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Vaccines in Civilian Defense Against Bioterrorism

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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: biodefen@jhsph.edu.                      needed to respond to the possible threat of a




Vol. 5, No. 4, July–August 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 today’s         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, July–August 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, July–August 1999                   533                                  Emerging Infectious Diseases

				
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