom manufactured by CSL Limited, Australia. The comparison included physicochemical properties and the preclinical assessment of the neutralisation of lethal neurotoxicity and the myotoxic, coagulant and phospholipase A(2) activities of the venom of O. scutellatus from PNG. The F(ab')(2) Antivenom had a higher protein concentration than whole IgG Antivenom. Both Antivenoms effectively neutralised, and had similar potency, against the lethal neurotoxic effect (both by intraperitoneal and intravenous routes of injection), myotoxicity, and phospholipase A(2) activity of O. scutellatus venom. However, the whole IgG Antivenom showed a higher potency than the F(ab')(2) Antivenom in the neutralisation of the coagulant activity of O. scutellatus venom from PNG. CONCLUSIONS/SIGNIFICANCE: The new whole IgG taipan Antivenom described in this study compares favourably with the currently used F(ab')(2) Antivenom, both in terms of physicochemical characteristics and neutralising potency. Therefore, it should be considered as a promising low-cost candidate for the treatment of envenomings by O. scutellatus in PNG, and is ready to be tested in clinical trials.

Andreas Hougaard Laustsen - One of the best experts on this subject based on the ideXlab platform.

  • Cost of Manufacturing for Recombinant Snakebite Antivenoms.
    Frontiers in Bioengineering and Biotechnology, 2020
    Co-Authors: Timothy Patrick Jenkins, Andreas Hougaard Laustsen
    Abstract:

    Snakebite envenoming is a neglected tropical disease that affects millions of people across the globe. It has been suggested that recombinant Antivenoms based on mixtures of human monoclonal antibodies, which target key toxins of medically important snake venom, could present a promising avenue toward the reduction of morbidity and mortality of envenomated patients. However, since snakebite envenoming is a disease of poverty, it is pivotal that next-generation therapies are affordable to those most in need; this warrants analysis of the cost dynamics of recombinant Antivenom manufacture. Therefore, we present, for the first time, a bottom-up analysis of the cost dynamics surrounding the production of future recombinant Antivenoms based on available industry data. We unravel the potential impact that venom volume, abundance of medically relevant toxins in a venom, and the molecular weight of these toxins may have on the final product cost. Furthermore, we assess the roles that antibody molar mass, manufacturing and purification strategies, formulation, antibody efficacy, and potential cross-reactivity play in the complex cost dynamics of recombinant Antivenom manufacture. Notably, according to our calculations, it appears that such next-generation Antivenoms based on cocktails of monoclonal immunoglobulin Gs (IgGs) could be manufacturable at a comparable or lower cost to current plasma-derived Antivenoms, which are priced at USD 13-1120 per treatment. We found that monovalent recombinant Antivenoms based on IgGs could be manufactured for USD 20-225 per treatment, while more complex polyvalent recombinant Antivenoms based on IgGs could be manufactured for USD 48-1354 per treatment. Finally, we investigated the prospective cost of manufacturing for recombinant Antivenoms based on alternative protein scaffolds, such as DARPins and nanobodies, and highlight the potential utility of such scaffolds in the context of low-cost manufacturing. In conclusion, the development of recombinant Antivenoms not only holds a promise for improving therapeutic parameters, such as safety and efficacy, but could possibly also lead to a more competetive cost of manufacture of Antivenom products for patients worldwide.

  • Biosynthetic Oligoclonal Antivenom (BOA) for Snakebite and Next-Generation Treatments for Snakebite Victims.
    Toxins, 2018
    Co-Authors: Raghavendra Kini, Sachdev S Sidhu, Andreas Hougaard Laustsen
    Abstract:

    Snakebite envenoming is a neglected tropical disease that each year claims the lives of 80,000⁻140,000 victims worldwide. The only effective treatment against envenoming involves intravenous administration of Antivenoms that comprise antibodies that have been isolated from the plasma of immunized animals, typically horses. The drawbacks of such conventional horse-derived Antivenoms include their propensity for causing allergenic adverse reactions due to their heterologous and foreign nature, an inability to effectively neutralize toxins in distal tissue, a low content of toxin-neutralizing antibodies, and a complex manufacturing process that is dependent on husbandry and procurement of snake venoms. In recent years, an opportunity to develop a fundamentally novel type of Antivenom has presented itself. By using modern antibody discovery strategies, such as phage display selection, and repurposing small molecule enzyme inhibitors, next-generation Antivenoms that obviate the drawbacks of existing plasma-derived Antivenoms could be developed. This article describes the conceptualization of a novel therapeutic development strategy for biosynthetic oligoclonal Antivenom (BOA) for snakebites based on recombinantly expressed oligoclonal mixtures of human monoclonal antibodies, possibly combined with repurposed small molecule enzyme inhibitors.

  • innovative immunization strategies for Antivenom development
    Toxins, 2018
    Co-Authors: Erick Bermudezmendez, Jose Maria Gutierrez, Bruno Lomonte, Albert Fuglsangmadsen, Sofie Fons, Andreas Hougaard Laustsen
    Abstract:

    Snakes, scorpions, and spiders are venomous animals that pose a threat to human health, and severe envenomings from the bites or stings of these animals must be treated with Antivenom. Current Antivenoms are based on plasma-derived immunoglobulins or immunoglobulin fragments from hyper-immunized animals. Although these medicines have been life-saving for more than 120 years, opportunities to improve envenoming therapy exist. In the later decades, new biotechnological tools have been applied with the aim of improving the efficacy, safety, and affordability of Antivenoms. Within the avenues explored, novel immunization strategies using synthetic peptide epitopes, recombinant toxins (or toxoids), or DNA strings as immunogens have demonstrated potential for generating Antivenoms with high therapeutic antibody titers and broad neutralizing capacity. Furthermore, these approaches circumvent the need for venom in the production process of Antivenoms, thereby limiting some of the complications associated with animal captivity and venom collection. Finally, an important benefit of innovative immunization approaches is that they are often compatible with existing Antivenom manufacturing setups. In this review, we compile all reported studies examining venom-independent innovative immunization strategies for Antivenom development. In addition, a brief description of toxin families of medical relevance found in snake, scorpion, and spider venoms is presented, as well as how biochemical, bioinformatic, and omics tools could aid the development of next-generation Antivenoms.

  • Antibody Cross-Reactivity in Antivenom Research.
    Toxins, 2018
    Co-Authors: Line Ledsgaard, Timothy Jenkins, Kamille Elvstrøm Krause, Andrea Martos-esteban, Mikael Engmark, Mikael Rordam Andersen, Kristian Davidsen, Ole Lund, Andreas Hougaard Laustsen
    Abstract:

    Antivenom cross-reactivity has been investigated for decades to determine which Antivenoms can be used to treat snakebite envenomings from different snake species. Traditionally, the methods used for analyzing cross-reactivity have been immunodiffusion, immunoblotting, enzyme-linked immunosorbent assay (ELISA), enzymatic assays, and in vivo neutralization studies. In recent years, new methods for determination of cross-reactivity have emerged, including surface plasmon resonance, Antivenomics, and high-density peptide microarray technology. Antivenomics involves a top-down assessment of the toxin-binding capacities of Antivenoms, whereas high-density peptide microarray technology may be harnessed to provide in-depth knowledge on which toxin epitopes are recognized by Antivenoms. This review provides an overview of both the classical and new methods used to investigate Antivenom cross-reactivity, the advantages and disadvantages of each method, and examples of studies using the methods. A special focus is given to Antivenomics and high-density peptide microarray technology as these high-throughput methods have recently been introduced in this field and may enable more detailed assessments of Antivenom cross-reactivity.

  • recombinant snakebite Antivenoms a cost competitive solution to a neglected tropical disease
    PLOS Neglected Tropical Diseases, 2017
    Co-Authors: Andreas Hougaard Laustsen, Kristoffer H Johansen, Mikael Engmark, Mikael Rordam Andersen
    Abstract:

    Snakebite envenoming is a major public health burden in tropical parts of the developing world. In sub-Saharan Africa, neglect has led to a scarcity of Antivenoms threatening the lives and limbs of snakebite victims. Technological advances within Antivenom are warranted, but should be evaluated not only on their possible therapeutic impact, but also on their cost-competitiveness. Recombinant Antivenoms based on oligoclonal mixtures of human IgG antibodies produced by CHO cell cultivation may be the key to obtaining better snakebite envenoming therapies. Based on industry data, the cost of treatment for a snakebite envenoming with a recombinant Antivenom is estimated to be in the range USD 60–250 for the Final Drug Product. One of the effective Antivenoms (SAIMR Snake Polyvalent Antivenom from the South African Vaccine Producers) currently on the market has been reported to have a wholesale price of USD 640 per treatment for an average snakebite. Recombinant Antivenoms may therefore in the future be a cost-competitive alternative to existing serum-based Antivenoms.