Yersinia pestis vaccine
Status: approved; not currently manufactured or marketed; replacement in development
Organizations involved:
Greer Labs., Inc. – Tech.; Manuf.; World mark.
U.S. Dept. of Defense (DOD) – USA mark.; Former
Bayer Inc. – R&D; Tech.; Former
Bayer AG – Parent; Former
Description: Plague vaccine is a formulation of whole Yersinia pestis (Pas-teurella pestis), a gram-negative bacterium, inactivated by formalin (formaldehyde). Yersinia pestis is the causative agent for plague (black plague).
Nomenclature: Plague vaccine [BIO FDA]; Yersinia pestis vaccine [SY]; Pasteurella pestis vaccine [SY]; Yersinia pseudo---tuberculosis vaccine [SY]
History: During the late 1960s, this vaccine effectively protected American troops in Vietnam. Only 8 cases of plague were reported among U.S. troops, with about 1/million person-years exposure, while the disease was endemic among the civilian population, occurring at a rate 330-times higher.
The first U.S. approval of a plague vaccine was Anti-Plague Vaccine from the Swiss Serum and Vaccine Institute Berne in 1908. Plague Bacillus Vaccine from Institute Pasteur de Paris was approved in 1911.
Companies.: The vaccine was developed and originally manufactured by Cutter Labs., Miles/Bayer Inc., CBER/FDA est. no. 0008. Greer Labs., Inc., CBER/FDA est. no. 0308, assumed manufacture and marketing from Bayer Corp. in 1992.
FDA class: Biologic PLA
CBER class: Bacterial Antigens and Vaccines
Approvals: Date = 19420514; first approval, PLA, granted to Cutter Labs., Miles/Bayer
Date = 19941005; licenses (original PLA/ELA) granted/transferred to Greer Labs. (approval time of 11.5 months)
Date = 19950524; license (PLA) revoked from Cutter/Bayer Corp. at company request (with Greer still holding its license)
Indications: immunization with this vaccine is recommended for those persons at particularly high risk of exposure to plague
Status: The product’s FDA approval remains valid. However, this vaccine is not commercially available, is no longer being manufactured, and Greer has no plans to resume manufacture.
Since Greer assumed manufacture of this product from Bayer (now Bayer Schering) in 1992 and received product and establishment licenses in 1994, the sole purchaser for plague vaccine had been units of the U.S. Department of Defense (DOD; although some other countries likely were allowed to purchase vaccine from Greer). The vaccine was used by DOD for its approved indication – for protection of persons in areas of endemic or epidemic plague (not for biological warfare defense).
The FDA issued a warning letter to Greer Labs. on Sept. 22, 1997, alleging serious Good Manufacturing Practices violations. Distribution and manufacture were halted after FDA requested further information about manufacture in July 1998.
Medical: The standard immunization schedule is 1.0 mL by intramuscular injection (IM), followed by 0.2 mL IM 1 to 3 months later, and 0.2 mL IM at 3 to 6 months later. Preliminary data indicate that a rapid immunization schedule of 0.5 mL IM at 0, 1, and 2 weeks produces similar antibody titers to that observed after the third dose of the standard schedule. After 3 doses, most recipients have titers greater than 1:128 against the Y. pestis F1 antigen. Approximately 7-8% of recipients do not show any antibody response to the vaccine. After this primary immunization, recipients should receive 3 additional doses (boosters) of a 0.2 mL IM booster spaced 6 months after the primary series, and then 0.2 mL every 1 to 2 years subsequently for continued protection. Extrapolations from animal studies indicate that at least 3 doses yield protective immune response to intradermal challenge at 4-7 months under the current dose schedule.
Efficacy of the vaccine varies with the route of Yersinia pestis exposure. Experience from U.S. military involvement in the Vietnam war, where plague was endemic, indicates that the vaccine protects against intradermal exposure. More recent animal studies (mice, guinea pigs, and primates), has cast doubt on the efficacy of the vaccine against inhalation exposure to Y. pestis (the most likely route for bioterrorism/biological warfare use of Y. pestis). About 8-10% of inoculations result in local reactions including redness, swelling, induration, and tenderness. These reactions usually resolve within 48 hours. About 7-10% of inoculations result in systemic side effects of malaise, lymph node swelling, and fever. Severe side effects are rare. Systemic side effects tend to increase in frequency after receiving more than five doses.
Disease: Plague is currently not common in the U.S. and most other countries because of improved sanitation. From 1947 to 1996, only 390 cases of plague were reported in the U.S., mostly in the Western states. Among humans, plague is spread by infected fleas, often associated with rats, that bite humans. A natural epidemic is often preceded by large number of dead rats. Only a small percentage of plague cases are spread from person to person.
Y. pestis could be released as an aerosol (causing pneumonic plague) in a biological warfare/terrorist attack. The effectiveness of the vaccine for this purpose has not been determined. Affected persons would develop symptoms within two to eight days, leading to swollen lymph nodes, pustules on the skin, and possible necrosis. Gangrene would not appear until later stages. Prompt treatment would be necessary. The first signs of illness (fever, cough, dyspnea, abdominal pain, and nausea) may be confused with other infections. No quick diagnostic tests are available to diagnose plague. The therapy generally recommended in case of biological warfare/terrorist exposure to Y. pestis is antibiotic treatment, e.g., strep-to-mycin, tetracycline, or doxycycline.
R&D: In Sept. 2004, ID Biomedical Corp. (now merged into GlaxoSmithKine) received a grant for up to $8 million from the National Institute of Allergy and Infectious Disease (NIAID), NIH, for development of a intranasally administered plague vaccine using recombinant Y. pestis FIV protein with the company’s Proteosome adjuvant/delivery technology.
In Jan. 2005, an injectable recombinant plague vaccine (rF1V) targeted to serotypes A and B from DVC LLC (formerly DynPort Vaccine Co, LLC), a subsidiary of Computer Sciences Corp. (CSC), entered a Phase I trial. This vaccine was originally developed by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), is manufactured by ID Biomedical Corp. (now part of GlaxoSmithKline), and its development is primarily funded by the Joint Vaccine Acquisition Program (JVAP), Department of Defense (DOD). The rF1V plague vaccine is designed to provide protection against Yersinia pestis in aerosolized form. In Sept. 2005, FDA granted fast track status to the expected BLA for this plague vaccine, allowing submission of portions of the BLA as they are completed. In July 2006, the vaccine entered a Phase II trial testing different vaccine dosages and schedules in 400 healthy volunteers between the ages of 18 and 55. In June 2008, JVAP, DOD stated its commitment to fund development of plague vaccines would be solely targeted to the rF1V product being developed by DVC.
Crucell N.V. concluded a Cooperative Research and Development Agreement (CRADA) with the Naval Medical Research Center, U.S. Navy, in Oct. 2005 for development of adenovirus vector vaccines cultured in PER.C6 cells, AdVac, vaccine against anthrax and plague, and is testing the vaccine in non-human primates.
In Sept. 2006, researchers at the Massachusetts Medical School reported that an a recombinant Y. pestis strain with a modified polysaccharide coat stimulates immune cells in mice, and showed that mice can survive infection with the engineered strain. The surviving mice also appeaedr to be protected from subsequent infection with normal, otherwise deadly, Y. pestis.
The Defense Appropriations Bill for Fiscal Year 2007, passed by Congress in Oct. 2006, included $2.6 million of specially ear-marked funds to support AVANT Immunotherapeutic’s (Celldex Therapeutics, Inc.) development of a combination oral anthrax and plague vaccine, primarily for clinical trials.
In Oct. 2007, Ichor Medical Systems, whose advanced electroporation system is being used worldwide to increase the effectiveness of DNA drug and vaccine delivery, was awarded a 2-year contract valued at over $2.3 million by the Defense Threat Reduction Agency (DTRA). Ichor will assist the Biological Defense Research Directorate (BDRD) of the Naval Medical Research Center (NMRC) in the development of a DNA vaccine for anthrax and plague.
Companies involvement:
Full monograph
511 Plague Vaccine
Nomenclature:
Plague vaccine [BIO FDA]
Pasteurella pestis vaccine [SY]
Yersinia pestis vaccine [SY]
Yersinia pseudotuberculosis vaccine [SY]
FDA Class: Biologic PLA
Year of approval (FDA) = 1942
Date of 1st FDA approval = 19420514
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
vaccines, bacterial
vaccines, inactivated
bacterial culture <!-- bacterialculture -->
Yersinia pestis (plague bacteria)
formaldehyde
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
conjugates
Good Manufacturing Practices (GMP) violations
North American coral snake
EU000 Not yet/Never filed with EU
UM100 Controlled/Gov't Distribution in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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