Notice of CDC's Discontinuation of Investigational Pentavalent (ABCDE) Botulinum Toxoid Vaccine for Workers at Risk for Occupational Exposure to Botulinum Toxins

Effective November 30, 2011, CDC will no longer provide investigational pentavalent (ABCDE) botulinum toxoid (PBT) for vaccination of workers at risk for occupational exposure to botulinum serotypes A, B, C, D, and E. This change might affect persons working in public health laboratories, research facilities, and manufacturing institutions who work with botulinum toxin or neurotoxin-producing species of Clostridium. CDC's decision is based on an assessment of the available data, which indicate a decline in immunogenicity of some of the toxin serotypes. The occurrence of moderate local reactions related to annual booster doses also has increased, which was noted in the 1990s at the U.S. Army Medical Research Institute for Infectious Diseases and resulted in a change in boosting from an annual requirement to only boosting when antibody titers have declined significantly (1--4). Additionally, the PBT was manufactured more than 30 years ago. CDC, therefore, has decided not to continue offering this investigational product.

Summary of PBT Uses and CDC's Rationale for Discontinuation

PBT has been available through CDC since 1965 under an Investigational New Drug (IND) Application (BB-IND 161) for nonresearch use of PBT for workers at risk for occupational exposure. Routine annual potency testing of PBT and adverse event reporting have guided CDC's risk-benefit assessments for continuing to offer PBT to eligible recipients under the IND, which is regulated by the Food and Drug Administration. Until 1976, the primary vaccination series included injections at 0, 2, and 12 weeks, followed by annual booster injections. An assessment of adverse events reported from 1966 to 1975 showed that approximately 10% of vaccinees who received booster injections experienced moderate local reactions, defined as edema or induration measuring 30--120 mm. An additional 3% experienced severe local reactions defined as a reaction size >120 mm, marked limitation of arm movement, or marked axillary node tenderness. Systemic reactions were reported in <0.3% of approximately 4,200 persons who received injections.

Starting in 1976, the interval for booster injections was increased to ≥2 years. To reduce the rate and severity of local reactions, vaccinees with continued potential for occupational exposure to botulinum toxins were given booster injections at the 2-year interval only if a 1:16 dilution of their serum did not protect mice in serotypes B and E toxin challenge studies (indicative of an antibody concentration of ≥0.2 IU/mL). In an evaluation of this schedule in 2002, adverse events were less frequent (7% and 0.3% moderate and severe local reactions, respectively) than when annual boosters were given routinely.

Until the mid-1990s, nearly 50% of vaccinees had anti-PBT antibody levels ≥0.2 IU/mL at the 2-year post-booster assessment. However, by 2004, this was true of <15% of vaccinees. Additionally, potency studies conducted in guinea pigs demonstrated that the PBT lots then in use, which were manufactured in 1976 and had been distributed since 1982, no longer protected guinea pigs challenged with serotypes D and E, and were associated with a decline in antibody induction for toxin serotypes C, D, and E (1--3). A study of one lot of vaccine designed to assess the need for a 6-month dose demonstrated that an additional injection at 6 months was required to achieve potentially protective antibody levels against all toxin serotypes (1-- 3). Because antibody levels declined rapidly, the 12-month booster also was required. Higher titers were observed after the 12-month booster and were generally 10-fold higher than what had been observed after the third dose of the primary series. Because of the decline in immune response to toxin serotypes C, D, and E, the PBT vaccine schedule was modified in 2004 to include a 6-month injection in the primary series (0, 2 weeks, 12 weeks, and 6 months) and an annual booster was reinstated to achieve a more robust immune response.

The decline in immunogenicity might be related to the age of the available product (>30 years). CDC's review of adverse events from 3,125 injections following the modified schedule showed a steady increase in moderate local reactions in booster recipients, from 12.4% in 2005 to 31.0% in 2010. No increase in severe local reactions was observed. The increase in moderate local reactions might be the result of reinstatement of the annual booster schedule in 2004. CDC data demonstrated some increase in moderate reactions in persons receiving the primary series in both 2009 (17.7%) and 2010 (17.9%) compared with reaction rates each year from 2003 to 2008 (4.3%, 5.2%, 6.0%, 9.0%, 7.7%, and 4.4%, respectively). However, this increase in moderate reactions in primary series vaccine recipients was not observed at the U.S. Army Medical Research Institute for Infectious Diseases. Studies by the U.S. Department of Defense (DoD) show that persons receiving this investigational product might still respond to toxin serotype A, and potency tests suggest that the PBT has not declined in recent years to toxin serotypes A and B (1), but evidence suggests this product is declining in immunogenicity for at least toxin serotypes C, D, and E because of its age. Although investigational PBT was provided on recognition of its potential protective benefit, a serologic correlate of protection was never defined. Based on evidence of declining immunogenicity, decreased product potency, increased occurrence of injection site--related adverse reactions, and the age of the product, CDC no longer recommends PBT and will no longer distribute PBT after November 30, 2011.

On average, approximately 200--300 persons received PBT annually during 2008--2010 under the CDC-sponsored IND for PBT (BB-IND 161). To allow recent vaccinees to complete the primary series, the IND will remain in effect through May 31, 2012 (6 months from the date of this notice). No replacement investigational or licensed botulism vaccine is available in the United States; however, a vaccine using recombinant technologies is under development by the DoD Chemical Biological Medical Systems Joint Project Management Office.

Laboratory Safety Recommendations

Laboratory workers performing research on botulinum toxin should continue to adhere strictly to study-specific safety protocols designed to prevent exposures. Laboratory directors should review carefully all recommended practices identified in Biosafety in Microbiological and Biomedical Laboratories (5) and within relevant Occupational Safety and Health Administration standards,* and ensure that all workers are adequately trained in the safe handling of botulinum toxin and early symptoms of intoxication. Laboratory workers with suspected exposure to botulinum toxin should follow their employer's postexposure protocols and immediately notify their health-care provider at the first symptoms of botulism. Select agent--registered facilities should follow National Select Agent Registry requirements† for reporting potential environmental releases or personnel exposures to botulinum toxin or botulinum neurotoxin--producing species of Clostridium. Suspected occupational exposures to botulinum toxin also must be reported to the appropriate local or state health department; all states maintain 24-hour telephone services for reporting suspected botulism cases and other public health emergencies. Emergency consultation also is available from the CDC botulism duty officer via the CDC Emergency Operations Center; telephone: 770-488-7100. Exposure to concentrated preparations of botulinum toxin might warrant hospitalization and administration of botulinum antitoxin, which is available from CDC (6); decisions about antitoxin use are made on a case-by-case basis in consultation with CDC.

References

1. Rusnak J, Smith LA. Botulinum neurotoxin vaccines: past history and recent developments. Human Vaccines 2009;5:794--805.
2. Smith L, Rusnak J. Botulinum neurotoxin vaccines: past, present, and future. Crit Rev Immunol 2007;27:303--18.
3. Rusnak JM, Harper IM, Abbassi I. Laboratory exposures to botulinum toxins: review and updates of therapeutics for the occupational health provider [Chapter 10]. In: JY Richmond, KB Meyers, eds. Anthologies in biosafety XII. Managing challenges for safe operations of BSL-3/ABSL-3 facilities. Mundelein, IL: American Biological Safety Association; 2011.
4. Smith L, Rusnak JM. Botulism vaccines and the immune response [Chapter 31]. In: Jankovic J, Albanes A, Atassi MZ, Dolly JO, Hallett M, Mayer NH, eds. Botulinum toxin: therapeutic clinical practice and science. Philadelphia, PA: Saunders (Elsevier); 2009.
5. US Department of Health and Human Services. Biosafety in microbiological and biomedical laboratories. Wilson DE, Chosewood LC, eds. 5th ed. Washington, DC: US Department of Health and Human Services; 2009. Available at http://www.cdc.gov/biosafety/publications/bmbl5/index.htm. Accessed October 19, 2011.
6. CDC. Investigational heptavalent botulinum antitoxin (HBAT) to replace licensed botulinum antitoxin AB and investigational botulinum antitoxin E. MMWR 2010;59:299.