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Chen and Zeng, J Bioterr Biodef 2012, S4
http://dx.doi.org/10.4172/2157-2526.S4-003
Bioterrorism & Biodefense
Commentary
Open Access
Anthrax Bioterrorism and Current Vaccines
Shan Chen* and Mingtao Zeng
Center of Excellence for Infectious Diseases, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center,
5001 El Paso Drive, El Paso, Texas 79905, USA
Abstract
Bacillus anthracis a Category A agent with the potential to be used in a large-scale bioterrorism attack. The current
vaccine, known as Anthrax Vaccine Adsorbed (AVA), consists of a culture filtrate from an attenuated strain adsorbed
to aluminum salts as an adjuvant. Although considered to be safe and effective, it is difficult to produce large amounts
within a short time frame. Thus, there exists a need to produce a new-generation vaccine against anthrax that can
be produced quickly. In order for the new candidate vaccines to be effective, they must elicit a high titer of antibodies
against protective antigen (PA). PA neutralization minimizes host susceptibility to anthrax toxemia. In addition, eliciting
antibodies against additional virulence factors, such as capsule antigens of B. anthracis, may enhance clearance
of pathogen from host. This review will discuss the history of bioterrorism and current vaccine development against
anthrax. To date, there have been advances in vaccine design that utilize manipulated spores, modified protein
subunits, conjugated vaccines and viral delivery vehicles. Utilizing one or more of these advances may provide a new,
better vaccine against anthrax.
Keywords: Anthrax; Vaccine; Protective antigen; Lethal factor;
Edema factor; Immunization
Introduction
Bacillus anthracis, a rod-shaped, Gram-positive, aerobic bacterium,
is the etiologic agent of the acute disease anthrax. The bacterium
can form endospores that survive in harsh conditions for decades.
After endospore exposure to humans or animals, illness occurs after
secretion of two toxins, lethal toxin (LeTx) and edema toxin (EdTx).
Depending on the route of exposure, mortality can be over 50%, even
with supportive care.
Because of the high virulence characteristic, anthrax is attractive
as a potential bioweapon. Indeed, it has been used previously to
incapacitate foreign economies or as fear tactics. In World War I,
German and French agents used glanders and anthrax in order to
infect foreign nations’ livestock; in World War II, Japan used anthrax,
plague, and other diseases on populations to test bioweapon potential
[1]. In the fall of 2001, B. anthracis spores were spread through letters
mailed in the United States. Twenty two people were known to have
been infected and five of those individuals died. A 92-page summary of
evidence against the suspect, Bruce Ivins, was released by the FBI [2].
This most recent anthrax attack drew attention to the almost unlimited
gaps in security and defense against bioterrorism. Research for anthrax
vaccines plays a very important role in mitigating this threat.
In 1881, Louis Pasteur developed the first effective vaccine, a live
attenuated B. anthracis strain, for anthrax [3]. Since the 1930s, the live
attenuated Stern strain has been widely used to vaccinate domesticated
animals. However, due to concerns about safety, live spore vaccines
have not been adopted for general vaccination in the United States [4].
Anthrax Vaccine Adsorbed, otherwise known as AVA or BioThrax, is the
only FDA licensed human anthrax vaccine available. This vaccine was
licensed in 1970 based on safety studies conducted on 7000 participants
[5]. In 1998, the Clinton administration required the immunization of
all military members against anthrax. However, due to petitions and
class-action lawsuits, mandatory immunization was halted for a period.
Despite the conclusion that AVA is safe, AVA has shortcomings that
warrant the development of new-generation vaccination strategies.
Therefore, this review will focus on the current knowledge about
anthrax pathogenesis and the requirements for development of an ideal
vaccine for anthrax.
J Bioterr Biodef
History of Bioterrorism and Biowarfare
Biological materials have been used as weapons throughout history.
In 1346, the Tartar army, inflicted with plague, catapulted thousands
of their own men, killed by plague, into the sieged city of Caffa. The
resulting epidemic decimated the residents of the city [6]. The infected
ones who escaped the siege likely transmitted the disease to other parts
of Europe and contributed to the spread of the Black Death.
After World War I and the signing of the Geneva Protocol of 1925,
many countries, including Germany, Great Britain, Japan, Belgium,
Canada, France, Italy, the Netherlands, Poland, the Soviet Union and
the United States conducted biological weapons research [7]. Although
the Geneva Protocol prohibited the use in war of “asphyxiating,
poisonous, or other gases and bacteriological methods of warfare,”
there was no method to enforce compliance. One example of further
bioweapons development during World War II includes Japan’s
military Unit 731. This unit developed plague as a biological weapon by
allowing laboratory fleas to feast on plague infected rats, and then the
Japanese military released the fleas over Chinese cities to initiate plague
epidemics. Unfortunately, the Japanese had not adequately prepared
their military personnel for the effects of a released biological weapon.
In addition to 10,000 casualties in the city of Changteh, 1700 deaths
were reported among Japanese troops [8].
In 1972, a “Convention on the Prohibition of the Development,
Production and Stockpiling of Bacteriological and Toxin Weapons
and on Their Destruction” was held. Known as the BWC, this treaty
*Corresponding author: Shan Chen, Center of Excellence for Infectious
Diseases, Department of Biomedical Sciences, Paul L. Foster School of Medicine,
Texas Tech University Health Sciences Center, 5001 El Paso Drive, El Paso,
Texas 79905, USA, Tel: +1 915 7831241 ext. 254; Fax: +1 915 7831271; E-mail:
[email protected]
Received December 06, 2011; Accepted February 03, 2012; Published February
16, 2012
Citation: Chen S, Zeng M (2012) Anthrax Bioterrorism and Current Vaccines. J
Bioterr Biodef S4:003. doi:10.4172/2157-2526.S4-003
Copyright: © 2012 Chen S, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Bioterrorism: Infectious Diseases
ISSN:2157-2526 JBTBD, an open access journal
Citation: Chen S, Zeng M (2012) Anthrax Bioterrorism and Current Vaccines. J Bioterr Biodef S4:003. doi:10.4172/2157-2526.S4-003
Page 2 of 5
prohibits development, production and stockpiling of pathogens or
toxins and requires parties to destroy stockpiles. In addition, signatories
to the BWC were required to submit information about facilities where
biological defense research was being conducted, scientific conferences
at special facilities and disease outbreaks. Unfortunately, like the
Geneva Protocol, the BWC did not provide guidelines for inspections,
control of disarmament and compliance. And so, it was not surprising
to find that by 1995, Iraq had produced 19,000 liters of concentrated
botulinum toxin, 8,500 liters of concentrated anthrax and 2,200 liters of
aflatoxin to be used in modern warfare [9].
Organizations and individuals have also produced, stockpiled and
released biological weapons on the general populace. In 1995, the Aum
Shinrikyo, a Japanese religious group, released sarin nerve gas into five
trains in the busy Tokyo subway killing 12 commuters and affecting
hundreds more. Police raids discovered many biological warfare agents
(anthrax and Ebola). The motives were unclear, but speculation ranged
from hastening an apocalypse to bringing down the government. In the
United States, the 2001 anthrax letters killed five individuals. Although
no direct evidence of Bruce Ivins’ involvement was uncovered, US
officials declared him the sole culprit [10]. It is clear that individuals
have relatively easy access to bioweapons capable of killing hundreds
and injuring thousands. The threat of bioterrorism in modern times
comes from both foreign and domestic sources.
Anthrax
Natural B. anthracis infections are rare in developed countries and
relatively few cases have been reported. When anthrax infection does
occur, it primarily presents itself in three different ways: pulmonary,
gastrointestinal, and cutaneous. A rare fourth syndrome involving soft
tissue infection in injectional drug users is emerging due to unsanitary
practices [11]. The deadliness of anthrax depends on the route of
infection. Aerosolized endospores, targeting the inhalation route, are
relatively easy to disseminate and were goals of bioweapons programs.
Unfortunately, pulmonary anthrax infection is the most deadly form
of anthrax. The aerosol LD50 for rhesus macaques against the virulent
anthrax Ames strain is about 5.5×104 spores [12]. After inhalation,
endospores may stay dormant within the lung for extended periods
before the host begins to show symptoms. During an accidental release
of anthrax spores in 1979 from a former Soviet biological warfare facility
in Sverdlovsk, human anthrax disease appeared between 2 to 43 days
after exposure [13]. The respiratory infection in humans presents flulike symptoms for several days followed by severe respiratory collapse
and major organ failures.
Gastrointestinal infection in humans is caused by eating anthraxinfected meator plant matter. Symptoms may include vomiting of
blood, severe diarrhea, inflammation and loss of appetite. It may spread
into the bloodstream and thus, cause major organ failure leading to
death. The cutaneous infection in humans presents as a boil-like skin
lesion between 2 and 5 days after exposure. This route of infection is
historically the most common due to anthrax spore contamination
of cuts. If left untreated, cutaneous anthrax causes mortality in
approximately 20% of cases [14]. However, with aggressive antibiotic
treatment, the danger is lessened.
Anthrax pXO1 and pXO2
B. anthracis has two principal virulence determinants carried on
two different plasmids, pXO1 and pXO2. The 181kb pXO1 plasmid,
previously sequenced [15], encodes the genes (pagA, cya and lef) for
secreted toxins PA, EF, and LF, respectively. The 90kb pXO2 plasmid
J Bioterr Biodef
encodes the genes for formation of an anti-phagocytic capsule. Both
plasmids are required for B. anthracis to be fully virulent, such as the
Ames strain. Strains such as the pXO2- Sterne strain cannot produce a
capsule to resist macrophage phagocytosis.
Protective antigen, edema factor and lethal factor
Each individual anthrax toxin protein by itself is non-toxic. The
proteins act as an A2B toxin complex. Protective antigen (PA or PA83)
is a 735 amino acid protein (83 kDa) B toxin component that binds to
either capillary morphogenesis gene 2 (CMG2) or tumor endothelial
marker 8 (TEM8) on cells. CMG2 is widely distributed in human
tissues, whereas TEM8 is highly expressed on macrophages, endothelial
cells and tumor cells [16]. A furin-like protease [17] cleaves 20 kDa
from PA83 to yield PA63, thus activating it. The PA63 forms a heptamer
[18] to expose binding sites for three edema factor (EF) or lethal factor
(LF), both A toxin components. The PA63 may also form an octamer
that is able to bind four EF or LF whichis more stable in bloodstream
pH than the heptamer configuration [19]. When the toxin-receptor
complex is internalized into an acidic endosome, the PA63 undergoes a
conformational change to form a pore. LF completely translocates into
the cytosol whereas EF remains membrane associated.
Edema toxin (EdTx) is an adenylyl cyclase that acts to impair water
homeostasis by catalyzing the conversion of ATP into cAMP [20]. In
contrast to EdTx, LeTx is both more lethal and active in only certain
cell lines and primary cultures of murine macrophages [21]. LeTx is a
zinc-dependent metalloprotease that cleaves the N-terminus of several
mitogen activated kinase (MAPKK) members. This cleavage allows for
activation of many pathways, including upregulating or downregulating
cytokines and leads to apoptosis.
Macrophage secondary effects
LeTx is also able to affect some cells by lysing them, thus leading to
the hypothesis that rapid onset of shock-like death is attributable to the
release of cytokines such as TNFα and IL-1β from macrophages [2123]. However, there has been some controversy regarding this issue [2427]. The sudden shock suggests a rapid change in body homeostasis.
When mice were treated with antibodies against IL-1 during LeTx
challenge, a protective effect was observed [22]. Antibodies against
TNFα did not show the same effect. There are inconclusive findings and
so, this area needs more research to elucidate the role of cytokines in
anthrax pathogenesis.
LeTx is a primary virulence factor that causes clinical symptoms
and specifically targets macrophages. Previous observations showed
that when mice were specifically depleted of macrophagesby silica
injections, they became resistant to LeTx challenge [22]. However, the
ubiquity of cellular receptors for PA demonstrates that there may be
other human cell types can still be affected by LeTx without causing
cellular lethal effects. Human umbilical vein endothelial cells undergo
apoptosis when exposed to LeTx [28]. This may account for the vascular
leakage demonstrated in some anthrax cases.
Vaccination Strategies
Current studies and advances for candidate vaccines are focused
on targeting either the toxemia (toxin) or septicemia (bacteria) aspects
of anthrax disease. Efforts have been made to develop modified toxin
subunits, characterize attenuated B. anthracis spores, encapsulate
genetic information into viral delivery vectors and conjugate capsule
antigens with proteins.
These candidate vaccines are tested in mouse models that are
Bioterrorism: Infectious Diseases
ISSN:2157-2526 JBTBD, an open access journal
Citation: Chen S, Zeng M (2012) Anthrax Bioterrorism and Current Vaccines. J Bioterr Biodef S4:003. doi:10.4172/2157-2526.S4-003
Page 3 of 5
sensitive to anthrax LeTx. Although results may be promising, there
are complications. Mechanisms underlying the susceptibility to anthrax
infection are unknown. So, if a study reports a successful candidate
vaccine in one strain of mouse, comparison strain studies and gender
studies must be done to verify results. For example, BALB/cJ and
C57BL/6J mice are much more resistant to LeTx compared to A/J
mice. In both BALB/cJ and C57BL/6J mice, females required 4-fold
more spores to attain 100% mortality compared with males of the same
strain [29]. Different macrophage sensitivities have been attributed to
genetic loci. Lethal toxin sensitivity 1 (Ltxs1) is mapped to a gene for
kinesin-like protein (Kif1C) on chromosome 11 [30,31]. Due to genetic
differences, results from testing candidate anthrax vaccines should be
carefully interpreted.
BioThrax
BioThrax, produced in the 1970s by Emergent BioDefense
Corporation (formerly BioPort Corporation), is the only FDA licensed
human anthrax vaccine in the United States. The vaccine is a protein
subunit vaccine produced from culture filtrates of a non-virulent, noncapsule strain known as V770-NP1-R. The PA-containing sterile filtrate
is adsorbed to aluminum hydroxide, an adjuvant. Human vaccination
with BioThrax requires five intramuscular injections in the deltoid (0
and 4 weeks, then 6, 12, and 18 months) followed by annual boosters.
There are three main drawbacks to this vaccine: 1) the pain
associated with five or more needle sticks, 2) the amount of doctor
visits and 3) slow and expensive production costs. The pain caused by
needle injections may diminish compliance for following the vaccine
schedule. Therefore, a nasal spray method for this vaccine may reduce
non-compliance. If the inhalation route generates the same safe and
protective effect, perhaps the BioThrax immunization routes can be
modified. In one study, immunization with BioThrax via an intranasal
route elicits PA specific antibodies and protects against challenge [32].
The high number of doctor visits may either reduce compliance, or,
in a bioterror situation, overwhelm current medical facilities. A nasal
spray requires little to no training compared to manipulating a needle,
therefore, a mass-immunization effort could be implemented quickly
and easily.
Subunit vaccines
Other subunit vaccines improve on the BioThrax paradigm by
providing more purified and characterized proteins, reducing the
number of doses needed to elicit the same protective effect and
expedite a production process. Current high-yield recombinant protein
techniques can yield substantial amounts of proteins, up to 0.5 g protein
per liter of bacteria [33]. These techniques are attractive because the
genetic codes for PA, EF, or LF can be modified to create more effective
novel vaccines.
In one study, A/J mice were vaccinated with three doses of a
combination of non-toxic mutant LF and PA63 to elicit high antibody
titers and induced a 100% protective effect against challenge with the
Sterne strain [34]. Another study demonstrated that domain 2 of PA, or
the loop neutralizing determinant (LND), is an important target for an
epitope-specific vaccine for anthrax. The n-terminus portion of LND
provided 100% protection against spore challenge in rabbits [35]. A
different study found that a novel fusion protein comprising domain
1 of LF and domain 4 of PA provided complete protection against
spore challenge in mice [36]. Although we see complete protection,
the amount of spores varies between experiments. The antibody titers
generated may not be as high as those produced from live attenuated
vaccines.
J Bioterr Biodef
Spore vaccines
In the Soviet Union, live attenuated vaccines based on B. anthracis
spores have been widely used for human immunization [37]. However,
due to safety concerns regarding pathogenicity, it was not used for
humans in the United States. Generally, an attenuated spore vaccine
would present a full complement of bacterial antigens to the host
immune system. It is thought that spores or other live attenuated
vaccines may elicit better neutralizing antibodies against multiple
targets, thus conferring higher degrees of efficacy than subunit vaccines
such as BioThrax. So, the main concern in developing a spore vaccine
is the safety profile.
Strains have been developed that express PA, LF and EF with point
mutations. A strain expressing PA with mutations in the furin binding
site or translocation site were more attenuated. It has been observed
that spores producing only EF or LF do not elicit high antibody titers
against EF or LF. However, when spores produce both PA and EF or
PA and LF, anti-EF and anti-LF antibodies were increased [38]. Other
methods combine inactivated spores with PA to elicit protective effects.
The addition of formaldehyde-inactivated spores to PA (PA-FIS)
elicits total protection against cutaneous anthrax [39]. Unfortunately,
production of the live attenuated vaccine takes time to produce. In the
event of a vaccine shortage and bioterror event, production may not be
enough to cover demand.
Genetic vaccines
Many novel delivery systems are being developed for use as the nextgeneration of vaccines. These delivery systems utilize viral vectors to
deliver target genetic information to the host to confer host immunity.
The vectors also act as stimulants for the immune system. A vaccine
using viral vectors may also be delivered intranasally or orally, thus
eliciting a mucosal immune response, which may be more relevant to
combating pulmonary anthrax. In one study, three times intramuscular
immunization with an adenoviral vectored vaccine coding the
n-fragment of EF (Ad/EFn) elicited antibodies that were against both
LF and EF and induced a 57% protective effect against challenge with
the Sterne strain in A/J mice [40]. DNA can also be directly used in
immunization strategies. A plasmid containing a fragment of either
PA for LF genes has been studied. Mice immunized with a plasmid
encoding PA63 were protected against challenge with LeTx [41].
The adenoviral vectors can be mass produced quickly and
efficiently by infecting tissue culture cells. If preexisting immunity
exists to the vector, a different vector, if effective and safe, can be used
as an alternative. So, there is a disadvantage in producing these types of
vaccines. DNA plasmid vaccines can also be produced quickly, but it
requires trained personnel to administer by needle sticks.
Conjugate vaccines
The previous vaccines have focused on the toxemia portion of
anthrax because targeting the bacterium itself is difficult because anthrax
capsule proteins are poorly immunogenic. Conjugating the capsule with
immunogenic proteins can solve this issue. Antibodies to the capsule
exist when patients are recovering from anthrax infection [42]. Passive
immunization in mice results in protection from pulmonary anthrax
[43]. Since the capsule portion is a weak immunogen, the poly-gammad-glutamic acid (PGA) portion of the capsule was conjugated to PA to
create a potent immunogen [44]. The immunized mice were protected
against LeTx challenge. And so, this reveals an important secondary
approach to immunize against B. anthracis.
Bioterrorism: Infectious Diseases
ISSN:2157-2526 JBTBD, an open access journal
Citation: Chen S, Zeng M (2012) Anthrax Bioterrorism and Current Vaccines. J Bioterr Biodef S4:003. doi:10.4172/2157-2526.S4-003
Page 4 of 5
Summary
There have been advances in different approaches to vaccine
technology. A new anthrax vaccine that can elicit high antibody titers
to both PA and capsule proteins, has a good safety profile, is easily
produced in mass quantities and encourages compliance is the ideal
vaccine. Animal studies can vary due to the nature of anthrax toxins,
but upon successful replication of results in different strains, there
should be a push to advance the vaccine to higher organisms.
Advances in anthrax vaccines may also be translated to other vaccine
efforts. Methods applied to the poorly immunogenic capsule proteins
can be applied to other pathogens’ poorly immunogenic proteins. Any
pathogen’s gene can be encoded into a viral vector as a delivery vehicle.
Since anthrax can be genetically manipulated and easily grown, perhaps
even the anthrax spore itself can become a delivery vehicle to produce
target antigens for immunization of other diseases.
Due to the ease of anthrax spore production, availability of virulent
spores and the history of organizations utilizing anthrax as a bioweapon,
there is a high potential for bioterrorist activity. Security measures may
be put into place, but they may also be easily circumvented. Vaccinations
are the key to mitigating damage that may be done by bioterrorists.
And so, there is an urgent need to develop a new-generation safe and
effective FDA approved anthrax vaccine.
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ISSN:2157-2526 JBTBD, an open access journal
Citation: Chen S, Zeng M (2012) Anthrax Bioterrorism and Current Vaccines. J Bioterr Biodef S4:003. doi:10.4172/2157-2526.S4-003
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200 Open Access Journals
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Bioterrorism: Infectious Diseases
ISSN:2157-2526 JBTBD, an open access journal