Status: biodefense gov’t controlled access under IND

Organizations involved:

BioPort Corp. – Manuf.; R&D; Tech.

Emergent BioSolutions Inc. – Parent

Centers for Disease Control and Prevention (CDC) Drug Service – USA mark.

Michigan Biologics Products Institute – Former

Cross ref: See the Botulinum Toxin Products entry (#600). See also human botulinum immune globulin (BabyBIG; #747); Botulism Antitoxin/A,B,E (#912); and equine botulism antitoxin (#714).

Description: Pentavalent Botulinum Toxoids is a pentavalent (5-antigen) vaccine containing formalin (formaldehyde) inactivated Clostridium botulinum toxins (toxoids) types A, B, C, D, and E. Clostridium botulinum bacterial strains of each of the five serotypes are independently cultured, inactivated, and the separate toxoids are pooled. The vaccine is used for prevention of botulism (poisoning from exposure to botulinum toxins). [Note, humans can be infected with live types A, B, E and F Clostridium botulinum. Other bacterial serotypes (C, D, and G) are not known to naturally cause disease in man, but are still highly toxic and serious bioterrorism/biological warfare threats].

Nomenclature: Botulinum Toxoid [BIO]; Botulinum Toxoid ABCDE [SY]; Pentavalent Botulinum Toxoids [SY]

Companies.: The vaccine is manufactured by BioPort Corp., now a subsidiary of Emergent BioSolutions Inc. It was originally developed and formerly manufactured by the Michigan Biologics Products Institute (before that, Michigan Department of Public Health), CBER/FDA est. no. 0099. BioPort acquired the Michigan Biologics Products Institute (see the Anthrax Vaccine entry). BioPort also manufactures monovalent Clostridium Botulinum Type B Toxoid approved for veterinary use.

The vaccine is available in the U.S. for non-military use exclusively from the Drug Service, National Center for Infectious Diseases (NFID), Centers for Disease Control and Prevention (CDC) and the Division of Quarantine, NFID, CDC. The Department of Defense (DOD) also holds stocks of vaccine.

FDA class: Biologic IND

Status: The product has not been approved. It is available under Investigational New Drug applications (INDs) held by the U.S. Army and the Centers for Disease Control and Prevention (CDC). DOD submitted a contingency protocol for biowarfare/bioterrorism defense in 1995.

The vaccine is available in the U.S. for non-military use exclusively from the CDC. It is available only to protect persons from accidental occupational exposure to botulinum toxin, and “should be administered only to individuals working in high risk laboratories who are actively working or expect to be working with cultures of Clostridium botulinum or the toxins.” The vaccine is supplied free to those needing it.

The U.S. Army and other components of the U.S. Department of Defense retain stocks and may selectively administer Botulinum Toxoid ABCDE to their own researchers, and to other personnel potentially exposed to biological warfare agents. This is managed by the Medical Biological Defense Research Program (Fort Detrick, Frederick, MD), U.S. Army.

This vaccine has been used in more than 11,000 people for more than 30 years under INDs held by CDC and DOD. As discussed below, development of replacement, more modern vaccines is underway.

Medical: The primary immunization regimen for pentavalent vaccine is a 0.5 mL dose subcutaneously at 0, 2, and 12 weeks. Limited primate studies indicate that protection against inhalant exposure to botulinum toxins may be afforded after a minimum of two doses. Boosters are recommended at one year and then as needed if annual neutralization titers decline.

Efficacy varies with the route of toxin exposure. Human challenge, field, and other studies of vaccine efficacy involving exposure to toxins have not been performed. The vaccine is presumed to protect against toxin exposure by inhalation and ingestion, although studies are lacking. Based on the CDC recommendation of 0.25 IU/ml as an adequate protective toxin antibody titer, about 83% of recipients develop protective antibody titers after the third (12th-week) dose. Antibody titers then decrease before the one year booster, after which nearly 100% demonstrate adequate levels of antibody.

Ongoing: In Jan. 2005, Emergent BioSolutions (parent of BioPort) and the Health Protection Agency (HPA), U.K., formed a two-year collaboration for the development of both toxoid (inactivated toxin) and recombinant botulinum vaccines, with the stated intension for protection against botulism (i.e., for biodefense). Emergent received worldwide exclusive (except in the U.K. where HPA retains rights for UK public health purposes) royalty-bearing licenses to manufacture, market and sell botulinum vaccines that incorporate HPA’s patented technologies. Emergent has committed to a minimum expenditure of $2 million for the development of these products over a two- year period. The initial objectives are the development of both multivalent botulinum toxoid vaccines and multivalent recombinant botulinum vaccines. These include a vaccine derived from the pentavalent ABCDE botulinum toxoid vaccine previously manufactured by BioPort. Recombinant technology will also be used to express the non-toxic LHN portion of botulinum toxins for use as vaccine antigens. LHN recombinant vaccines may possess significant advantages over vaccines based upon the Hc portion of the toxin. Initial studies have shown efficacy in a variety of animal models and advantages in stability, immunogenicity, and the potential for multivalent formulations.

Starting in the mid-late 1980s, Porton International plc, under contract to the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID), sponsored development of a botulinum type G toxoid (inactivated botulinum toxin type G vaccine) by the Centre for Applied Microbiology and Research (CAMR), Public Health Laboratory Service (PHLS), now the Microbiological Research Authority, Health Protection Agency (HPA), U.K. Presumably, like Botulinum Toxoids ABCDE, this type G toxoid may still be available from the U.S. Army/DOD for military personnel and others with a need for it (e.g., researchers handling type G toxin or bacteria).

Federal agencies, led by the Department of Defense (DOD) and the National Institute of Allergy and Infectious Diseases (NIAID), NIH, are sponsoring the development of a new heptavalent (ABCDEFG) botulinum toxoid vaccine(s) (or individual components). This includes DynPort Vaccine Co, LLC (now DVC LLC), DOD’s prime contractor for biodefense vaccine R&D and manufacture, a subsidiary of Computer Sciences Corp. (CSC), which receiving a $11 million grant in Sept. 2003 for recombinant botulinum neurotoxin vaccine development. The goal is to develop a safe and effective recombinant pentavalent toxoid-based vaccine against botulinum toxin types A, B, C, E and F. Within five years, the company will also develop the manufacturing processes for a heptavalent (7-immunogen) vaccine that will include antigens designed to also protect against botulinum toxin serotypes D and G. USAMRIID, DOD, owns the intellectual property for the vaccine(s) to be produced and has filed patent applications.

Emergent BioSolutions (parent of BioPort) is developing rBOT, a recombinant bivalent A/B vaccine using non-active toxin subunits expressed by E. coli complexed with aluminum adjuvant. The company has received NIAID/NIH grants supporting rBOT development. The vaccine may be combined with a E toxin-based vaccine also in development. The bivalent AB and trivalent ABE botulinum vaccines have shown efficacy against toxin challenge in animals when administered in a single dose.

DVC LLC, with DOD sponsorship, is developing a bivalent recombinant Pichia pastoris (yeast)-expressed botulinum neurotoxin toxin heavy chain fragment A/B vaccine with aluminum phosphate and aluminum hydroxide adjuvants. The serotype A antigen is basic, and pretreatment with phosphate anions is required for favorable adsorption conditions to aluminum hydroxide adjuvant. The serotype B antigen displays a high affinity to aluminum hydroxide adjuvant even when the two species possess the same charge.

DynPort awarded a $1.22 million (sub)contract to MicroTest Laboratories (MTL; Agawam, WA) in Dec. 2002 for manufacture of a series of recombinant vaccines against botulinum neurotoxins. The University of Nebraska (Lincoln, NE) received (sub)contracts from DynPort for “Fast Track Production of A Heptavalent Botulinum Vaccine,” $283,278, in Feb. 2003, and $300,494 in Oct. 2003. In Sept. 2003, the University of Colorado Health Science Center and HTD Biosystems Inc. (Hercules, CA) received a $1.2 million grant from NIAID, NIH, for fast-track production of two botulism vaccines in collaboration with the DynPort. The University is developing recombinant botulinum neurotoxin serotype heavy chain fragments expressed in Pichia pastoris (yeast).

In June 2004, DOR BioPharma (Miami, FL) and Thomas Jefferson University (Philadelphia, PA) jointly entered into a Collaborative R&D Agreement (CRADA) with the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) to develop mucosally (oral or intranasal) delivered botulinum toxoid(s) as a multi-valent vaccine, BT-VACC, for biological warfare/bioterrorism defense. DOR has exclusively licensed related technology from the University, including U.S. 6,051,239 regarding recombinant botulinum toxin muteins.

In the Oct. 2003 issue of Vaccine, results were reported from a Phase II trial of a botulinum toxoid type F vaccine adsorbed on aluminum hydroxide manufactured under a Department of Defense contract. This was designed to be a stand-alone monovalent vaccine or to be added to the current botulinum pentavalent toxoid vaccine to make a hexavalent vaccine. Even the most immunogenic schedule left 7-16% of volunteers unprotected at day 56 and 33-42% of vaccinees unprotected at 1 year. The booster dose administered at 1 year induced high levels of protective serum anti-toxin in all persons assayed which persisted for at least one additional year. However, it was concluded that a a more potent vaccine formulation would be required to protect more individuals after primary immunization.

In Sept. 2006, DOR Biopharma Inc. received several a $0.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to continue development of BT-VACC, a multivalent mucosal vaccine against botulinum toxin. BT-VACC is composed of the heavy chains of each of the A, B, and E serotypes. These components lack the region of the toxin that are responsible for blocking neurotransmitter functions. The vaccine stimulates both humoral and mucosal antibodies, which in lung and gastrointestinal secretions may block the uptake of toxin before entering the bloodstream. DOR has received EP 1024827 B1, with claims related to oral vaccination using mutated non-toxic forms of botulinum neurotoxin as a vaccine to prevent poisoning. U.S. 6,051,239 was granted in April, 2000 and contains equivalent claims for oral vaccination. DOR exclusively licensed these from Thomas Jefferson University.

In March 2005, the National Institute of Allergy and Infectious Diseases (NIAID) awarded a contract to XOMA Ltd. for the development of manufacturing processes and manufacture of experimental quanitities of three recombinant botulinum neurotoxin monoclonal antibodies. XOMA Ltd. completed/ended its contract in Nov. 2006 having created production cell lines using its proprietary antibody expression systems, built and qualified master and manufacturer’s working cell banks, developed production processes, and produced initial cGMP quantities of the three antibodies. A $16 million follow-on contract was awarded to XOMA in July 2006.

Cambridge Biostability, in collaboration with DynPort Vaccine Company LLC (DVC), is developing a room-temperature stable liquid heptavalent (7-antigen), botulinum toxoid (vaccine) with a £1.8 million grant from the National Institute of Allergy and Infectious Diseases (NIAID).