Heptavalent botulism antitoxin

The Heptavalent Botulism AntiToxin — HBAT, made by 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 and is also stockpiled for the eventuality of botulinum nerve toxins being used in a future bioterrorist attack.

HBAT was approved in 2010 by the CDC for the indication of treating naturally occurring non-infant botulism on an investigational basis, replacing two earlier products. It was licensed for commercial marketing by the FDA in 2013.

History
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 (within the US Department of Health and Human Services' 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 (CDC).

On June 1, 2006, the DHHS awarded a $363 million contract to Cangene Corporation for 200,000 doses of HBAT over five years for delivery into the US Strategic National Stockpile (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, or “BabyBIG”) and the investigational monovalent botulinum antitoxin E (BAT-E) with HBAT when the former two products indications expired. This action left HBAT as the only botulinum antitoxin available in the US for naturally occurring non-infant botulism.

On 22 March 2013, the US Food and Drug Administration (FDA) approved HBAT 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 attack. The CDC continues to distribute the stockpiled antitoxin.

The FDA approved HBAT 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.

Neutralizing efficacy
HBAT is derived from "despeciated" equine IgG antibodies, 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 HBAT 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 HBAT, 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.

Indications
HBAT 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. HBAT 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 infant botulism.

Administration
Early administration of HBAT 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 HBAT 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.