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Special Issue Vaccines in Civilian Defense Against Bioterrorism Philip K. Russell Johns Hopkins School of Public Health, Baltimore, Maryland, USA In the United States, over the past half epidemic and prevention of a global pandemic, century, we have lived under the protective postexposure prophylaxis against anthrax (with umbrella of vaccination programs that shield our antibiotics), and preexposure prophylaxis in population from a dozen serious and sometimes first-responders at high risk, laboratory work- fatal naturally transmitted illnesses. Vaccina- ers, and health-care providers. tion has been the single most cost-effective public Smallpox and anthrax, which pose the health intervention. However, the value of greatest risk for causing large numbers of vaccines in protecting the population against the casualties in the event of an effective release by a deliberate release of infectious organisms is not terrorist group, are at the top of the list of threat so clear-cut. agents. Licensed vaccines against both anthrax The U.S. armed forces have recognized the and smallpox that protect against aerosol military value of vaccines against biological transmission are available. An existing licensed threats and have a long-standing research and plague vaccine is protective against flea- development program for a series of vaccines to transmitted disease but not against aerosol protect service members from hostile use of a challenge in animal experiments or against biological agent. Vaccination against anthrax is pneumonic plague. This vaccine is in limited under way in all three armed services. The supply, and the manufacturer has recently Department of Defense has a large program to ceased production. develop and license additional vaccines for The Department of Defense Joint Vaccine biological defense. For the military, vaccination Acquisition Program has several experimental is an effective means of countering a known vaccines in development (Table). These vaccines threat because the population at risk is easily will be further developed and tested with the defined and a high level of vaccine coverage can intent of obtaining products licensed by the U.S. be achieved. Food and Drug Administration. In evaluating the role of vaccines for protecting the civilian population, quite different Table. Vaccines against biological agents answers are reached. Despite the protective efficacy of vaccines against individual organ- Licensed Vaccines in research vaccines and development isms, the very high costs and the great difficulties involved in vaccinating large popula- Anthrax Vaccinia (cell culture) Smallpox (vaccinia) Botulinum toxoids tions, along with the broad spectrum of potential Plague Tularemia agents, make it impossible to use vaccines to Q fever protect the general population against VEE, EEE, WEE bioterrorism. Thus, vaccines cannot be consid- VEE, Venezuelan equine encephalitis; EEE, Eastern equine ered a first line of defense against bioterrorism encephalitis; WEE, Western equine encephalitis. for the general population, as they can be for the relatively small military population. However, if suitable vaccines can be made available, they Smallpox have several potential uses: control of a smallpox One vaccine in development that is of great importance to civilian biodefense is the vaccinia Address for correspondence: Philip K. Russell, Johns Hopkins Center for Civilian Biodefense Studies, Candler Building, virus vaccine made in cell culture. A new Suite 850, 111 Market Place, Baltimore, MD 21202, USA; fax: national stockpile of vaccinia vaccine is urgently 410-223-1665; e-mail: firstname.lastname@example.org. needed to respond to the possible threat of a Vol. 5, No. 4, JulyAugust 1999 531 Emerging Infectious Diseases Special Issue deliberate release of smallpox virus. Even Anthrax though such release is unlikely, the conse- Anthrax is the second threat that requires a quences of being unprepared would be a global major research and development effort to meet catastrophe. An unchecked epidemic in todays civilian needs. A covert attack, which exposes an unvaccinated, densely packed urban populations urban population to an anthrax spore aerosol, is linked by rapid air travel could kill millions. The thought by some to be the most likely scenario for only possible course of action would be to mount a bioterrorism attack. If the release is detected or a global effort to control the spread and eradicate the first cases are rapidly diagnosed, rapid action the disease using vaccinia virus vaccine. The can save many lives. Providing the exposed number of deaths due to secondary and population with antibiotics followed by vaccina- subsequent spread of this highly contagious tion could be lifesaving for exposed persons who virus would be determined by the rapidity of the would otherwise become ill with untreatable public health response, the effectiveness of a inhalation anthrax in the subsequent few weeks. vaccination campaign, and, most importantly, Prophylactic antibiotics alone will prevent the availability of vaccine. disease in persons exposed to antibiotic- The national stockpile (fewer than 7 million susceptible organisms, but incorporating vacci- doses of vaccinia virus vaccine) is insufficient to nation into the treatment regime can greatly meet national and international needs in this reduce the length of treatment with antibiotics. scenario. The stockpile is also deteriorating and Without vaccination, antibiotics must be has a finite life span. The vaccine was made continued for 60 days; if effective vaccination can using the traditional method of scarifying and be provided, this can be reduced to 30 days. infecting the flanks and bellies of calves and Vaccination of persons affected by an attack will harvesting the infected lymph. No manufacturer also face the issue of environmental contamina- exists today with the capability to manufacture tion of urban areas after an attack. Stockpiling a calf lymph vaccine by the traditional method. vaccine capable of inducing protective immunity Replacing the stockpile will require the with two doses could be extremely valuable in development and licensure of a new vaccine reducing the impact of a terrorist release of using modern cell-culture methods. This anthrax. development program, which will include process The current anthrax vaccine manufactured development, validation of a new manufacturing by Bioport (formerly the Michigan Department process, and extensive clinical testing, will be of Public Health Laboratory) is an alum- expensive and may take several years (1). adsorbed, partially purified culture filtrate of Obstacles to the development of the vaccine Bacillus anthracis with a high protective include the lack of satisfactory stocks of vaccinia antigen content. The schedule for administra- immune globulin necessary for managing tion is 0, 2, and 4 weeks and 6, 12, and 18 months. complications of vaccination. Clinical testing This vaccine is safe and efficacious and is being cannot proceed without a supply of vaccinia used by the armed forces to protect personnel immune globulin. As part of the development against the use of anthrax as a weapon. effort, the problems associated with manufac- Immunization of rhesus monkeys followed by a ture of sufficient quantities of vaccinia immune high-dose aerosol challenge has convincingly globulin will have to be addressed and solved. demonstrated the capability of this vaccine to The Department of Defense program is moving protect against aerosol challenge with B. ahead with development of a cell-culture vaccine anthracis spores. The multiple dose require- by using a cloned strain of vaccinia derived from ment, however, is a drawback for civilian use. another strain. Both civilian and military Studies in progress may find ways to allow requirements could be met by a combined and modification of the schedule. Vaccine supply is expanded development effort using either the limited, as is production capacity. As a result, at cloned strain or one of the licensed vaccinia least for the immediate future, the armed forces strains. The development costs will undoubtedly will require the entire available supply. This be high, as for any new biologic product, but the vaccine is made by a method developed before the cost of preparedness is insignificant when advent of molecular biology and requires weighed against the costs of an unchecked dedicated facilities because B. anthracis is a smallpox epidemic. spore-forming organism. In addition to having a Emerging Infectious Diseases 532 Vol. 5, No. 4, JulyAugust 1999 Special Issue multiple-dose requirement, the vaccine is not The value of vaccinating law-enforcement highly purified and contains multiple extraneous and emergency response personnel, who must proteins. The characteristics of the vaccine and respond to threats (real or otherwise), depends the constraints on the present method of on the nature of their work and the immediacy of manufacturing argue strongly against procuring the threat. Laboratory personnel who must work large amounts for civilian use when the with unknown materials and with high technology and the science base exist to rapidly concentrations of known infectious materials develop a second-generation, improved anthrax must be vaccinated. These are additional vaccine. justifications for moving ahead with a vigorous Anthrax depends on two toxins (lethal factor development program for anthrax and smallpox and edema factor) for virulence. A protein called vaccines. protective factor is an essential component of Dr. Russell is professor, Center for Immunization both toxins. The protective factor content is the Research, Johns Hopkins School of Public Health; former basis for the effectiveness of the current vaccine. Commander, United States Army Medical Research and A vaccine based on purified protective factor Development Command. made by recombinant technology has been protective in animals (2). Use of a modern adjuvant with purified recombinant protective References 1. Committee on R&D Needs for Improving Civilian factor should make it possible to have a very Medical Response to Chemical and Biological effective two-dose vaccine. A recent report of the Terrorism Incidents. Institute of Medicine, National Institute of Medicine Committee on Research Academy of Sciences. Chemical and Biological and Development to Improve Civilian Medical Terrorism. Research and Development to Improve Response to Chemical and Biological Terrorism Civilian Medical Response. Washington: National Academy Press; 1999. makes a strong case for a major research and 2. Zajtchtchuk R, Bellamy RF, editors. Textbook of development effort leading to an improved military medicine: medical aspects of chemical and second-generation vaccine (1). biological warfare. Office of the Surgeon General, Questions regarding the ability of existing Department of the Army. Washington, D.C.; 1997. anthrax vaccines to protect against anthrax 3. Pomeratnsev AP, Startsin NA, Mockov YV, Marnin LI. Expression of cereolysin AB genes in Bacillus strains engineered to contain additional viru- Anthracis vaccine strain ensures protection against lence genes have been raised in Russia (3). experimental hemolytic anthrax infection. Vaccine Research is needed to address this and related 1997;15:1846-50. questions about the pathogenesis of anthrax and protective immunity. Vol. 5, No. 4, JulyAugust 1999 533 Emerging Infectious Diseases
"Vaccines in Civilian Defense Against Bioterrorism"