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

Botulinum neurotoxins (BoNT) are some of the most toxic proteins known, with a human LD50 of ~1 ng/kg. Equine antitoxin has a half-life in circulation of less than 1 day and is limited to a treatment rather than a prevention indication. The development of monoclonal antibodies (mAbs) may represent an alternative therapeutic option that can be produced at high quantities and of high quality and with half-lives of >10 days. Two different three mAb combinations are being developed that specifically neutralize BoNT serotypes A (BoNT/A) and B (BoNT/B). We investigated the pharmacokinetics of the anti-BoNT/A and anti-BoNT/B antibodies in guinea pigs (Cavia porcellus) and their ability to protect guinea pigs against an aerosol challenge of BoNT/A1 or BoNT/B1. Each antibody exhibited dose-dependent exposure and reached maximum circulating concentrations within 48 h post intraperitoneal or intramuscular injection. A single intramuscular dose of the three mAb combination protected guinea pigs against an aerosol challenge dose of 93 LD50 of BoNT/A1 and 116 LD50 of BoNT/B1 at 48 h post antibody administration. These mAbs are effective in preventing botulism after an aerosol challenge of BoNT/A1 and BoNT/B1 and may represent an alternative to vaccination to prevent type A or B botulism in those at risk of BoNT exposure.

Section: Methodsmentioning

confidence: 99%

Monoclonal Antibody Combinations Prevent Serotype A and Serotype B Inhalational Botulism in a Guinea Pig Model

Tomic¹,

Espinoza²,

Martinez³

et al. 2019

“…The first one—BabyBIG ® —which was initially based on human immunoglobulins, is supplied by the California Department of Public Health. This formulation has been recently discontinued and will be replaced with a new formulation currently under clinical development [33]. The second antidote consists of a modified HBAT (Cangene Corporation) with limitations due to the risk of serum sickness like other therapeutic equine sera [34] (Table 1).…”

Section: Current Therapeutic Anti-bonts Antibodiesmentioning

confidence: 99%

“…The BabyBIG antitoxin reduced hospital time for infant botulism cases by about 50% but its high cost limits its wide use. The new formulation of BabyBIG will be based on a bi-valent receptor binding domain vaccine to BoNT/A and /B [33].…”

Section: Generation Of Anti-bont Human Immunoglobulinsmentioning

confidence: 99%

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Antibodies and Vaccines against Botulinum Toxins: Available Measures and Novel Approaches

Rasetti-Escargueil

Popoff

2019

Botulinum neurotoxin (BoNT) is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum. As one of the most poisonous toxins known and a potential bioterrosism agent, BoNT is characterized by a complex mode of action comprising: internalization, translocation and proteolytic cleavage of a substrate, which inhibits synaptic exocytotic transmitter release at neuro-muscular nerve endings leading to peripheral neuroparalysis of the skeletal and autonomic nervous systems. There are seven major serologically distinct toxinotypes (A–G) of BoNT which act on different substrates. Human botulism is generally caused by BoNT/A, B and E. Due to its extreme lethality and potential use as biological weapon, botulism remains a global public health concern. Vaccination against BoNT, although an effective strategy, remains undesirable due to the growing expectation around therapeutic use of BoNTs in various pathological conditions. This review focuses on the current approaches for botulism control by immunotherapy, highlighting the future challenges while the molecular underpinnings among subtypes variants and BoNT sequences found in non-clostridial species remain to be elucidated.

“…With the discontinuation of the PBT vaccine, the Joint Vaccine Acquisition Program (JVAP) and the Dynport Vaccine Company LLC. (DVC) coordinated with the CDPH to investigate assessing the rBV A/B as a potential replacement immunogen for boosting volunteer plasma donors for production of BIG-IV with promising results [ 33 ]. In 2010, HBAT (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)) became the only botulism antitoxin available in the United States for naturally occurring non-infant botulism.…”

Section: Introductionmentioning

confidence: 99%

Engineering of Botulinum Neurotoxins for Biomedical Applications

Webb

2018

Botulinum neurotoxins (BoNTs) have been used as therapeutic agents in the clinical treatment of a wide array of neuromuscular and autonomic neuronal transmission disorders. These toxins contain three functional domains that mediate highly specific neuronal cell binding, internalization and cytosolic delivery of proteolytic enzymes that cleave proteins integral to the exocytosis of neurotransmitters. The exceptional cellular specificity, potency and persistence within the neuron that make BoNTs such effective toxins, also make them attractive models for derivatives that have modified properties that could potentially expand their therapeutic repertoire. Advances in molecular biology techniques and rapid DNA synthesis have allowed a wide variety of novel BoNTs with alternative functions to be assessed as potential new classes of therapeutic drugs. This review examines how the BoNTs have been engineered in an effort to produce new classes of therapeutic molecules to address a wide array of disorders.