Yersinia pestis
In each example which level applies is marked with colour and with (A).
Those with more information and notes can be found in the accordion below each section (Technical feasibility, Public Health value, time scale and cost of development). They are marked with the notepen 
icon.
| Criterion | Low feasibility | Medium feasibility | High feasibility |
|---|---|---|---|
| Provenance of pathogen | No understanding of provenance | Some understanding of provenance, with limited understanding of epidemiology | Known disease, with well understood epidemiology (A)
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| Similarity to known pathogen | Dissimilar, at least in initial analysis, to any known pathogen | From a known family of pathogens | Closely related to a well characterized pathogen (A) |
| Can the pathogen be cultured in a laboratory | Very difficult to culture | Possible to culture, but lengthy and difficult process | Can be cultured (A) |
| Complexity and size of pathogen | Large and complex pathogen | Medium sized pathogen (A) |
Small and simple pathogen |
| Antigenic diversity | High genetic diversity, with high mutation rate and lack of annotated genomic data | Some genetic diversity with moderate mutation rate | Little genetic diversity, with low mutation rate. Large amounts of well annotated genomic data available (A) |
| Biomarkers for safety/efficacy | No understanding of biomarkers for safety or efficacy | Some understanding of biomarkers that may relate to safety/efficacy | Clear understanding of biomarkers for both safety and efficacy (A) |
| Host-immune response | No known cases of natural immunity, and pathogen is immune modulatory | Some cases of natural immunity, but unclear whether this is durable and protective. Pathogen is generally perceived as not being immune modulatory (A) |
Cases of natural immunity which are both durable and protective, pathogen is not immune modulatory, and neutralising antibodies are protective |
| Available model organisms, including human challenge models | Lack of suitable animal model, and/or suitable human challenge model | Suitable animal model and/or suitable human challenge model may require some development | Suitable animal model, and/or suitable human challenge model is available (A) |
Yersinia pestis is the causative agent of plague. Disease dynamics and pathogen provenance is well studied and understood. Previous outbreak epidemiology and current status of disease prevalence is well reported.
Yersinia pestis pathogenicity is well studied due to several pandemics caused by this organism in the past. However, Yersinia pestis is a member of the Enterobacteriaceae and is thought to have evolved from Y. pseudotuberculosis an organism that causes a gastrointestinal illness.
Bacterial culture is highly feasible with Yersinia pestis as it can readily be cultured on blood agar or chocolate agar at 28 ˚C or 37 ˚C. Colony morphology has been described as fried egg in appearance.
The genome of Yersinia pestis was first reported in 2001 from strain CO92 (biovar orientalis). Consists of a 4.65 megabase chromosome and three plasmids of 96.2 kilobase, 70. 3 kb and 9.6 kb. The genome codes for just over 4,000 proteins. Compared to other known bacterial pathogens the size of genome is similar to that of Mycobacterium tuberculosis, an organism with quite a complex disease presentation and resistance to multiple antibiotics. The size is also similar to the well studied Escherichia coli K-12. Certainly the genome of Yersinia pestis would not be described as particularly small and perhaps would be best considered medium to small in size.
To score as highly feasible. The organism should have little genetic diversity with low mutation rate. Alternatively, large amounts of genomic data should be available.
The genome sequence of Yersinia pestis reveals a genome rich in insertion sequences and has anomalies in GC base composition indicating intragenomic recombination. The organism is thought to be a clone of Y. pseudotuberculosis that evolved between 1,500-20,000 years ago and is not considered a bacterium with high antigenic diversity.
In terms of genetic data, the first Yersinia pestis genome sequence strain was published in 2001 from a biovar orientalis, this was followed in 2002 by a medievalis strain, and by the antiqua biovar in 2006.
Currently EBI lists at least 22 genome sequences so there is considerable genomic data available on public databases. Phylogenetic analysis indicates that Yersinia pestis evolved in or near China and spread though multiple radiation in Europe, South America, Africa and Southeast Asia leading to country specific lineages.
Several vaccine trials have been carried out against Yersinia pestis, therefore biomarkers for safety and efficacy are established.
In order for a vaccine to be assembled against a particular organism, there should be reported cases of natural immunity that is both protective and durable. The pathogen must not be immunomodulatory and neutralising antibodies must be protective.
Throughout history Yersinia pestis is thought to have caused 3 pandemics resulting in the deaths of hundreds of millions of people. However, reports exist of bubonic plague victims that survive the disease and appear to develop immunity.
Tests have demonstrated that a neutralizing antibody response to the antigens F1 and LcrV are protective.
However, Yersinia pestis is an intracellular pathogen capable to evading immune responses by injecting effector proteins called Yersinia outer proteins (Yops) to impair cellular functions. Yersinia pestis has also been shown to be able to target and interfere with denditric cells.
Overall it is accepted that Y. pesits exhibits the ability to invade host cells but also to counteract phagocytosis. The organism can modulate and subvert the host immune system.
Available model organisms, including human challenge models
Animal models of infection for Yersinia pestis have been utilised for over 100 years. Included in this are mice, rats, non-human primates as well as utilisation of invertebrate models such as Caenorhabditis elegans and the rat flea Xenopsylla cheopsis.
| Criterion | Low priority | Medium priority | High priority |
|---|---|---|---|
| Infectivity or rate of spread of pathogen |
Rapid spread with high attack rate | Moderate rate of spread and attack rate | Pathogen is poorly transmitted, spread is very slow, and attack rate is low |
| Case fatality rate/disability burden | Low case fatality rate/ disability burden | Moderate case fatality rate/disability burden | High case fatality rate/disability burden (A) |
| Infectivity before symptom onset | Not infectious before the onset of symptoms | May be infectious before the onset of disease | Highly infectious before disease onset (A) |
| Environmental factors | Environmental factors are easily modulated | Moderately difficult to address environmental factors | Environmental factors cannot be modulated (A) |
| Geographical spread | Small isolated pockets of disease | Moderately spread | Large disseminated disease outbreak (A) |
| Target population | Lack of clarity on target population, with the level of prevention that is acceptable/desirable unclear | Some clarity on target population and level of prevention desirable | Clarity on target population and level of prevention desirable (A) |
| Availability of potential alternatives to vaccination | There are good alternatives to vaccination currently available which can be rapidly deployed to control the disease outbreak | Effective alternatives to vaccination could be rapidly developed | Effective alternatives to vaccination are not currently available and are not on the horizon (A) |
For a pathogen to be considered high priority in this category it should be poorly transmitted with very slow rate of spread and low attack rate.
In this category Yersinia pestis historically would be considered low priority*. Transmission is via flea bites or inhalation and person to person spread does occur although rare. Hundreds of millions have died from plague. Current estimates indicate that the disease appears to target all age groups equally and approximately 1,000-2,000 cases annually are reported to the CDC. Clearly however, one cannot rule out that the potential for a pandemic exists.
*In this category notice that under low priority are organisms that have rapid spread and attack rates, one must point out that this is indicated with the caveat that such organisms should be considered low priority unless there is potential to prevent a pandemic by vaccinating populations outside of the affected country.
Plague exists in three forms
- Bubonic plague: fever, headaches, chills and weakness.
- Septicaemic plague: fever, chills, weakness, abdominal pain, shock and bleeding.
- Pneumonic plague: fever, headaches, weakness, pneumoniae, cough with bloody or watery mucous.
The current death rate reported by the CDC is 10% which is in agreement with WHO figures. If untreated the case fatality rate increases to 30-60%. The pneumonic form of the disease is the most serious, 100% fatality if untreated and 50% if treated and is the only form of disease that can spread by aerosol from person to person.
The potential for high case fatality rates, especially if untreated, indicate that a vaccine against Yersinia pestis should be categorised as high priority.
Incubation period:
Published reports indicate two sets of incubation periods depending on the type of plague. Bubonic plague occurs 2 to 6 days after initial infection. Pneumonic plague acquired through inhalation has an incubation period of 1 to 3 days before the person starts to show signs of illness.
Due to this short incubation period Yersinia pestis is categorised as high priority.
The pneumonic form of plague, transmitted via the aerosol route, presents very soon after infection. Potentially as quickly as 24 hrs. This lack of interval between initial infection and disease onset also means that the organism has potential to spread before confirmation of the causative agent can be obtained.
These cannot be modulated easily in the case of Yersinia pestis and as such vaccine development is considered high priority.
The worldwide distribution of the organism has been studied and clearly there is potential for a large disseminated disease outbreak.
Yersinia pestis is relatively well studied epidemiologically. There appears to be no preference for age/gender/race. Therefore the level of coverage required from a Yersinia pestis vaccine would indicate that a vaccine is high priority.
Availability of potential alternatives to vaccination
Antibiotic treatment can reduce the lethality of disease. Pneumonic plague is considered invariably fatal, but with optimal antibiotic treatment this can be reduced to 50%.
However, in 1995 a strain of Yersinia pestis (17/95) was identified in Madagascar that displayed high level resistance of antimicrobial agents. Including all drugs recommended for plague therapy or even prophylaxis. A pandemic caused by such a MDR strain means that vaccine production is high priority.
| Criterion | Low priority | Medium priority | High priority |
|---|---|---|---|
| Available vaccine candidate(s) | No vaccine in development and route map for getting to Phase I trials not yet developed | Promising candidates exist, and means of rapidly developing to Phase I can be identified | Suitable vaccine may be in late stages of development (A) |
Available vaccine candidate(s)
There is no globally approved vaccine against Yersinia pestis.
Several subunit vaccine candidates have been developed using antigens such as F1, LcrV (V-antigen) and YadC.
In addition several live attenuated mutant strains have been tested and shown to have efficacy in animal models, these include strain EV76 or pcm mutants that have varying degrees of efficacy.
Killed whole cell vaccines have also been tested, but several vaccinations are required with adverse effects in 10% of subjects. In addition vaccination with killed vaccine appears to protect against bubonic but not pneumonic disease.
In this category the development of a vaccine against Yersinia pestis must be considered as highly feasible as several options exist, some of which have been tested in animal models and humans.