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The Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) - (Equine) – BAT, made by Emergent BioSolutions Canada Inc. (formerly Cangene Corporation) – is a licensed, commercially available botulism anti-toxin that effectively neutralizes all seven known botulinum nerve toxin serotypes (types A, B, C, D, E, F and G). It is indicated for sporadic cases of life-threatening
botulism Botulism is a rare and potentially fatal illness caused by a toxin produced by the bacterium ''Clostridium botulinum''. The disease begins with weakness, blurred vision, feeling tired, and trouble speaking. This may then be followed by weakne ...
and is also stockpiled for the eventuality of botulinum nerve toxins being used in a future
bioterrorist Bioterrorism is terrorism involving the intentional release or dissemination of biological agents. These agents are bacteria, viruses, insects, fungi, and/or toxins, and may be in a naturally occurring or a human-modified form, in much the sam ...
attack. BAT was first approved in 2010 by the Centers for Disease Control for the indication of treating naturally occurring non-infant botulism on an investigational basis, replacing two earlier products. It was then licensed for commercial marketing by the United States FDA in 2013.


History


Development and domestic contracts

BAT (formerly known as HBAT) was developed from equine (horse) plasma at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). The main funding stream was the
Biomedical Advanced Research and Development Authority The Biomedical Advanced Research and Development Authority (BARDA) is a U.S. Department of Health and Human Services (HHS) office responsible for the procurement and development of medical countermeasures, principally against bioterrorism, inc ...
(within the US
Department of Health and Human Services The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the U.S. federal government created to protect the health of all Americans and providing essential human services. Its motto is ...
' Office of the Assistant Secretary for Preparedness and Response). It was then available for many years on an IND (investigational) basis from the US
Centers for Disease Control and Prevention The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georg ...
(CDC). On June 1, 2006, the DHHS awarded a $363 million contract to Emergent BioSolutions, (then Cangene Corporation) for 200,000 doses of BAT over five years for delivery into the US
Strategic National Stockpile The Strategic National Stockpile (SNS), originally called the National Pharmaceutical Stockpile (NPS), is the United States' national repository of antibiotics, vaccines, chemical antidotes, antitoxins, and other critical medical supplies. Its ...
(SNS). The CDC began supplying doses to the SNS in 2007 under a now $427 million contract with the DHHS, according to a Cangene press release. In 2010, the CDC replaced the licensed bivalent botulinum antitoxin AB (''BAT-AB'') and the investigational monovalent botulinum antitoxin E (''BAT-E'') with ''BAT'' when the former two products indications expired. This action left BAT as the only botulinum antitoxin available in the US for naturally occurring non-infant botulism. On March 22, 2013, the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) approved BAT as the first product to treat all serotypes of botulism. This was considered a significant step in the US armamentarium for emergency use against a
bioterrorist Bioterrorism is terrorism involving the intentional release or dissemination of biological agents. These agents are bacteria, viruses, insects, fungi, and/or toxins, and may be in a naturally occurring or a human-modified form, in much the sam ...
attack. The CDC continues to distribute the stockpiled antitoxin. The FDA approved BAT for marketing based on its efficacy as established in animal studies (efficacy trials in humans not being considered feasible or ethical). The safety of the antitoxin, however, was established in a study of 40 healthy volunteers as well as in the experimental treatment of 228 patients in a CDC program. After the February 2014 acquisition of Cangene Corporation by Emergent BioSolutions, Emergent took control of Cangene's products and contracts, including BAT. In March 2017, Emergent extended its contract with the
Biomedical Advanced Research and Development Authority The Biomedical Advanced Research and Development Authority (BARDA) is a U.S. Department of Health and Human Services (HHS) office responsible for the procurement and development of medical countermeasures, principally against bioterrorism, inc ...
(BARDA), adding $53 million in value throughout 2022 for the production and bulk storage of BAT. Under the conditions of the extension, future transport of BAT to the SNS was approved. BAT remains the only recognized, licensed, and distributed botulism antitoxin within the FDA and the CDC.


Other Licensed Jurisdictions and Contracts

In 2012, Emergent signed a 10-year contract to provide BAT to the Canadian Department of National Defense and the Public Health Agency of Canada, as well as individual provincial health officials. In December 2016, Health Canada approved Emergent's New Drug Submission for BAT under the Extraordinary Use New Drug Regulations, which provide guidelines for consideration of drugs that do not have clinical information about impacts on humans due to the nature of the conditions that the drugs are used to treat. Pleased with Canada’s decision to prepare for
botulinum toxin Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neurom ...
events, one of the "more likely biological threat agents", Adam Havey, executive vice president and president of the biodefense division at Emergent BioSolutions, said, "Emergent is committed to helping allied governments fulfill their preparedness needs. We expect to expand upon our longstanding relationship with the Canadian government and develop similar relations outside of North America..." BAT was approved by the Health Sciences Authority in Singapore in July 2019.


Description


Neutralizing efficacy

BAT is derived from "despeciated" equine
IgG antibodies Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG a ...
, which have had the Fc portion cleaved off, leaving the F(ab')2 portions. This process renders it less efficacious at neutralizing toxin than the other product trivalent botulinum antitoxin (TBAT) available from local health departments (via the CDC) for treatment of wound and foodborne botulism. TBAT (effective against types A, B, and E) is derived from equine sources utilizing whole antibodies (Fab & Fc portions). But only BAT is considered effective against all known strains of botulism (A, B, C, D, E, F, and G). These antitoxins neutralize only circulating toxin in patients with symptoms of botulism that are continuing to progress; they have no effect on toxin already bound to the nerve terminals. (This is not, however, considered a reason to withhold the product from any patient, even if treatment has been delayed.)


Side effects

In CDC studies of BAT, headache, fever, chills, rash, itching, and nausea were the most observed adverse events. It can trigger allergic reactions and delayed hypersensitivity reactions in people sensitive to horse proteins.


''HE-BAT''

A related product ''Botulism AntiToxin, Heptavalent, Equine, Types A, B, C, D, E, F and G'' (''HE-BAT'') is also available to the U.S. military under IND (experimental) protocols. This "equine" antitoxin requires skin testing with escalating dose challenges before full dose administration to obviate serious sensitivity to horse serum.


FDA clinical trials

BAT has undergone extensive testing for effectiveness and safety. Emergent BioSolutions, in a 2017 document published to describe prescription information for BAT, said that the effectiveness of the antitoxin is based on efficacy studies that demonstrably prove increased chances of survival. In two clinical studies cited by the company, the safety profile of BAT was proven acceptable when one or two vials of the antitoxin were intravenously delivered to healthy subjects. Another clinical trial, the BT-011 study, known also as Pharmacokinetics of Botulism Antitoxin Heptavalent in Pediatric Patients, was initiated to test the success of BAT in children who had contracted botulism (or had been suspected of contracting botulism). In the study, a serum sample was collected from pediatric patients to analyze the pharmacokinetics of BAT to better adjust pediatric dosing recommendations. The details of the study from ClinicalTrials.gov, are as follows:


Use


Indications

BAT is the only product available for treating botulism in adults, and for botulism in infants caused by botulinum toxins other than types A and B. BAT has been used to treat a case of type F infant botulism and, on a case-by-case basis, may be used for future cases of non-type A and non-type B infant botulism.


Administration

Early administration of BAT is considered critical as the antitoxin can neutralize only circulating toxin, not toxin that has become bound to nerve terminals. One vial (20 mL) of BAT is administered to a patient as an intravenous infusion. It must be diluted with 0.9% sodium chloride in a 1:10 ratio before use. A volumetric infusion pump is used for slow administration (0.5 mL/min for the initial 30 minutes) to minimize the possibility of allergic reactions. If no reactions are noted, the rate is increased to 1 mL/min for another 30 minutes, and then if still no reaction is evident, to 2 mL/min for the remainder of the procedure.


See also

*
Passive immunity Passive immunity is the transfer of active humoral immunity of ready-made antibodies. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and it can also be induced artificially, when ...
*
Antitoxin An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria in response to toxin exposure. Although they are most effective in neutralizing toxins, they can also ...


References

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External links

* CDC/MMWR (March 19, 2010)
"Investigational Heptavalent Botulinum Antitoxin (HBAT) to Replace Licensed Botulinum Antitoxin AB and Investigational Botulinum Antitoxin E"
* FDA News Release (March 22, 2013)

Antitoxins Immune system Immunology Medical treatments Biological warfare Botulism