Emerging Infectious Diseases
[Volume 5 No.4 / July - August 1999]


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 century, we have lived under
the protective umbrella of vaccination programs that shield our
population from a dozen serious and sometimes fatal naturally
transmitted illnesses. Vaccination has been the single most
cost-effective public health intervention. However, the value of
vaccines in protecting the population against the deliberate release
of infectious organisms is not so clear-cut.

The U.S. armed forces have recognized the military value of
vaccines against biological threats and have a long-standing
research and development program for a series of vaccines to
protect service members from hostile use of a biological agent.
Vaccination against anthrax is under way in all three armed
services. The Department of Defense has a large program to
develop and license additional vaccines for biological defense. For
the military, vaccination is an effective means of countering a
known threat because the population at risk is easily defined and a
high level of vaccine coverage can be achieved.

In evaluating the role of vaccines for protecting the civilian
population, quite different answers are reached. Despite the
protective efficacy of vaccines against individual organisms, the
very high costs and the great difficulties involved in vaccinating
large populations, along with the broad spectrum of potential
agents, make it impossible to use vaccines to protect the general
population against bioterrorism. Thus, vaccines cannot be
considered a first line of defense against bioterrorism for the general
population, as they can be for the relatively small military
population. However, if suitable vaccines can be made available,
they have several potential uses: control of a smallpox epidemic and
prevention of a global pandemic, postexposure prophylaxis against
anthrax (with antibiotics), and preexposure prophylaxis in
first-responders at high risk, laboratory workers, and health-care
providers.

Smallpox and anthrax, which pose the greatest risk for causing
large numbers of casualties in the event of an effective release by a
terrorist group, are at the top of the list of threat agents. Licensed
vaccines against both anthrax and smallpox that protect against
aerosol transmission are available. An existing licensed plague
vaccine is protective against flea-transmitted disease but not against
aerosol challenge in animal experiments or against pneumonic
plague. This vaccine is in limited supply, and the manufacturer has
recently ceased production.

The Department of Defense Joint Vaccine Acquisition Program has
several experimental vaccines in development (Table). These
vaccines will be further developed and tested with the intent of
obtaining products licensed by the U.S. Food and Drug
Administration.

Table. Vaccines against biological agents
  ------------------------------------------------------
  Licensed vaccines        Vaccines in research
                           and development
  ------------------------------------------------------
  Anthrax                  Vaccinia (cell culture)

  Smallpox (vaccinia)      Botulinum toxoids

  Plague                   Tularemia

                           Q fever

                           VEE EEE WEE

  ------------------------------------------------------
VEE, Venezuelan equine encephalitis; EEE, Eastern equine  
encephalitis; WEE, Western equine encephalitis.


Smallpox

One vaccine in development that is of great importance to civilian
biodefense is the vaccinia virus vaccine made in cell culture. A new
national stockpile of vaccinia vaccine is urgently needed to respond
to the possible threat of a deliberate release of smallpox virus. Even
though such release is unlikely, the consequences of being
unprepared would be a global catastrophe. An unchecked epidemic
in today's unvaccinated, densely packed urban populations linked by
rapid air travel could kill millions. The only possible course of
action would be to mount a global effort to control the spread and
eradicate the disease using vaccinia virus vaccine. The number of
deaths due to secondary and subsequent spread of this highly
contagious virus would be determined by the rapidity of the public
health response, the effectiveness of a vaccination campaign, and,
most importantly, the availability of vaccine.

The national stockpile (fewer than 7 million doses of vaccinia virus
vaccine) is insufficient to meet national and international needs in
this scenario. The stockpile is also deteriorating and has a finite life
span. The vaccine was made using the traditional method of
scarifying and infecting the flanks and bellies of calves and
harvesting the infected lymph. No manufacturer exists today with
the capability to manufacture calf lymph vaccine by the traditional
method. Replacing the stockpile will require the development and
licensure of a new vaccine using modern cell-culture methods. This
development program, which will include process development,
validation of a new manufacturing process, and extensive clinical
testing, will be expensive and may take several years (1).

Obstacles to the development of the vaccine include the lack of
satisfactory stocks of vaccinia immune globulin necessary for
managing complications of vaccination. Clinical testing cannot
proceed without a supply of vaccinia immune globulin. As part of
the development effort, the problems associated with manufacture
of sufficient quantities of vaccinia immune globulin will have to be
addressed and solved. The Department of Defense program is
moving ahead with development of a cell-culture vaccine by using a
cloned strain of vaccinia derived from another strain. Both civilian
and military requirements could be met by a combined and
expanded development effort using either the cloned strain or one
of the licensed vaccinia strains. The development costs will
undoubtedly be high, as for any new biologic product, but the cost
of preparedness is insignificant when weighed against the costs of
an unchecked smallpox epidemic.

Anthrax

Anthrax is the second threat that requires a major research and
development effort to meet civilian needs. A covert attack, which
exposes an urban population to an anthrax spore aerosol, is thought
by some to be the most likely scenario for a bioterrorism attack. If
the release is detected or the first cases are rapidly diagnosed, rapid
action can save many lives. Providing the exposed population with
antibiotics followed by vaccination could be lifesaving for exposed
persons who would otherwise become ill with untreatable inhalation
anthrax in the subsequent few weeks. Prophylactic antibiotics alone
will prevent disease in persons exposed to antibiotic-susceptible
organisms, but incorporating vaccination into the treatment regime
can greatly reduce the length of treatment with antibiotics. Without
vaccination, antibiotics must be continued for 60 days; if effective
vaccination can be provided, this can be reduced to 30 days.
Vaccination of persons affected by an attack will also face the issue
of environmental contamination of urban areas after an attack.
Stockpiling a vaccine capable of inducing protective immunity with
two doses could be extremely valuable in reducing the impact of a
terrorist release of anthrax.

The current anthrax vaccine manufactured by Bioport (formerly the
Michigan Department of Public Health Laboratory) is an
alum-adsorbed, partially purified culture filtrate of Bacillus
anthracis with a high protective antigen content. The schedule for
administration is 0, 2, and 4 weeks and 6, 12, and 18 months. This
vaccine is safe and efficacious and is being used by the armed forces
to protect personnel against the use of anthrax as a weapon.
Immunization of rhesus monkeys followed by a high-dose aerosol
challenge has convincingly demonstrated the capability of this
vaccine to protect against aerosol challenge with B. anthracis
spores. The multiple dose requirement, however, is a drawback for
civilian use.

Studies in progress may find ways to allow modification of the
schedule. Vaccine supply is limited, as is production capacity. As a
result, at least for the immediate future, the armed forces will
require the entire available supply. This vaccine is made by a
method developed before the advent of molecular biology and
requires dedicated facilities because B. anthracis is a spore-forming
organism. In addition to having a multiple-dose requirement, the
vaccine is not highly purified and contains multiple extraneous
proteins. The characteristics of the vaccine and the constraints on
the present method of manufacturing argue strongly against
procuring large amounts for civilian use when the technology and
the science base exist to rapidly develop a second-generation,
improved anthrax vaccine.

Anthrax depends on two toxins (lethal factor and edema factor) for
virulence. A protein called protective factor is an essential
component of both toxins. The protective factor content is the basis
for the effectiveness of the current vaccine. A vaccine based on
purified protective factor made by recombinant technology has been
protective in animals (2). Use of a modern adjuvant with purified
recombinant protective factor should make it possible to have a
very effective two-dose vaccine. A recent report of the Institute of
Medicine Committee on Research and Development to Improve
Civilian Medical Response to Chemical and Biological Terrorism
makes a strong case for a major research and development effort
leading to an improved second-generation vaccine (1).

Questions regarding the ability of existing anthrax vaccines to
protect against anthrax strains engineered to contain additional
virulence genes have been raised in Russia (3). Research is needed
to address this and related questions about the pathogenesis of
anthrax and protective immunity.

The value of vaccinating law-enforcement and emergency response
personnel, who must respond to threats (real or otherwise),
depends on the nature of their work and the immediacy of the
threat. Laboratory personnel who must work with unknown
materials and with high concentrations of known infectious
materials must be vaccinated. These are additional justifications for
moving ahead with a vigorous development program for anthrax
and smallpox vaccines.

--------------------------------------------------------

 Dr. Russell is professor, Center for Immunization Research, Johns
Hopkins School of Public Health; former Commander, United
States Army Medical Research and Development Command.

 Address for correspondence: Philip K. Russell, Johns Hopkins
Center for Civilian Biodefense Studies, Candler Building, Suite
850, 111 Market Place, Baltimore, MD 21202, USA; fax:
410-223-1665; e-mail: biodefen@jhsph.edu.

References

  1. Committee on R&D Needs for Improving Civilian Medical
Response to Chemical and Biological Terrorism Incidents. Institute
of Medicine, National Academy of Sciences. Chemical and
Biological Terrorism. Research and Development to Improve
Civilian Medical Response. Washington: National Academy Press;
1999.
  2. Zajtchtchuk R, Bellamy RF, editors. Textbook of military
medicine: medical aspects of chemical and biological warfare.
Office of the Surgeon General, Department of the Army.
Washington, D.C.; 1997.
  3. Pomeratnsev AP, Startsin NA, Mockov YV, Marnin LI.
Expression of cereolysin AB genes in Bacillus Anthracis vaccine
strain ensures protection against experimental hemolytic anthrax
infection. Vaccine 1997;15:1846-50.
  

  
Emerging Infectious Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, GA

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