Management and Control: Plague (Yersinia pestis)
IUCN SSC Invasive Species Specialist Group (ISSG)
1.0
GENERAL MANAGEMENT STRATEGIES
1.1
PREDICTING OUTBREAKS
2.0
PREVENTION
2.1
CHEMICAL CONTROL OF FLEA VECTORS FOR PREVENTION OF
Y. PESTIS SPREAD
2.2
PLAGUE VACCINES
2.2.1 KILLED WHOLE CELL VACCINES
2.2.2 SUBUNIT BASED VACCINES
2.2.3 LIVE ATTENUATED STRAIN VACCINES
3.0
TREATMENT
3.1
HISTORICAL TREATMENT
3.2
ANTIBIOTIC TREATMENT
3.3
ALTERNATIVES TO ANTIBIOTICS
3.3.1 IMMUNOTHERAPY
3.3.2 NON-PATHOGEN-SPECIFIC IMMUNOMODULATORY THERAPY
3.3.3 PHAGE THERAPY
3.3.4 BACTERIOCIN THERAPY
3.3.5 INHIBITORS OF VIRULENCE FACTORS
1.0 GENERAL MANAGEMENT STRATEGIES
“Outbreaks are usually tackled with a fire-fighting approach. Teams move into an infected area
to kill fleas with insecticides, treat human cases, and give chemoprophylaxis to exposed people.
Many experts have argued that this crisis management approach is insufficient as the outbreak is
likely to be on the wane by the time action is taken. Informed, pre-emptive decisions about
plague management and prevention before outbreaks occur would certainly be more sustainable
and cost-beneficial” (Stenseth et al. 2008).
1.1 PREDICTING OUTBREAKS
“Plague cannot be eradicated, since it is widespread in wildlife rodent reservoirs. Hence, there is
a critical need to understand how human risks are affected by the dynamics of these wildlife
reservoirs” (Stenseth et al. 2008). Humans and other susceptible mammals experience their
greatest exposure risk during epizootic periods where disease spreads rapidly. Thus
understanding the factors that lead to epizootics is highly important (Gage and Kosoy 2005).
Climatic factors may be important in some areas (e.g. Cavanaugh 1971 in Gage and Kosoy
2005). Parmenter et al. (1999) proposed a trophic cascade hypothesis where increased
precipitation caused greater plant and food production for rodents. Increased host rodent
populations led to a greater likelihood of epizootics and human cases of Yersinia pestis
(Parmenter et al. 1999 in Gage and Kosoy 2005).
There have been other recent progresses, “such as development of rapid diagnosis tools
(Chanteau et al. 2003), some challenging of accepted dogma about the dynamics of sylvatic
plague in the United States (Webb et al. 2006) and in Central Asia (Begon et al. 2006), and the
identification of predictive critical rodent abundance thresholds for plague in Kazakhstan (Davis
et al. 2004). What is striking, though, is our lack of understanding of this high profile disease in
even the best-studied foci, particularly in Africa: often, we do not even know the natural
reservoir of the bacilli. The capacity of the plague bacillus to form permanent foci under highly
diverse ecological conditions attests to its extraordinary adaptability. During its emergence in
Central Asia, Y. pestis accumulated copies of insertion sequences rendering its genome highly
plastic (Parkhill et al. 2001). The capacity to undergo genomic rearrangements may thus be an
efficient means for the plague bacillus to adapt to new ecological niches. Y. pestis was,
furthermore, recently shown to be able to acquire antibiotic resistance plasmids under natural
conditions (Galimand et al. 1997; Guiyoule et al. 2001)” (Stenseth et al. 2008).
2.0 PREVENTION
The Center for Disease Control (2002) states that the spread of Y. pestis in humans can be
controlled by eliminating sources of food and shelter for rodents in and near homes, modifying
homes to prevent rodent access, using insecticides in the home when Y. pestis has been detected
in the rodent population, and using insect repellents containing N, N-diethyl-m-toluamide
(DEET) on skin and repellents or appropriate insecticidal sprays containing permethrin on
clothing. Travelers should avoid sick or dead animals or rodent nests and burrows, and whenever
possible they should avoid visiting areas that have experienced recent plague epidemics or
epizootics.
Animal fleas vector Y. pestis so control measures should be taken around animals, such as
treating domestic dogs and cats weekly with appropriate insecticides, avoiding direct contact
with sick or dead rodents, handling severely ill cats with extreme caution (these animals should
be examined by a veterinarian), and avoiding rodent nests and burrows. Hunters should always
wear gloves when handling dead animals (Gage et al. 2001).
Y. pestis is designated as a Class I notifiable disease because of its high fatality rate and its
epidemic potential, thus it is subject to International Health Regulations. These regulations
require that all suspected cases be reported to and investigated by public health authorities and
that confirmed cases be reported to the World Health Organization (WHO) in Geneva,
Switzerland.
For more information on transmission, clinical signs, diagnosis, recommended action if plague is
suspected, quarantine and disinfection, please see Factsheet Plague from the Institute for
International Cooperation in Animal Biologics.
2.1 CHEMICAL CONTROL OF FLEA VECTORS FOR PREVENTION OF Y. PESTIS
SPREAD
In North America use of insecticidal dust in rodent burrows to control flea vectors is a common
method used to control spread of Y. pestis, particularly during epizootics. Carbaryl or permethrin
formulations have been used in the past successfully (Barnes et al. 1972; Beard et al. 1992 in
Seery et al. 2003), although permethrin is no longer commercially available.
Seery et al. (2003) tested the effectiveness of deltamethrin, a synthetic pyrethroid similar to
permethrin. It was found to significantly reduce flea populations for at least 84 days following
just one application, and even seemed to suppress an epizootic of plague.
Wilder et al. (2008) highlight the importance of timing when using insecticidal dust to treat
rodent burrows to maximize effectiveness. The two main flea vectors in prairie dogs Oropsylla
hirsuta and O. tuberculata cynomuris reach their peak abundances in March and October
respectively. Thus insecticidal application is likely to be the most effective when times to reduce
the peak times for flea-borne transmission: late February and August-September.
Resistance to deltamethrin has been recorded in a number of vector species, including fleas (e.g.
Bossard et al. 1998 in Wilder et al. 2008). Thus it is important that insecticidal dust is used
carefully, and that colonies are chosen based on risk of plague exposure to humans and
conservation importance (Wilder et al. 2008).
2.2 PLAGUE VACCINES
2.2.1 KILLED WHOLE CELL VACCINES
There are a number of different forms of vaccines against Y. pestis which continue to be
developed. Killed whole cells (KWC) of Y. pestis have been used in plague vaccines as early as
1897 (Titball and Williamson 2001). A formalin-inactivated preparation known as Plague
Vaccine USP was licensed for use in the United States until recently, but was withdrawn in 1999
and is no longer available (Morris 2007). Currently there is another KWC vaccine available but it
is not licensed by the FDA (Morris 2007). “Data from animal and human investigations suggest
that KWC vaccines are effective in preventing or ameliorating bubonic plague, but are not
effective in preventing primary pneumonic plague” (Morris 2007). Killed whole cell vaccines
also have the disadvantage that they often cause significant adverse reactions, particularly after
booster injections, which are needed to maintain protection (Buller 1983 in Smiley 2008).
2.2.2 SUBUNIT BASED VACCINES
Subunit vaccines containing Y. pestis proteins offer great promise for development of safe and
effective protection against plague (Kummer et al. 2008). “For development of a subunit vaccine
to plague, efforts have focused on two primary Y. pestis antigens (Ags), the outer capsule protein
(F1-Ag), which is believed to help avoid phagocytosis and the low calcium response protein
(lcrV) or V-Ag.” Much research is being conducted using these proteins, either in equal
concentrations or as a fusion protein and different variations of these proteins (Cornelius et al.
2008).
Vaccination with recombinant F1 likewise protects mice against aerosolized Y. pestis (Andrews
et al. 1996 in Smiley 2008). “However F1-negative Y. pestis strains exist, so vaccines based
solely on F1 may fail to protect against weaponized pneumonic plague” (Smiley 2008).
Unlike F1, LcrV is critical for virulence. “Vaccination with purified LcrV protects mice against
subcutaneous Y. pestis challenge, as does passive transfer of LcrV-specific antibodies.
Vaccination with recombinant LcrV protects mice against aerosol challenge with either F1positive or F1-negative Y. pestis strains”. However “vaccines based on LcrV alone also may fail
to protect against weaponized pneumonic plague, because pathogenic Yersinia species express
LcrV variants that may not confer crossprotective immunity (Roggenkamp et al. 1997)” (Smiley
2008).
Vaccines containing both F1 and LcrV will be more difficult for Y. pestis to overcome, and
provide better protection than vaccines comprised of just one of these subunits (Williamson et al.
1995; Williamson et al. 1996 in Smiley 2008). A recombinant plague vaccine, rF1V, a fusion of
the Y. pestis F1 capsular and V virulence proteins, was designed developed at the United States
Army Medical Research Institute of Infectious Diseases (USAMRIID). The vaccine has been
demonstrated to protect animals against aerosol challenge (Heath et al. 1998; Powell et al. 2005
in Morris 2007). Preliminary studies suggest that the vaccine is safe, well-tolerated and
immunogenic (Morris 2007). Similarly the United Kingdom’s defense department demonstrated
that an alum formulation of the Y. pestis F1 and LcrV proteins protects mice against pulmonary
Y. pestis challenge (Williamson et al. 1997; Jones et al. 2000 in Smiley 2008).
Although subunit vaccines comprised of F1 and LcrV proteins are well-tolerated and
immunogenic in humans, they cannot be tested for efficacy because of ethical reasons against
intentional infection of humans. These vaccines protect mice and cynomolgus macaques, but
inconsistently do not adequately protect African green monkeys. There is currently no
explanation for this observation, and it is unclear whether F1/LcrV-based vaccines will provide
humans with effective protection as observed with cynomolgus macaques, or the inadequate
protection observed in African green monkeys (Smiley 2008).
“A number of approaches are underway to improve the efficacy of F1/LcrV-based vaccines
(Titball and Williamson 2004). Some researchers are genetically modifying the antigens (Goodin
et al. 2007; DeBord et al. 2006), while others are exploring the use of alternate adjuvants (Jones
et al. 2006; Glynn et al. 2005; Eyles et al. 2000; Honko et al. 2006) and delivery platforms
(Wang et al. 2004; Oyston et al.1995; Titball et al. 1997; Leary et al. 1997; Garmory et al. 2003;
Yang et al. 2007; Palin et al. 2007; Chiuchiolo et al. 2006). These approaches are certainly
promising” (Smiley 2008).
Research has also gone into vaccines for some animal species. Prairie dogs (Cynomys spp.) are
highly susceptible to Y. pestis, and plague outbreaks can totally eliminate colonies. Rocke et al.
(2008-A) determined that groups immunized with recombinant raccoon poxvirus expressing the
F1 antigen of Y. pestis incorporated into a palatable bait had higher survival rates than
unimmunized control group. Vaccines for black-footed ferrets (Mustela nigripes) have also been
developed based on the F1-V fusion protein. The vaccine protects against injection directly with
Y. pestis and also plague contracted via ingestion of infected mice, a probably route for natural
infection (Rocke et al. 2008-B).
2.2.3 LIVE ATTENUATED STRAIN VACCINES
Live attenuated (avirulent) strains of Y. pestis have also been developed for use as vaccines
(Meyer et al. 1974 in Gage et al. 2001). “Vaccines based on live attenuated organisms provide
the theoretical advantage of simultaneously priming immunity against many antigens, thereby
reducing opportunities for circumvention by weapons engineers” (Smiley 2008). However these
vaccines can be unstable and may become virulent, sometimes killing experimental non-human
primate test subjects (Meyer 1970; Meyer et al. 1974; Russell et al. 1995; Welkos et al. 2002 in
Smiley 2008).
“Safety concerns have limited enthusiasm for the development of live attenuated vaccines in the
United States and Europe, where plague is uncommon and the risk of harm may outweigh the
benefits of vaccination. However, live attenuated vaccines were administered to tens of millions
of humans in Indonesia, Madagascar, and Vietnam, apparently without causing any deaths
(Girard 1963)” (Smiley 2008). Currently the live attenuated Y. pestis strain EV76 is still
available for use in Russia (Smiley 2008), but is not licensed by the FDA (Russell et al. 1995;
Titball and Williamson 2001; Titball and Williamson 2004 in Morris 2007).
Recently Blisnick et al. (2008) investigated the possibility of using Yersinia pseudotuberculosis
as an oral live vaccine for Y. pestis. Y. pseudotuberculosis shares high genetic similarity with Y.
pestis as well as being much less virulent, genetically more stable and deliverable orally.
Protection given by Y. pseudotuberculosis Strain IP32680 was high (one inoculation 75%, two
inoculations 88%). Another advantage is that if Y. pseudotuberculosis were to be accidently
released into the environment it would be less problematic that Y. pestis. The final advantage of
an oral inoculation is the avoidance of syringes, which the World Health Organization mentions
as a major source of disease transmission in its vaccination guidelines (WHO 2003 in Blisnick et
al. 2008). The authors conclude that “our results thus validate the concept that an attenuated Y.
pseudotuberculosis strain can be an efficient, inexpensive, safe, and easy-to-produce live vaccine
for oral immunization against bubonic plague.”
However strain IP32680 cannot be used for human vaccination because the causes of its
attenuation are unknown, and thus it could become pathogenic. More research is needed to
develop live attenuated strains of Y. pseudotuberculosis which have defined, irreversible
mutations (Blisnick et al. 2008).
3.0 TREATMENT
“The main limitation of the prevention of plague by vaccination is that protection is delayed for at least 1 week after
immunization, and this time may be crucial with respect to the lethal outcome of the disease (Butler, 1983; Dennis
et al., 1999; Domaradskii, 1993, 1998; Inglesby et al., 2000; Lien-Teh et al., 1936; Naumov & Samoilova, 1992;
Nikolaev, 1972; Perry & Fetherston, 1997; Pollitzer, 1954; Rudnev, 1940). As a consequence, antibiotics are
employed for the early initiation of prophylaxis and therapy of plague” (Anisimov and Amoako 2006).
Diagnosis must be made quickly due to the fast progression of the disease and the high mortality
rate followed by appropriate antibiotic treatment (Eisen et al. 2007-A). An examination of
sputum or a lymph node biopsy will reveal gram-negative, bipolar staining coccobacilli.
In the United States, suspected cases of plague should be reported to state health departments,
which in turn notify the Center for Disease Control (CDC). All cases subsequently confirmed by
laboratory analysis are reported by CDC to WHO.
3.1 HISTORICAL TREATMENT
“Until the nineteenth century, the treatment of plague was based on mysticism and superstition.
Such ‘remedies’ as magic and talismans, mixtures of bird and animal blood, tablets made from
rattlesnake meat, and even material squeezed from fresh horse dung, were widely used
(Afanas’ev & Vaks, 1903). Later, methods such as phlebotomy, emetics, purgatives and
diaphoretics were also applied to plague treatment (Rudnev, 1940). The isolation of the plague
pathogen (Y. pestis), in 1894 (Yersin, 1894) made possible scientific approaches to the cure of
plague infected patients. The local application of antiseptics such as iodine, mercuric chloride,
carbolic acid or quinine, together with the incision or even searing of bubos, were promising in
some cases, as were attempts to surmount severe systemic disease by the use of the same
remedies, specific bacteriophages or animal hyperimmune sera (Lien-Teh et al., 1936; Rudnev,
1940); however, real success in plague therapy was observed when sulfanilamides (Carman,
1938) and then streptomycin (Hornibrook, 1946) became available” (Anisimov and Amoako
2006).
3.2 ANTIBIOTIC TREATMENT
Cases of bubonic plague can often be successfully treated using antibiotic prophylaxis and therapy.
Antibiotics used are usually streptomycin, tetracycline or chloramphenicol (Perry 1997 in Titball
and Williamson 2001), which the World Health Organization Expert Committee on Plague name
as the ‘gold standard’ treatment (Anisimov and Amoako 2006). Treatment must be quick and
aggressive in order to be successful. Antibiotic treatment of septicemic and pneumonic plague is
less successful because the disease develops rapidly, and treatment must begin during the early
stages of infection.
Gage et al. (2001) state that persons suspected of having pneumonic plague should be
maintained under respiratory droplet precautions until 48 hours after antibiotic treatment begins.
Persons who have confirmed cases of pneumonic plague should be kept under droplet
precautions until sputum cultures are negative. Prophylactic antibiotics should be administered to
persons who have had close exposure (6.5 feet or 2 metres) to persons suspected of having
pneumonic plague.
3.3 ALTERNATIVES TO ANTIBIOTICS
Recent detection of antibiotic resistant strains of Y. pestis indicate that antibiotics may not be a
feasible for long-term use to treat plague (Galimand et al. 1997 in Titball and Williamson 2001)
and has led to exploration of alternatives to antibiotics (Anisimov and Amoako 2006). These
include immunotherapy, non-pathogen-specific immunomodulatory therapy, phage therapy,
bacteriocin therapy, and treatment with inhibitors of virulence factors as reviewed in Anisimov
and Amoako (2006).
3.3.1 IMMUNOTHERAPY
Serum therapy has been used since 1896 by A. Yersin and others. Serum therapy involves using
the serum of vaccinated animals to cure infected patients. Treatment of bubonic plague obtained
mildly successful results, but serum therapy is less successful against sepicemic and pneumonic
forms. This type of therapy also frequently caused side effects of serum sickness and
anaphylactic shock. In 1970, the WHO Expert Committee on Plague recommended the
continuation of further development of plague antitoxic sera that might be used for the treatment
of plague patients with severe toxicosis (WHO 1970 in Anisimov and Amoako 2006).
Antibody therapy begun to be developed in the 1960s for preventing and treating infectious
diseases. In contrast to older remedies based on animal sera, these specific immunoglobulins
contained antibodies derived from immunized human donors, rather than animals, and so had
minimal side effects. As well as limitations such as high cost, low availability and potential to
transmit disease; therapy based on a single antibody against a single antigen or epitope will be
ineffective in the case of infection with a virulent strain lacking the antigen or expressing a
different serological variant of the antigen (Anisimov et al. 2004; Friedlander et al. 1995;
Roggenkamp et al. 1997 in Anisimov and Amoako 2006).
3.3.2 NON-PATHOGEN-SPECIFIC IMMUNOMODULATORY THERAPY
“Y.pestis is known to efficiently overcome the innate immune system of many mammals.
However, it has been shown that neutrophils (Cavanaugh & Randall, 1959) and CD11c+ cells
(Bosio et al., 2005), which represent the initial line of host defence against invading pathogens,
play an important role in suppressing the initial replication and dissemination of inhaled Y.
pestis” (Anisimov and Amoako 2006). Recent studies have shown that that granulocyte colony-
stimulating factor, granulocytemacrophage colony-stimulating factor and interferon-c can
augment the functional antimicrobial activities of neutrophils, and may be useful for plague
therapy (Liles 2001 in Anisimov and Amoako 2006).
Y. pestis causes septic shock which includes an inability to regulate the inflammatory response
and is one of the major causes of death (Butler 1983; Dmitrovskii 1994; Van Amersfoort et al.
2003 in Anisimov and Amoako 2006). The group of cholesterol-lowering drugs known as
statins which also have immunomodulatory and anti-inflammatory properties may have use in
plague therapy. Studies show that simvastatin (Merx et al. 2004 in Anisimov and Amoako 2006)
and cerivastatin (Ando et al. 2000 in Anisimov and Amoako 2006) pretreatment improve
survival rates to sepsis.
3.3.3 PHAGE THERAPY
Bacteriophages were first used to treat plague in 1925 by d’Herelle. Four patients with serious plague
infectious were treated effectively by injection of the phage. This work led to a number of attempts to
confirm the efficacy of the phage therapy in animal and clinical trials. However a poor understanding of
phage-bacterial interactions and poorly designed trials led to conflicting results (Skurnik and Strauch
2006; Sulakvelidze, 2005; Summers, 1999, 2001 in Anisimov and Amoako 2006).
Bacteriophages have received renewed attention lately as possible agents against bacterial pathogens. A
number of recent trials have found that phage therapy can be effective, although treatment depends on the
route and frequency of phage application (Skurnik and Strauch 2006; Sulakvelidze, 2005; Summers,
1999, 2001 in Anisimov and Amoako 2006). However there are a number of obstacles to use of phage to
treat plague. These include phage resistance, possibility of phage mediated transfer of genetic material to
bacterial hosts. A number of Y. pestis specific phage genomes have recently been sequenced, which
could provide the basis for a revival in phage therapy for plague.
A safer possibility than using live phage agents is therapeutic use of enzymes extracted from
bacteriophages. A potential class of enzymes is endolysins, which have cell-wall-hydrolysing action
against specific bacteria (Young 1992; Berchieri et al. 1991; Goode et al. 2003 in Anisimov and Amoako
2006).
3.3.4 BACTERIOCIN THERAPY
Bacteriocins are bacterially produced antimicrobial peptides. Purified bacteriocins have potential
to be used for reduction or elimination of pathogens, including plague (Braude and Siemienski;
Riley and Wertz 2002 in Anisimov and Amoako 2006) and many have been successfully used
against pathogens including Streptococcus dysgalactiae and Y. pseudotuberculosis. A purified
bacteriocin NRRL-B- 30509 secreted by Paenibacillus polymyxa has shown to inhibit growth of
Y. pestis in vitro (E. A. Svetoch and B. V. Eruslanov, personal communication in Anisimov and
Amoako 2006) in doses similar to those recommended by the WHO Expert Committee on
Plague (WHO, 1970 in Anisimov and Amoako 2006) for antibiotics. Currently the bacteriocin
Gallidermin shows the most promise as a therapeutic agent, with relatively low cytotoxicity and
potent antimicrobial activities (Maher & McClean, 2006 in Anisimov and Amoako 2006).
3.3.5 INHIBITORS OF VIRULENCE FACTORS
“Microbial factors involved in the process of virulence are unique, in that their inhibition, by
definition, should interfere with the process of infection rather than with bacterial viability.
Inhibitors of such targets would be unlikely to affect host cells, to be cross-resistant to existing
therapies, or to induce resistance themselves. Bacterial virulence may therefore offer unique
opportunities to inhibit the establishment of infection or alter its course as a method of
antimicrobial chemotherapy.” (Alksne, 2002; Lee et al. 2003; Marra, 2004 in Anisimov and
Amoako 2006).
One focus of current research into Y. pestis virulence factors is bacterial adhesins, which are
responsible for adhesion to host surfaces which is a necessary step in successful colonization and
disease production by pathogens. Short-chain oligosaccharides have potential anti-adhesion
therapeutics (Thomas & Brooks 2004 in Anisimov and Amoako 2006). Also Ysc-Yop Type III
weaponry which delivers effector proteins into cytosol of target cells is a major pathogenicity
factor of Yersinia. Inhibitors specifically targeting type III secretion are becoming a research
focus (Chen et al. 2003; Lee et al. 2003, 2005; Kauppi et al. 2003a,b; Nordfelth et al, 2005; Xie
et al. 2004 in Anisimov and Amoako 2006).
“Other possible targets for inhibiting Y. pestis virulence are quorum sensing (Suga & Smith
2003), the two-component regulatory systems (Oyston et al. 2000; Winfield et al. 2005) that
govern virulence, and/or the enzymes for the biosynthesis of the LPS that is believed to
determine antimicrobial-cationic-peptide (Anisimov et al. 2005; Bengoechea et al. 1998) and
serum resistance (Anisimov et al. 2005; Porat et al. 1995)” (Anisimov an Amoako 2006).