Human Botulism Immune Globulin Research Articles

Safety and immunogenicity of investigational recombinant botulinum vaccine, rBV A/B, in volunteers with pre-existing botulinum toxoid immunity

ObjectivesWe undertook an open-label, uncontrolled study of investigational recombinant botulinum vaccine for botulinum neurotoxin (BoNT) serotypes A and B (rBV A/B) to assess its safety and immunogenicity in healthy volunteers who had been previously immunized with investigational pentavalent botulinum toxoid. Study participants who wished to do so could donate their hyperimmune plasma for production of Human Botulism Immune Globulin Intravenous (BIG-IV, BabyBIG®). Study designA single 0.5 ml (mL), 40-microgram intramuscular injection of rBV A/B was administered to study participants. Post-vaccination sera collected at approximately 2-week intervals were evaluated for anti-BoNT/A and anti-BoNT/B neutralizing antibody concentrations (NAC). Local and systemic treatment-emergent adverse events (TEAEs) were identified by clinical and laboratory monitoring for 12 weeks post-vaccination with a final telephone follow-up for additional safety assessment at 6 months. The primary endpoint for immunogenicity was a ≥4-fold rise in NAC in ≥50% of participants by Week 4 post-vaccination. ResultsAll 45 enrolled participants completed the study. Forty-two of 45 participants (93.3%) experienced at least one TEAE. Overall, 138 of 218 (63.3%) reported TEAEs were treatment-related, the majority of which were mild injection-site reactions. No serious or unexpected adverse events occurred. The study achieved its primary immunogenicity endpoint with 37/45 (82.2%) participants and 39/45 (86.7%) participants having a ≥4-fold rise in NAC to anti-BoNT/A and to anti-BoNT/B, respectively, by Week 4 post-vaccination. ConclusionA single 0.5 mL dose of rBV A/B was safe, well-tolerated and immunogenic in participants previously immunized with pentavalent botulinum toxoid. The tolerability and immunogenicity characteristics of rBV A/B vaccination of individuals with existing BoNT immunity support its potential future use to provide occupational protection to botulism laboratory workers. Almost all study participants donated hyperimmune plasma for production of BIG-IV.ClinicalTrials.gov registration number: NCT01701999.

More Clinical Mimics of Infant Botulism

To ascertain the actual diagnoses of 76 patients (2005-2015) whose clinical presentations so closely resembled infant botulism that the patients were treated with Human Botulism Immune Globulin Intravenous (BIG-IV; BabyBIG), but whose illnesses subsequently were not laboratory confirmed as infant botulism ("clinical mimics" of infant botulism). The California Department of Public Health produces BIG-IV and distributes it nationwide as a public service (ie, not-for-profit) orphan drug to treat patients hospitalized with suspected infant botulism. During the study period, admission records and discharge summaries for all patients treated with BIG-IV but who lacked a laboratory-confirmed diagnosis of infant botulism were collected and abstracted. The patients' discharge diagnoses were identified, categorized, and compared with previously reported clinical mimics categories for 32 patients (1992-2005). From 2005 to 2015, 76 clinical mimic illnesses were identified. These illnesses were distributed into the 5 categories previously reported of (1) probable infant botulism lacking confirmatory testing (26.3%); (2) spinal muscular atrophy (19.7%); (3) miscellaneous (15.8%); (4) metabolic disorders (11.8%); and (5) other infectious diseases (10.6%). Of the 76 clinical mimic illnesses, 15.8% had no alternate diagnosis established and were therefore categorized as undetermined. Over the 23 years 1992-2015, patients presenting with illnesses so clinically similar to infant botulism that they were treated with BIG-IV had actual diagnoses that were distributed into 5 main categories. These categories and their individual components constitute a working bedside differential diagnosis of infant botulism.

Efficacy of Human Botulism Immune Globulin for the Treatment of Infant Botulism: The First 12 Years Post Licensure

To report the efficacy of Human Botulism Immune Globulin Intravenous (BIG-IV) in the first 12 years following its licensure in 2003 and to characterize its use nationwide in treating patients with infant botulism. Medical records and billing information were collected for US patients treated with BIG-IV from 2003 to 2015. Length of hospital stay (LOS) and hospital charge information for treated patients were compared with the BIG-IV Pivotal Clinical Trial Placebo Group to quantify decreases in LOS and hospital charges. The use of BIG-IV reduced mean LOS from 5.7 to 2.2 weeks. This shortened hospital stay resulted in a mean decrease in hospital charges of $88 900 per patient. For all US patients 2003-2015, total decreases in LOS and hospital charges were 66.9 years and $86.2 million, respectively. The decrease in mean LOS was time dependent: BIG-IV treatment on hospital days 0-3 reduced mean LOS by 3.7 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group), on hospital days 4-7 by 2.6 weeks (P <.001 vs the BIG-IV Pivotal Clinical Trial Placebo Group) and on hospital days 8-10 by just 1 week (P = NS). Since licensure, 1192 patients in 48 states and Washington, DC, have been treated with BIG-IV. The use of BIG-IV since its licensure in 2003 treated approximately 93% of US patients with laboratory-confirmed infant botulism, and prevented >65 years in hospital stay and >$85 million in hospital charges from occurring. The greatest LOS reduction was achieved when BIG-IV was administered soon after hospital admission. Effective and appropriate use of BIG-IV in the US has continued in the postlicensure period.

A 3-month-old Boy With Concomitant Respiratory Syncytial Virus Bronchiolitis and Infant Botulism

To the Editors: A 3-month-old boy with respiratory failure was admitted to the pediatric intensive care unit of a Northern California medical center in February 2011. The illness began 3 days earlier with progressively worsening lethargy, cough and stridor, decreased oral intake and decreased urine output. A review of systems was notable for decreased bowel movements in the past week and the presence of copious clear secretions from the infant’s nose and oropharynx. The infant was born at term with no complications, was exclusively breastfed other than a dropperful of chicken broth given when the child was ill in the days before admission and had received no vaccines. A nasal aspirate polymerase chain reaction was positive for respiratory syncytial virus. Over the next 4 days, ventilatory settings were weaned as oxygenation normalized. The child was extubated twice, but each time developed hypercapnia requiring reintubation. Seven days after admission, the infant remained intubated and ventilated with poor respiratory effort. Neurologic examination revealed a nearly complete bilateral ptosis; facial diplegia with tears produced under stimulation and no facial grimace. Infant botulism was suspected. Stool was sent for Clostridium botulinum toxin, and botulism immune globulin was administered empirically. Two days later, stool tests revealed C. botulinum toxin type A and the diagnosis of infant botulism was confirmed. During the next 3 weeks, the child received nasogastric feeds and ventilatory support and slowly regained bulbar strength. He was extubated 9 days after botulism immune globulin administration and was discharged to home 1 month after admission with a mixed breastfeeding/tubefeeding regimen. He required supplemental oxygen by nasal cannula until 2 days before discharge. On discharge, the child was still noted to have decreased tone, a weak cry and mildly uncoordinated feeding mechanics. Infant botulism results from ingestion of spores of Clostridium species, which germinate and colonize the infant intestine, producing botulinum toxin. This toxin is absorbed and causes a descending, symmetric paralysis. Constipation is almost always the first sign of illness and is often overlooked (as in the case above).1 Diagnosis is confirmed by identification of C. botulinum organisms in the feces of an infant with a presentation consistent with the disease. Supportive care forms the cornerstone of therapy, though specific treatment has been available in the form of intravenous human botulism immune globulin since 1992, through the California Department of Public Health. Botulism immune globulin should be initiated as early as possible in the course of illness and should not be delayed for laboratory confirmation. Acute coinfection with respiratory syncytial virus and Clostridium spp. has not previously been described. This case serves to demonstrate the necessity to maintain an open differential diagnosis even when presented with laboratory confirmation of an apparent causative etiology. Kevin K. Quinn, MD James D. Cherry, MD, MSc Division of Pediatric Infectious Diseases UCLA David Geffen School of Medicine Neeta R. Shah, MD Laura J. Christie, MD Department of Pediatrics Kaiser Permanente Northern California Oakland, CA

U.S. Army Botulinum Neurotoxin (BoNT) Medical Therapeutics Research Program: past accomplishments and future directions

AbstractThe United States Army (USA) under the auspices of the Medical Research and Material Command (USAMRMC) and the Defense Threat Reduction Agency (DTRA) sponsored several major efforts to develop an effective medical countermeasure against botulinum neurotoxin (BoNT). This review focuses on the U.S. Army's research and development efforts for a BoNT therapeutic over the period from 1975–2007. Two antitoxin preparations: Human botulism immunoglobulin (BIG) and Botulism Immune Globulin F(ab')2 Heptavalent Equine (BIGHE) were administered to humans and shown to possess acceptable efficacy and safety levels. BIGHE was deployed in Operation Desert Storm/Desert Shield. BoNT/A monoclonal antibodies were developed and are currently undergoing clinical evaluation with funding from the National Institute of Allergy and Infectious Disease (NIAID). The development of small molecules for the treatment of BoNT has also been supported. Efforts have focused on molecules to inhibit nearly every aspect of BoNT pathogenesis. This would include toxin binding, translocation, catalytic activity, and recovery following intoxication. Several compounds capable of inhibiting toxin activity or mitigating the severity of paralysis have been identified. To date, none of the compounds possess the appropriate properties (safety, efficacy, solubility) to be considered for clinical studies. Drug Dev Res 70:266–278, 2009. Published 2009 Wiley‐Liss, Inc.

Infant Botulism: Two Recent Cases and Literature Review

Infant botulism is a cause for significant pediatric morbidity in the United States, though early recognition and supportive care can greatly improve clinical outcomes. Since the approval of human botulism immune globulin by the United States Food and Drug Administration (FDA) for the treatment of infant botulism in 2003, the importance of prompt initiation of therapy has been emphasized, with clinical suspicion remaining the mainstay of diagnosis. In this report, 2 cases of infant botulism are described. Each presented to the Pediatric Neurology service at our institution in Upstate New York in the spring and summer months of 2007 and were felt to be related to markedly dusty environmental conditions and the probable ingestion of C. botulinum organisms present in soil. Following this, a comprehensive review of the literature regarding infant botulism in the United States is presented, wherein the pathophysiology, clinical features, epidemiology, and treatment are discussed.

Infant Botulism Type Ba: First Culture-Confirmed Case in the United Arab Emirates

We report on a 3-month-old girl with culture-confirmed infant botulism caused by a rare double toxin-producing Clostridium botulinum type Ba. This case was not related to honey-feeding. The clinical course was prolonged, with minimal spontaneous improvement at onset, and a period of fluctuating motor weakness and nasogastric feeding dependence afterward. Neurophysiologic studies produced normal results. Human botulism immune globulin was administered empirically on day 23 of presentation, with rapid full recovery. This case highlights the importance of pursuing diagnoses of infant botulism despite normal results of neurophysiologic testing and no history of honey-feeding. Our case also demonstrates a favorable response to human botulism immune globulin, despite the relatively late treatment.

Global Occurrence of Infant Botulism, 1976–2006

To summarize the worldwide occurrence of reported infant (intestinal toxemia) botulism cases since first recognition of the disease in 1976. We collected information on infant botulism cases by active and passive surveillance, by provision of therapeutic Human Botulism Immune Globulin to suspected cases, and by searching the medical literature. We defined a case as laboratory-confirmed botulism that occurred in an infant <or=12 months of age that was not caused by the ingestion of botulinum toxin in food. Twenty-six countries representing 5 continents reported the occurrence of at least 1 case of infant botulism among their residents. The United States, Argentina, Australia, Canada, Italy, and Japan, in this order, reported the largest number of cases. A history of honey exposure was significantly more common among case subjects hospitalized outside of the United States than among those who were recently hospitalized in California. Most countries have not yet reported cases of infant botulism. This limited reporting of the disease to date contrasts with the known global occurrence of Clostridium botulinum spores in soils and dust and suggests that infant botulism may be under-recognized, underreported, or both. When bulbar palsies, hypotonia, and weakness are present, physicians should consider the possibility of infant botulism even if the patient has not been fed honey. Publication of additional case reports and surveillance summaries will enhance understanding of the occurrence and extent of this under-recognized disease.

Human botulism immune globulin for the treatment of infant botulism: The first four years post-licensure

Infant botulism is the intestinal (infectious) toxemia in which swallowed spores of Clostridium botulinum activate in the lumen of the colon and thereby produce botulinum toxin, which after absorption causes flaccid paralysis. Human Botulism Immune Globulin (BIG-IV) neutralizes botulinum toxin types A and B. The US FDA licensed BIG-IV to the California Department of Public Health, its creator and developer, as the public service orphan drug BabyBIG ® in October 2003 (N. Engl. J. Med. 2006;354:462–471). International distribution began on a trial basis in July 2005. This report summarizes the 2003–2007 distribution, efficacy and safety data for BIG-IV. In the US, a total of 333 eventually laboratory-confirmed patients residing in 35 states were treated within 1 week of hospital admission: 142 type A, 188 type B, 2 type Ba and 1 type Bf. Mean length of hospital stay was 2.2±1.5 vs. 5.7±5.1 wks for untreated patients in the 1992–97 BIG-IV randomized clinical trial ( P ® ), its use globally to treat infant botulism patients has demonstrated its continued safety, efficacy and US cost-effectiveness.

Botulismo del lactante

We report a case of botulism in a 40 day old infant. The patient presented a descending flaccid paralysis requiring mechanical ventilation for 12 days. She is the first European patient treated with Human Botulism Immune Globulin. A few weeks later a second case of infant botulism was detected in our geographical region in Southern Spain. We emphasise the importance of an early diagnosis and treatment with Human Botulism Immune Globulin to decrease morbidity.

Clinical Mimics of Infant Botulism

Since 1992, Human Botulism Immune Globulin has been provided by the California Department of Health Services to infants with probable infant botulism, the intestinal toxemia form of human botulism. Human Botulism Immune Globulin became available in California in 1992-1997 within a randomized, controlled, double-blinded, pivotal clinical trial and subsequently became available nationwide in 1998-2003 in an open-label study until its licensure in October 2003 as BabyBIG. Thereafter, Human Botulism Immune Globulin remained available nationwide as an approved orphan-drug product. To achieve prompt neutralization of circulating botulinum toxin, the decision to treat with Human Botulism Immune Globulin has been based on clinical criteria that include a consistent history and physical findings of bulbar palsies, hypotonia, and weakness. After licensure, the charts of patients who did not have laboratory-confirmed infant botulism were reviewed to identify their actual diagnoses. The approximately 5% of 681 patients treated with Human Botulism Immune Globulin who did not have infant botulism fell into 5 categories: spinal muscular atrophy, metabolic disorders, other infectious diseases, miscellaneous, and probable infant botulism lacking laboratory confirmation.

Creation and Development of the Public Service Orphan Drug Human Botulism Immune Globulin

The public service orphan drug Human Botulism Immune Globulin for the treatment of infant botulism would not have come into existence without the federal Orphan Drug Act and the funding mechanism that it provided to conduct pivotal clinical trials. Nonetheless, creating, developing, and achieving licensure of Human Botulism Immune Globulin took approximately 15 years and approximately $10.6 million (2005 dollars) to accomplish. Use of Human Botulism Immune Globulin to treat patients with infant botulism has resulted thus far in more than 30 years of avoided hospital stay and more than $50 million (2005 dollars) of avoided hospital costs. To provide a possible paradigm for others, the circumstances that enabled a state public health department to create, test, license, and distribute an orphan drug are described here.

Botulism Immune Globulin as a Therapy for Infant Botulism

These authors asked whether administration of human botulism immune globulin (BIG-IV) would accelerate recovery and reduce the hospitalization-related

Immune Globulin for Infant Botulism

Critical Care| April 01 2006 Immune Globulin for Infant Botulism AAP Grand Rounds (2006) 15 (4): 42–43. https://doi.org/10.1542/gr.15-4-42 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Immune Globulin for Infant Botulism. AAP Grand Rounds April 2006; 15 (4): 42–43. https://doi.org/10.1542/gr.15-4-42 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: immunoglobulins, infantile botulism Source: Arnon SS, Schechter R, Maslanka SE, et al. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354:462–471. The authors from the California Department of Health Services report the results of both a randomized, double-blind, placebo-controlled trial of 122 infants with laboratory-confirmed cases of infant botulism, and an open label study of 382 patients with infant botulism treated with botulism immune globulin (BIG) within 18 days after hospital admission. For the randomized study, infants were eligible if they had acute flaccid paralysis consistent with infant botulism according to medical history, physical examination, and laboratory findings at admission. Enrollment was limited to the first 3 days of hospital admission. Stool specimens were sent for Clostridium botulinum toxin and culture; however, patients were generally treated before diagnosis confirmation by these studies. The treatment group received an intravenous infusion of 50... You do not currently have access to this content.

Human Botulism Immune Globulin for the Treatment of Infant Botulism

We created the orphan drug Human Botulism Immune Globulin Intravenous (Human) (BIG-IV), which neutralizes botulinum toxin, and evaluated its safety and efficacy in treating infant botulism, the intestinal-toxemia form of human botulism. We performed a five-year, randomized, double-blind, placebo-controlled trial statewide, in California, of BIG-IV in 122 infants with suspected (and subsequently laboratory-confirmed) infant botulism (75 caused by type A Clostridium botulinum toxin, and 47 by type B toxin); treatment was given within three days after hospital admission. We subsequently performed a 6-year nationwide, open-label study of 382 laboratory-confirmed cases of infant botulism treated within 18 days after hospital admission. As compared with the control group in the randomized trial, infants treated with BIG-IV had a reduction in the mean length of the hospital stay, the primary efficacy outcome measure, from 5.7 weeks to 2.6 weeks (P<0.001). BIG-IV treatment also reduced the mean duration of intensive care by 3.2 weeks (P<0.001), the mean duration of mechanical ventilation by 2.6 weeks (P=0.01), the mean duration of tube or intravenous feeding by 6.4 weeks (P<0.001), and the mean hospital charges per patient by 88,600 dollars (in 2004 U.S. dollars; P<0.001). There were no serious adverse events attributable to BIG-IV. In the open-label study, infants treated with BIG-IV within seven days of admission had a mean length of hospital stay of 2.2 weeks, and early treatment with BIG-IV shortened the mean length of stay significantly more than did later treatment. Prompt treatment of infant botulism type A or type B with BIG-IV was safe and effective in shortening the length and cost of the hospital stay and the severity of illness.

Trial of Immune Globulin in Infant Botulism

A 5-year, randomized, double-blind, placebo-controlled trial of the orphan drug Human Botulism Immune Globulin Intravenous (BIG-IV) in 122 infants in California with confirmed infant botulism (75 caused by type A Clostridium botulinum toxin, and 47 by type B toxin) was conducted at the California Department of Health Services, Richmond, CA; National Botulism Surveillance and Reference Laboratory, CDC and P, Atlanta; and Division of Biostatistics, University of California, Berkeley.

Randomized and Open-Label Clinical Trials of Human Botulism Immune Globulin Intravenous for the Treatment of Infant Botulism

Randomized and Open-Label Clinical Trials of Human Botulism Immune Globulin Intravenous for the Treatment of Infant Botulism