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Immunogenicity of Botulinum Toxin

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 21648

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Dr. Sara Samadzadeh

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Guest Editor

1. Departments of Neurology, University of Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany
2. Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
3. Department of Regional Health Research and Molecular Medicine, University of Southern Denmark, Odense, Denmark
4. Department of Neurology, Slagelse Hospital, Slagelse, Denmark
Interests: multiple sclerosis; clinical neurology; movement disorders; demyelinating diseases; neuroimmunology; neuro-ophthalmology

Prof. Dr. Harald Hefter

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Guest Editor

Department of Neurology, University of Dusseldorf, Moorenstr 5, D-40225 Dusseldorf, Germany
Interests: botulinum toxin therapy; pathogenesis of sensorimotor integration disorders; heavy metal intoxication
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Special Issue Information

Dear Colleagues,

This Special Issue is aimed at describing the immunogenicity of botulinum neurotoxins (BoNT). BoNTs are clostridial products and form a family of highly specialized proteins that attack the mechanism of exocytosis in a variety of cells. The clostridial protein complex contains hemagglutinins, non-hemagglutinins, and pure BoNT. These different components all work to induce immune responses. Therefore, the responses to BoNTs are not uniform, and a broad spectrum of responses is observed.

The contact of the human body with BoNTs may occur by chance, during food poisoning, when BoNTs are used as biological weapons, or when BoNTs are clinically applicated. This implies that antibody formation can be life-saving on the one hand, and may be a therapy-limiting factor on the other hand. Several BoNTs have been tried for clinical applications. However, today only BoNT/A is mainly used for clinical applications owing to its long-lasting effect and low antigenicity.

However, even for the development of clinically applicable preparations of botulinum neurotoxin type A (BoNT/A), attempts at purification and improvement in biological function and reduction of immunoresistance are absolutely necessary. Thus far, in all attempts, BoNT/A-treatment can still cause primary, secondary, partial or complete treatment failure. Furthermore, for a good clinical outcome of this highly effective, symptomatic therapy, tissue, muscle, and dose selection have to be optimized and different guidance techniques should be used. Knowledge of the course of disease before and after BoNT/A-therapy is important. This underlines the relevance of the documentation of injection sites, dose per site, and the use of clinical scores for the careful monitoring of BoNT-therapy and the assessment of the patient´s experience of improvement in quality of life. The side effects of BoNT-therapy are usually mild and sometimes overestimated. Nevertheless, BoNTs should be applied with care, since supersensitive patients exist. Different clinical and laboratory tests have been developed for the early detection of a partial secondary treatment failure.

This issue would cover the mentioned above aspects in general with a focus on the following points:

Issues related to BoNT/A therapy and neutralizing antibodies

a. Laboratory and clinical tests for detecting antibody formation
b. Special cases in Botulinum Toxin Therapy (case reports and literature reviews)

(Cases without BoNT indication approval—therapy-resistant cases, unusual cases -…)

Dr. Sara Samadzadeh
Prof. Dr. Harald Hefter
Guest Editors

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Keywords

botulinum neurotoxin (BoNT)
botulinum neurotoxin type A (BoNT/A)
neutralizing antibodies
immunoresistance
primary and secondary treatment failure
antigenicity
complex protein-free BoNT/A
complex protein containing BoNT/A
therapy switching

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Published Papers (9 papers)

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Research

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12 pages, 1247 KiB

Open AccessArticle

“Pseudo”-Secondary Treatment Failure Explained via Disease Progression and Effective Botulinum Toxin Therapy: A Pilot Simulation Study

by Harald Hefter, Dietmar Rosenthal and Sara Samadzadeh

Toxins 2023, 15(10), 618; https://doi.org/10.3390/toxins15100618 - 18 Oct 2023

Viewed by 1651

Abstract

Background: The objective of this study was to provide evidence from a simple simulation. In patients with focal dystonia, an initial good response to botulinum neurotoxin (BoNT) injections followed by a secondary worsening does not necessarily arise from an antibody-induced secondary treatment failure (NAB-STF), but may stem from a “pseudo”-secondary treatment failure (PSEUDO-STF). Methods: The simulation of the outcome after BoNT long-term treatment was performed in four steps: 1. The effect of the first single BoNT injection (SI curve) was displayed as a 12-point graph, corresponding to the mean improvement from weeks 1 to 12. 2. The remaining severity of the dystonia during the nth injection cycle was calculated by subtracting the SI curve (weighted by the outcome after n − 1 cycles) from the outcome after week 12 of the (n − 1)th cycle. 3. A graph was chosen (the PRO curve), which represents the progression of the severity of the underlying disease during BoNT therapy. 4. The interaction between the outcome during the nth BoNT cycle and the PRO curve was determined. Results: When the long-term outcome after n cycles of BoNT injections (applied every 3 months) was simulated as an interactive process, subtracting the effect of the first cycle (weighted by the outcome after n − 1 cycles) and adding the progression of the disease, an initial good improvement followed by secondary worsening results. This long-term outcome depends on the steepness of the progression and the duration of action of the first injection cycle. We termed this response behavior a “pseudo”-secondary treatment failure, as it can be compensated via a dose increase. Conclusion: A secondary worsening following an initial good response in BoNT therapy of focal dystonia might not necessarily indicate neutralizing antibody induction but could stem from a “PSEUDO”-STF (a combination of good response behavior and progression of the underlying disease). Thus, an adequate dose adaptation must be conducted before diagnosing a secondary treatment failure in the strict sense. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

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11 pages, 1659 KiB

Open AccessCommunication

Addressing the Real-World Challenges of Immunoresistance to Botulinum Neurotoxin A in Aesthetic Practice: Insights and Recommendations from a Panel Discussion in Hong Kong

by Wilson W. S. Ho, Lisa Chan, Niamh Corduff, Wang-Tak Lau, Michael U. Martin, Clifton Ming Tay, Sandy Wang and Raymond Wu

Toxins 2023, 15(7), 456; https://doi.org/10.3390/toxins15070456 - 12 Jul 2023

Cited by 7 | Viewed by 2660

Abstract

With increasing off-label aesthetic indications using higher botulinum neurotoxin A (BoNT-A) doses and individuals starting treatment at a younger age, particularly in Asia, there is a greater risk of developing immunoresistance to BoNT-A. This warrants more in-depth discussions by aesthetic practitioners to inform patients and guide shared decision-making. A panel comprising international experts and experienced aesthetic practitioners in Hong Kong discussed the implications and impact of immunoresistance to BoNT-A in contemporary aesthetic practice, along with practical strategies for risk management. Following discussions on a clinical case example and the results of an Asia-Pacific consumer study, the panel concurred that it is a priority to raise awareness of the possibility and long-term implications of secondary non-response due to immunoresistance to BoNT-A. Where efficacy and safety are comparable, a formulation with the lowest immunogenicity is preferred. The panel also strongly favored a thorough initial consultation to establish the patient’s treatment history, explain treatment side effects, including the causes and consequences of immunoresistance, and discuss treatment goals. Patients look to aesthetic practitioners for guidance, placing an important responsibility on practitioners to adopt risk-mitigating strategies and adequately communicate important risks to patients to support informed and prudent BoNT-A treatment decisions. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

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13 pages, 917 KiB

Open AccessArticle

No Secondary Treatment Failure during Incobotulinumtoxin—A Long-Term Treatment Demonstrated by the Drawing of Disease Severity

by Harald Hefter, Raphaela Brauns, Beyza Ürer, Dietmar Rosenthal, Philipp Albrecht and Sara Samadzadeh

Toxins 2023, 15(7), 454; https://doi.org/10.3390/toxins15070454 - 12 Jul 2023

Cited by 1 | Viewed by 1321

Abstract

The aim of this study was to detect clinical hints regarding the development of secondary treatment failure (STF) in patients with focal dystonia who were exclusively treated with incobotulinumtoxin/A (incoBoNT/A). In total, 33 outpatients (26 with idiopathic cervical dystonia, 4 with Meige syndrome and 3 with other cranial dystonia) who were treated with repeated injections of incoBoNT/A for a mean period of 6.4 years without interruptions were recruited to draw the course of their disease severity (CoD) from the onset of symptoms to the onset of BoNT therapy (CoDB graph) and from the onset of BoNT therapy to recruitment (CoDA graph). At the time of recruitment, the patients assessed the change in severity as a percentage of the severity at the onset of BoNT therapy. Blood samples were taken to test the presence of neutralizing antibodies (NABs) using the mouse hemidiaphragm assay (MHDA). Patients reported an improvement of about 70% with respect to the mean. None of the patients tested positive for MHDA. Three different types of CoDB and three different types of CoDA graphs could be distinguished. The patients with different CoDB graphs reported different long-term outcomes, but there was no significant difference in long-term outcomes between patients with different CoDA graphs. None of the patients produced a CoDA graph with an initial improvement and a secondary worsening as a hint for the development of STF. A primary non-response was not observed in any of the patients. During long-term treatment with BoNT/A, NABs and/or STF may develop. However, in the present study on patients with incoBoNT/A long-term monotherapy, no hints for the development of NABs or STF could be detected, underlining the low antigenicity of incoBoNT/A. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

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16 pages, 2107 KiB

Open AccessArticle

Lessons about Botulinum Toxin A Therapy from Cervical Dystonia Patients Drawing the Course of Disease: A Pilot Study

by Harald Hefter, Isabelle Schomaecker, Max Schomaecker, Beyza Ürer, Raphaela Brauns, Dietmar Rosenthal, Philipp Albrecht and Sara Samadzadeh

Toxins 2023, 15(7), 431; https://doi.org/10.3390/toxins15070431 - 30 Jun 2023

Cited by 5 | Viewed by 1659

Abstract

Aim of the study: To compare the course of severity of cervical dystonia (CD) before and after long-term botulinum toxin (BoNT) therapy to detect indicators for a good or poor clinical outcome. Patients and Methods: A total of 74 outpatients with idiopathic CD who were continuously treated with BoNT and who had received at least three injections were consecutively recruited. Patients had to draw the course of severity of CD from the onset of symptoms until the onset of BoNT therapy (CoDB graph), and from the onset of BoNT therapy until the day of recruitment (CoDA graph) when they received their last BoNT injection. Mean duration of treatment was 9.6 years. Three main types of CoDB and four main types of CoDA graphs could be distinguished. The demographic and treatment-related data of the patients were extracted from the patients’ charts. Results: The best outcome was observed in those patients who had experienced a clear, rapid response in the beginning. These patients had been treated with the lowest doses and with a low number of BoNT preparation switches. The worst outcome was observed in those 17 patients who had drawn a good initial improvement, followed by a secondary worsening. These secondary nonresponders had been treated with the highest initial and actual doses and with frequent BoNT preparation switches. A total of 12 patients were primary nonresponders and did not experience any improvement at all. No relation between the CoDB and CoDA graphs could be detected. Primary and secondary nonresponses were observed for all three CoDB types. The use of initial high doses as a relevant risk factor for the later development of a secondary nonresponse was confirmed. Conclusions: Patients’ drawings of their course of disease severity helps to easily detect “difficult to treat” primary and secondary nonresponders to BoNT on the one hand, but also to detect “golden responders” on the other hand. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

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16 pages, 1912 KiB

Open AccessArticle

Neutralizing Antibody Formation with OnabotulinumtoxinA (BOTOX^®) Treatment from Global Registration Studies across Multiple Indications: A Meta-Analysis

by Joseph Jankovic, Jean Carruthers, Markus Naumann, Patricia Ogilvie, Terry Boodhoo, Mayssa Attar, Swati Gupta, Ritu Singh, John Soliman, Irina Yushmanova, Mitchell F. Brin and Jie Shen

Toxins 2023, 15(5), 342; https://doi.org/10.3390/toxins15050342 - 17 May 2023

Cited by 13 | Viewed by 5062

Abstract

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and post-treatment was tested and examined for impact on clinical safety and efficacy. Overall, 27 of the 5876 evaluable subjects (0.5%) developed NAbs after onabotulinumtoxinA treatment. At study exit, 16 of the 5876 subjects (0.3%) remained NAb positive. Due to the low incidence of NAb formation, no clear relationship was discernable between positive NAb results and gender, indication, dose level, dosing interval, treatment cycles, or the site of injection. Only five subjects who developed NAbs post-treatment were considered secondary nonresponders. Subjects who developed NAbs revealed no other evidence of immunological reactions or clinical disorders. This comprehensive meta-analysis confirms the low NAb formation rate following onabotulinumtoxinA treatment across multiple indications, and its limited clinical impact on treatment safety and efficacy. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

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Review

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8 pages, 236 KiB

Open AccessReview

Onabotulinumtoxin A for the Treatment of Post-Traumatic Headache: Is It Better than Anti-CGRP Antibodies?

by Lanfranco Pellesi, Dilara Onan and Paolo Martelletti

Toxins 2024, 16(10), 427; https://doi.org/10.3390/toxins16100427 - 2 Oct 2024

Viewed by 1010

Abstract

Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A’s ability to target multiple pain pathways may make it a more promising candidate. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

25 pages, 3146 KiB

Open AccessReview

Continuous Treatment with IncobotulinumtoxinA Despite Presence of BoNT/A Neutralizing Antibodies: Immunological Hypothesis and a Case Report

by Michael Uwe Martin, Clifton Ming Tay and Tuck Wah Siew

Toxins 2024, 16(10), 422; https://doi.org/10.3390/toxins16100422 - 1 Oct 2024

Viewed by 1360

Abstract

Botulinum Neurotoxin A (BoNT/A) is a bacterial protein that has proven to be a valuable pharmaceutical in therapeutic indications and aesthetic medicine. One major concern is the formation of neutralizing antibodies (nAbs) to the core BoNT/A protein. These can interfere with the therapy, resulting in partial or complete antibody (Ab)-mediated secondary non-response (SNR) or immunoresistance. If titers of nAbs reach a level high enough that all injected BoNT/A molecules are neutralized, immunoresistance occurs. Studies have shown that continuation of treatment of neurology patients who had developed Ab-mediated partial SNR against complexing protein-containing (CPC-) BoNT/A was in some cases successful if patients were switched to complexing protein-free (CPF-) incobotulinumtoxinA (INCO). This seems to contradict the layperson’s basic immunological understanding that repeated injection with the same antigen BoNT/A should lead to an increase in antigen-specific antibody titers. As such, we strive to explain how immunological memory works in general, and based on this, we propose a working hypothesis for this paradoxical phenomenon observed in some, but not all, neurology patients with immunoresistance. A critical factor is the presence of potentially immune-stimulatory components in CPC-BoNT/A products that can act as immunologic adjuvants and activate not only naïve, but also memory B lymphocyte responses. Furthermore, we propose that continuous injection of a BoN/TA formulation with low immunogenicity, e.g., INCO, may be a viable option for aesthetic patients with existing nAbs. These concepts are supported by a real-world case example of a patient with immunoresistance whose nAb levels declined with corresponding resumption of clinical response despite regular INCO injections. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

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20 pages, 1353 KiB

Open AccessEditor’s ChoiceReview

Complexing Protein-Free Botulinum Neurotoxin A Formulations: Implications of Excipients for Immunogenicity

by Michael Uwe Martin, Juergen Frevert and Clifton Ming Tay

Toxins 2024, 16(2), 101; https://doi.org/10.3390/toxins16020101 - 10 Feb 2024

Cited by 1 | Viewed by 3981

Abstract

The formation of neutralizing antibodies is a growing concern in the use of botulinum neurotoxin A (BoNT/A) as it may result in secondary treatment failure. Differences in the immunogenicity of BoNT/A formulations have been attributed to the presence of pharmacologically unnecessary bacterial components. Reportedly, the rate of antibody-mediated secondary non-response is lowest in complexing protein-free (CF) IncobotulinumtoxinA (INCO). Here, the published data and literature on the composition and properties of the three commercially available CF-BoNT/A formulations, namely, INCO, Coretox^® (CORE), and DaxibotulinumtoxinA (DAXI), are reviewed to elucidate the implications for their potential immunogenicity. While all three BoNT/A formulations are free of complexing proteins and contain the core BoNT/A molecule as the active pharmaceutical ingredient, they differ in their production protocols and excipients, which may affect their immunogenicity. INCO contains only two immunologically inconspicuous excipients, namely, human serum albumin and sucrose, and has demonstrated low immunogenicity in daily practice and clinical studies for more than ten years. DAXI contains four excipients, namely, L-histidine, trehalosedihydrate, polysorbate 20, and the highly charged RTP004 peptide, of which the latter two may increase the immunogenicity of BoNT/A by introducing neo-epitopes. In early clinical studies with DAXI, antibodies against BoNT/A and RTP004 were found at low frequencies; however, the follow-up period was critically short, with a maximum of three injections. CORE contains four excipients: L-methionine, sucrose, NaCl, and polysorbate 20. Presently, no data are available on the immunogenicity of CORE in human beings. It remains to be seen whether all three CF BoNT/A formulations demonstrate the same low immunogenicity in patients over a long period of time. Full article

(This article belongs to the Special Issue Immunogenicity of Botulinum Toxin)

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11 pages, 303 KiB

Open AccessReview

Deep Brain Stimulation for Focal or Segmental Craniocervical Dystonia in Patients Who Have Failed Botulinum Neurotoxin Therapy—A Narrative Review of the Literature

by Thorsten M. Odorfer and Jens Volkmann

Toxins 2023, 15(10), 606; https://doi.org/10.3390/toxins15100606 - 9 Oct 2023

Cited by 1 | Viewed by 1909

Abstract

(1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) may then be used as a backup strategy in this situation. (2) Methods: Here, we reviewed the current study literature to answer a specific question regarding the efficacy and safety of the use of DBS, particularly for cervical dystonia (CD) and Meige syndrome (MS) in patients with documented treatment failure under BoNT. (3) Results: There are only two studies with the highest level of evidence in this area. Despite this clear limitation, in the context of the narrowly defined research question of this paper, it is possible to report 161 patients with CD or MS who were included in studies that were able to show a statistically significant reduction in dystonic symptoms using DBS. Safety and tolerability data appeared adequate. However, much of the information is based on retrospective observations. (4) Conclusions: The evidence base in this area is in need of further scientific investigation. Most importantly, more randomized, controlled and double-blind trials are needed, possibly including a head-to-head comparison of DBS and BoNT. Full article

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