• Vaccine Name: PBT
• Target Pathogen: Clostridium botulinum
• Target Disease: Botulism
• Vaccine Ontology ID: VO_0004075
• Type: Toxoid vaccine
• Adjuvant:
  • Adjuvant name:
  • VO adjuvant ID: VO_0000127
  • Description: Currently, a pentavalent botulinum toxoid (PBT) against serotypes A-E is used to immunize specific populations of at-risk individuals. The manufacture of PBT, by the Michigan Department of Public Health (MDPH), took place in stages and over many years. The fermentation, isolation, purification and detoxification steps for each serotype took place in the late 1960s and early 1970s. The monovalent bulks were completed in 1971, and first packaged in 1978. Investigational New Drug (IND) status was granted for the PBT under the CDC's IND 161 (at risk workers) and under the United States Army's Office of Surgeon General IND 3723 (for military deployment). The MDPH product was studied and used as an investigational vaccine from 1979 until the present time.
    An effort is ongoing on the part of the US Army to obtain Food and Drug Administration (FDA) licensure for the PBT lots PBP003 and PBP004. For licensure of the PBT, FDA required that a pivotal clinical trial be performed to re-evaluate safety and assess immunogenicity of the toxoid,and that a new lot of toxoid be manufactured to demonstrate reproducibility and robustness of the manufacturing process and consistency of the manufactured product. The final report on the pivotal clinical study was expected in June 2000. This study will have evaluated, in a significant number of participants, the protective immunogenicity of all 5 serotype vaccines with respect to their homologous neurotoxins. Results from this pivotal study and the status of a new-generation, recombinant vaccine will be factors in deciding whether to proceed with a new lot of toxoid (Byrne et al., 2000).
• Preparation: The toxoid was manufactured by initially culturing C. botulinum serotypes A-E to produce crude preparations of neurotoxins. The toxins were separated from the culture fluid by acid precipitation overnight in the cold then separated from the supernatant fluid by filtration and/or centrifugation. The precipitated toxin was washed, extracted, and filtered to remove any particulate material. Toxins were again precipitated, filter-sterilized, and detoxified by adding formalin. Residual formalin was left in the vaccine products to ensure that the neurotoxins remained non-toxic. Monovalent vaccines were then adsorbed to the adjuvant and blended into a pentavalent vaccine (Byrne et al., 2000).
• Virulence: Even though toxoid vaccines are available, there are numerous shortcomings with their current use and ease of production. First, because C. botulinum is a spore-former, a dedicated facility is required to manufacture a toxin-based product. The requirement for a dedicated manufacturing facility is not trivial. It is extremely costly to renovate and upgrade an existing facility or to build a new one and then to maintain the facility in accordance with current Good Manufacturing Practices (cGMP) to manufacture one vaccine. Second, the yields of toxin production from C. botulinum are relatively low. Third, the toxoiding process involves handling large quantities of toxin and thus is dangerous, and the added safety precautions increase the cost of manufacturing. Fourth, the toxoid product for types A-E consists of a crude extract of clostridial proteins that may influence immunogenicity or reactivity of the vaccine, and the type F toxoid is only partially purified (IND 5077). Fifth, because the toxoiding process involves the use of formaldehyde, which inactivates the toxin, and residual levels of formaldehyde (not to exceed 0.02%) are part of the product formulation to prevent reactivation of the toxin, the vaccine is reactogenic. An additional component of the toxoid vaccines is the preservative thimerosal (0.01%), which also increases the reactogenicity of the product (Byrne et al., 2000).
• Description: Currently, a pentavalent botulinum toxoid (PBT) against serotypes A-E is used to immunize specific populations of at-risk individuals. The manufacture of PBT, by the Michigan Department of Public Health (MDPH), took place in stages and over many years. The fermentation, isolation, purification and detoxification steps for each serotype took place in the late 1960s and early 1970s. The monovalent bulks were completed in 1971, and first packaged in 1978. Investigational New Drug (IND) status was granted for the PBT under the CDC's IND 161 (at risk workers) and under the United States Army's Office of Surgeon General IND 3723 (for military deployment). The MDPH product was studied and used as an investigational vaccine from 1979 until the present time.
  An effort is ongoing on the part of the US Army to obtain Food and Drug Administration (FDA) licensure for the PBT lots PBP003 and PBP004. For licensure of the PBT, FDA required that a pivotal clinical trial be performed to re-evaluate safety and assess immunogenicity of the toxoid,and that a new lot of toxoid be manufactured to demonstrate reproducibility and robustness of the manufacturing process and consistency of the manufactured product. The final report on the pivotal clinical study was expected in June 2000. This study will have evaluated, in a significant number of participants, the protective immunogenicity of all 5 serotype vaccines with respect to their homologous neurotoxins. Results from this pivotal study and the status of a new-generation, recombinant vaccine will be factors in deciding whether to proceed with a new lot of toxoid (Byrne et al., 2000).

Human Response

• Host Strain: Homo sapiens
• Vaccination Protocol: Primary series of three immunizations of 0.5 ml were administered to immunize personnel considered to be at risk for botulism in the laboratory of this given study at 0, 2, and 12 weeks, with the third immunization given 10 weeks after the second. The initial booster is given 12 months after the first immunization of the primary series, and additional boosters are administered annually (Byrne et al., 2000).
• Persistence: Immunological response indicated that 61 to 83% of the study subjects met the criteria for a booster dose at 1 year because of their low antitoxin levels (i.e. < 0.10 IU/mL) at 6 months. One hundred percent of the subjects boosted at 1 year developed high concentrations of protective antitoxin by day 56 post-boost, and protective levels (≥ 0.02 IU/mL) persisted for at least 360 days in all subjects (Byrne et al., 2000).
• Side Effects: None were noted. At a pre-IND meeting on April 9, 1999, held to review the recombinant BoNT(HC) vaccines, a CBER panel voiced concern as to the potential of our putative HC vaccine to cause adverse neurological reactions or disorders due to its nature of binding to specific receptors on cholinergic nerve cells (Byrne et al., 2000).
• Efficacy: After the primary series of 3 immunizations, 21/23 persons tested (91%) had a titer for type A that was 20.08 international units (IU)/ml, and 18 (78%) had a titer for type B of 0.02 IU/ml. Just before the first annual booster, 10/21 (48%) and 14/21 (67%) people lacked a detectable titer for type A and for type B, respectively. After the first booster, all individuals tested had a demonstrable titer to both types A and B. Of 77 persons who had previously received from 1-8 boosts of the toxoid, 74 (96%) had an A titer of 0.25 IU/ml (Byrne et al., 2000).
• Description: PBT was produced by MDPH in 1969-1971 and bottled under contract to the US Army in 1978. Lot A-2, manufactured to contain less residual formaldehyde (Byrne et al., 2000).