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Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases:...
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Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963)

A special issue of Toxins (ISSN 2072-6651).

Deadline for manuscript submissions: 31 January 2025 | Viewed by 18192

Special Issue Editor

Dr. Jean-Philippe Chippaux

E-Mail Website
Guest Editor
Institut de Recherche pour le Développement, UMR 261-MERIT, 4 Ave de l'observatoire, 75270 Paris, France
Interests: snakebite; scorpion sting; antivenom; neglected tropical diseases; epidemiology; public health; health policy; clinical trial; clinical; treatment

Special Issue Information

Dear Colleagues,

Passive immunotherapy (or serum therapy against diphtheria, tetanus, venoms or virus) has developed gradually since its discovery in 1894 by Césaire Phisalix and Albert Calmette separately. To date, many improvements have been made to obtain the high-efficacy and high-tolerance products that we use today.

In 2023, we will commemorate sixty-year anniversary of the death of Gaston Ramon (1886–1963). G. Ramon was a veterinarian and immunologist who made major contributions to the enhancement of immunization, through the development of flocculation, toxoids, adjuvants and antigen combinations for vaccination. Despite 155 independent nominations for the Nobel Prize in Medicine between 1930 and 1953, a record number of nominations, G. Ramon never received this prize.

This Special Issue aims to provide an update of Gaston Ramon’s various discoveries in the field of passive immunotherapy and its applications in the context of envenomation and infectious diseases.

Potential topics include but are not limited to:

  • History of the development of antitoxins and antivenoms;
  • Mechanism of action of toxoids;
  • Role of flocculation in the neutralization of toxins;
  • Significance of flocculation to measure the affinity of antibodies for their target;
  • Mechanism of action of adjuvants;
  • Benefit of adjuvants for the immunization and production of antibodies;
  • Relevance and limits of the combination of antigens for immunization;
  • Application of passive immunity in the management of infectious diseases (including Ebola, COVID, Dengue, Zika, etc.);
  • Use of the serum of convalescent patients in the treatment of infectious diseases.

Dr. Jean-Philippe Chippaux
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • passive immunotherapy
  • serum therapy
  • antitoxin
  • antivenom
  • toxoid
  • flocculation
  • adjuvant
  • antibody

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

16 pages, 1318 KiB  
Editorial
Gaston Ramon’s Big Four
by Jean-Philippe Chippaux
Toxins 2024, 16(1), 33; https://doi.org/10.3390/toxins16010033 - 9 Jan 2024
Viewed by 1722
Abstract
When immunology was still in its infancy, Gaston Ramon made several major contributions to humoral immunology [...] Full article
(This article belongs to the Special Issue Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963))
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Research

Jump to: Editorial, Review

22 pages, 2906 KiB  
Article
Neutralizing Nanobodies against Venoms from Naja haje Species Captured in North Africa
by Hiba Mejri, Rym Mokrani, Ayoub Ksouri, Mabrouk Seddik, Nour Awad, Gabriel Ayme, Thouraya Chagour, Ahlem Mokrani, Charraf eddine Louchene, Imed Salhi, Rahma Ben Abderrazek, Rym Ben Khalifa, Zakaria Benlasfar, Pierre-Jean Corringer, Mohamed Hammadi, Selma Djilani, Pierre Lafaye and Balkiss Bouhaouala-Zahar
Toxins 2024, 16(9), 393; https://doi.org/10.3390/toxins16090393 - 14 Sep 2024
Viewed by 1250
Abstract
Snakebite envenoming (SBE) remains a severely neglected public health issue, particularly affecting tropical and subtropical regions, with Africa experiencing an estimated 435,000 to 580,000 snakebites annually, leading to high morbidity and mortality rates, especially across Africa and Asia. Recognized as a Neglected Tropical [...] Read more.
Snakebite envenoming (SBE) remains a severely neglected public health issue, particularly affecting tropical and subtropical regions, with Africa experiencing an estimated 435,000 to 580,000 snakebites annually, leading to high morbidity and mortality rates, especially across Africa and Asia. Recognized as a Neglected Tropical Disease, SBE management is further complicated by the inadequate efficacy of current antivenom treatments. Of particular concern are cobras (Naja sp.), whose neurotoxins can induce rapid fatal respiratory paralysis. In this study, we investigate the potential of nanobodies as a promising next-generation of immunotherapeutics against cobra venoms. Through a dual strategy of the characterization of venom toxic fractions from cobras captured for the first time in Algeria and Tunisia biotopes, coupled with in vitro assays to evaluate their interactions with acetylcholine receptors, and subsequent immunization of dromedaries to produce specific nanobodies, we identified two lethal fractions, F5 and F6, from each venom, and selected five nanobodies with significant binding and neutralizing of 3DL50 (0.74 mg/kg). The combination of these nanobodies demonstrated a synergistic effect, reaching 100% neutralizing efficacy of 2DL50 lethal venom fraction (0.88 mg/kg) doses in mice. Additionally, our findings highlighted the complex mechanism of cobra venom action through the lethal synergism among its major toxins. Full article
(This article belongs to the Special Issue Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963))
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17 pages, 5095 KiB  
Article
Development and Efficacy of the Antivenom Specific to Severe Envenomations in Morocco and North Africa: Advancements in Scorpion Envenomation Management
by Bouchra Darkaoui, Ines Hilal, Soukaina Khourcha, Ayoub Lafnoune, Salma Chakir, Ayoub Aarab, Abdellah Moustaghfir, Ouafaa Aniq Filali and Naoual Oukkache
Toxins 2024, 16(5), 214; https://doi.org/10.3390/toxins16050214 - 4 May 2024
Cited by 1 | Viewed by 1949
Abstract
Scorpion envenomation poses a global public health issue, with an estimated 1,500,000 cases worldwide annually resulting in 2600 deaths. North Africa, particularly Morocco, experiences severe envenomations, mainly attributed to Androctonus mauretanicus and Buthus occitanus in Morocco, and Buthus occitanus and Androctonus australis hector [...] Read more.
Scorpion envenomation poses a global public health issue, with an estimated 1,500,000 cases worldwide annually resulting in 2600 deaths. North Africa, particularly Morocco, experiences severe envenomations, mainly attributed to Androctonus mauretanicus and Buthus occitanus in Morocco, and Buthus occitanus and Androctonus australis hector in Algeria and Tunisia, with case numbers often underestimated. Current treatment relies mainly on symptomatic approaches, except in Morocco, where management is limited to symptomatic treatment due to controversies regarding specific treatment. In Morocco, between 30,000 and 50,000 scorpion envenomation cases are reported annually, leading to hundreds of deaths, mainly among children. Controversies among clinicians persist regarding the appropriate course of action, often limiting treatments to symptomatic measures. The absence of a specific antivenom for the venoms of the most lethal scorpions further exacerbates the situation. This study aims to address this gap by developing a monovalent antivenom against the endemic and most dangerous scorpion, Androctonus mauretanicus. The antivenom was produced by immunizing albino rabbits with a mixture of Androctonus mauretanicus venom collected from high-risk areas in Morocco. Immunizations were performed by subcutaneous injections at multiple sites near the lymphatic system, following an immunization schedule. Production control of neutralizing antibody titers was conducted through immunodiffusion. Once a sufficient antibody titer was achieved, blood collection was performed, and the recovered plasma underwent affinity chromatography. The efficacy of purified IgG was evaluated by determining the ED50 in mice, complemented by histological and immunohistochemical studies on its ability to neutralize venom-induced tissue alterations and the neutralization of toxins bound to receptors in the studied organs. The monovalent antivenom demonstrated specificity against Androctonus mauretanicus venom and effective cross-protection against the venom of the scorpions Buthus occitanus and Androctonus australis hector, highly implicated in lethal envenomations in the Maghreb. This study shows that the developed monovalent antivenom exhibits notable efficacy against local scorpions and a surprising ability to neutralize the most lethal envenomations in North Africa. These results pave the way for a new, more specific, and promising therapeutic approach to countering severe scorpion envenomations, especially in Morocco, where specific treatment is lacking. Full article
(This article belongs to the Special Issue Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963))
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14 pages, 968 KiB  
Article
Snakebites in Cameroon: Tolerance of a Snake Antivenom (Inoserp™ PAN-AFRICA) in Africa in Real-Life Conditions
by David Benhammou, Jean-Philippe Chippaux, Rodrigue Ntone, Yoann Madec, Pierre Amta, Gaëlle Noel, Fai Njuwa Karl, Anaïs Perilhou, Lucrece Matchim, Marie Sanchez, Mark Ndifon, Pedro Clauteaux, Lucrèce Eteki, Yap Boum II, Armand Seraphin Nkwescheu and Fabien Taieb
Toxins 2024, 16(4), 165; https://doi.org/10.3390/toxins16040165 - 22 Mar 2024
Viewed by 1871
Abstract
Snakebite envenomation (SBE) is a public health issue in sub-Saharan countries. Antivenom is the only etiological treatment. Excellent tolerance is essential in managing SBE successfully. This study aimed to evaluate tolerance of InoserpTM PAN-AFRICA (IPA). It was conducted on fourteen sites across [...] Read more.
Snakebite envenomation (SBE) is a public health issue in sub-Saharan countries. Antivenom is the only etiological treatment. Excellent tolerance is essential in managing SBE successfully. This study aimed to evaluate tolerance of InoserpTM PAN-AFRICA (IPA). It was conducted on fourteen sites across Cameroon. IPA was administered intravenously and repeated at the same dose every two hours if needed. Early and late tolerance was assessed by the onset of clinical signs within two hours and at a visit two weeks or more after the first IPA administration, respectively. Over 20 months, 447 patients presenting with a snakebite were included. One dose of IPA was administered to 361 patients and repeated at least once in 106 patients. No significant difference was shown between the proportion of adverse events in patients who received IPA (266/361, 73.7%) and those who did not (69/85, 81.2%) (p = 0.95). Adverse reactions, probably attributable to IPA, were identified in four (1.1%) patients, including one severe (angioedema) and three mild. All these reactions resolved favorably. None of the serious adverse events observed in twelve patients were attributed to IPA. No signs of late intolerance were observed in 302 patients. Tolerance appears to be satisfactory. The availability of effective and well-tolerated antivenoms would reduce the duration of treatment and prevent most disabilities and/or deaths. Full article
(This article belongs to the Special Issue Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963))
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23 pages, 33447 KiB  
Article
Neutralization Capacity of Tissue Alterations Caused by the Venoms of the Most Dangerous Scorpions in North Africa Using a Selective Antivenom
by Bouchra Darkaoui, Mohamed Aksim, Ayoub Aarab, Ayoub Lafnoune, Soukaina Khourcha, Rachida Cadi, Ouafaa Aniq Filali and Naoual Oukkache
Toxins 2024, 16(1), 16; https://doi.org/10.3390/toxins16010016 - 27 Dec 2023
Cited by 2 | Viewed by 1798
Abstract
In North Africa, scorpion stings pose an urgent public health problem, particularly for children with high morbidity and mortality rates. The main species implicated are the Androctonus mauretanicus (Am), Androctonus australis hector (Aah), and Buthus occitanus (Bo). [...] Read more.
In North Africa, scorpion stings pose an urgent public health problem, particularly for children with high morbidity and mortality rates. The main species implicated are the Androctonus mauretanicus (Am), Androctonus australis hector (Aah), and Buthus occitanus (Bo). Immunotherapy is the specific therapeutic approach aimed at directly neutralizing toxins, despite their severity and rapid diffusion. In the present study, we evaluate, histologically and immunohistologically, the neutralization potency of the selective antivenom produced against, among other species, the Am, Aah, and Bo at the level of the tissue alterations in Swiss mice, as experimental subjects. Firstly, the lethal doses 50 test was conducted to assess the venom’s toxic activity, and then the median effective dose of the antivenom was determined against each venom. The histological and immunohistological analyses were performed by injecting the sublethal dose of venom, the complex venom and antivenom, or the antivenom 2 h following inoculation of venom. Our study revealed the highest toxicity of the Am, followed by the Aah and then the Bo venom. The neutralizing ability and effectiveness of the antivenom to completely or partially neutralize the tissular damages were demonstrated in all organs studied: brain, heart, lungs, liver, and kidneys. Our results highlighted the important cytoplasmic and membranous staining in the heart compared to the brain tissue for the three scorpion venoms. Therefore, the scorpionic antivenoms are able to reach their target even at the tissue level. Immunotherapy represents the specific and recommended treatment against the scorpionic stings in North Africa. Full article
(This article belongs to the Special Issue Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963))
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Review

Jump to: Editorial, Research

11 pages, 1230 KiB  
Review
Polyvalent Snake Antivenoms: Production Strategy and Their Therapeutic Benefits
by Kavi Ratanabanangkoon
Toxins 2023, 15(9), 517; https://doi.org/10.3390/toxins15090517 - 24 Aug 2023
Cited by 8 | Viewed by 5268
Abstract
Snake envenomation remains an important yet neglected medical problem in many countries, with around five million people affected, and over a hundred thousand deaths annually. Plasma-derived antivenoms are the main therapeutic agent available. Monovalent antivenoms are produced via the immunization of large animals, [...] Read more.
Snake envenomation remains an important yet neglected medical problem in many countries, with around five million people affected, and over a hundred thousand deaths annually. Plasma-derived antivenoms are the main therapeutic agent available. Monovalent antivenoms are produced via the immunization of large animals, e.g., horses, with one venom, after which the horse serum can neutralize the homologous venom, with minimal or no cross neutralization against other venoms. It is necessary, therefore, for the culprit snake to be identified, so that the appropriate specific antivenom can be selected. Polyvalent antivenoms (pAVs) are produced via immunization with a number of snake venoms, and the serum can neutralize all the venoms used in its production. Thus, pAVs can be used to treat several venoms from a country/region, and the identification of the culprit snake is not necessary. There are various parameters and processes involved in the production of pAVs, depending on the requirements and resources available. Most commercial pAVs use a mixture of both elapid and viperid venoms as immunogens, while some pAVs use either elapid or viperid venoms. Some pAVs are produced through the mixing of more than one monovalent or polyvalent antivenom. These various types of pAVs have their own characteristics, and have benefits and drawbacks. The major benefits of pAVs are the wide coverage of many medically important venoms, including many heterologous venoms. They also remove the need to identify the culprit snake, and they can be produced at a lower cost than several monovalent antivenoms. Interesting polyvalent antivenoms, termed ‘syndromic pAVs’ (s-pAVs), have recently gained attention. They are produced for use according to the syndromes manifested in snakebite patients. The venoms that produce these syndromes are used as immunogens in the production of ‘syndromic antivenoms’. For example, ‘neurotoxic polyvalent antivenom’ and ‘hematotoxic polyvalent antivenom’ are produced using the neurotoxic elapid and hematotoxic viperid venoms as immunogens, respectively. They were first marketed by the Thai Red Cross in 2012, and have since gained attention as a possible therapeutic modality to help solve the problem of snakebite envenomation globally. The merits of these s-pAVs, including their efficacy and wide paraspecificities, are discussed. Full article
(This article belongs to the Special Issue Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963))
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23 pages, 3384 KiB  
Review
Snake Antivenoms—Toward Better Understanding of the Administration Route
by Erika Gamulin, Sanja Mateljak Lukačević, Beata Halassy and Tihana Kurtović
Toxins 2023, 15(6), 398; https://doi.org/10.3390/toxins15060398 - 15 Jun 2023
Cited by 3 | Viewed by 3329
Abstract
Envenomations induced by animal bites and stings constitute a significant public health burden. Even though a standardized protocol does not exist, parenterally administered polyclonal antivenoms remain the mainstay in snakebite therapy. There is a prevailing opinion that their application by the i.m. route [...] Read more.
Envenomations induced by animal bites and stings constitute a significant public health burden. Even though a standardized protocol does not exist, parenterally administered polyclonal antivenoms remain the mainstay in snakebite therapy. There is a prevailing opinion that their application by the i.m. route has poor efficacy and that i.v. administration should preferentially be chosen in order to achieve better accomplishment of the antivenom therapeutic activity. Recently, it has been demonstrated that neutralization not only in the systemic circulation but also in the lymphatic system might be of great importance for the clinical outcome since it represents another relevant body compartment through which the absorption of the venom components occurs. In this review, the present-day and summarized knowledge of the laboratory and clinical findings on the i.v. and i.m. routes of antivenom administration is provided, with a special emphasis on the contribution of the lymphatic system to the process of venom elimination. Until now, antivenom-mediated neutralization has not yet been discussed in the context of the synergistic action of both blood and lymph. A current viewpoint might help to improve the comprehension of the venom/antivenom pharmacokinetics and the optimal approach for drug application. There is a great need for additional dependable, practical, well-designed studies, as well as more practice-related experience reports. As a result, opportunities for resolving long-standing disputes over choosing one therapeutic principle over another might be created, improving the safety and effectiveness of snakebite management. Full article
(This article belongs to the Special Issue Passive Immunotherapy and Its Applications in Envenomation and Infectious Diseases: In Tribute to Gaston Ramon (1886–1963))
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