Yersinia pestis, a gram-negative bacterium, is the etiological agent for pneumonic and bubonic plague. Plague pandemics have been responsible for millions of deaths throughout human civilization. Current advances in medicine and public awareness have reduced the incidence of continental pandemics, although outbreaks continue to occur on most continents. Isolated bubonic outbreaks usually are contained and treated with antibiotics, namely streptomycin; pneumonic episodes are treated less successfully.

Recent isolation of multiple antibiotic-resistant strains of Y. pestis indicates that the long term potential for the use of antibiotics to treat plague is uncertain (Titball et al. 2001). Live attenuated and killed whole-cell vaccines have been developed for use on humans. Pneumonic infections have been reported in vaccinated individuals, demonstrating ineffective protection against that form of the plague (Williamson et al. 2001). With the continuing incidences of plague throughout the world and the potential use of Y. pestis in bioterorist applications, there is a need for a vaccine that protects against both bubonic and pneumonic plague.

Current studies have led to new vaccine developments using fraction 1 (F1) and LcrV (V) recombinant proteins of Y. pestis. These proteins have been shown to prevent against both pneumonic and bubonic forms. Lcr V and F1 antibodies also are being considered potentially useful for post exposure prophylaxis against plague (Philipovski et al. 2005).

The protein subunit vaccines utilizing virulence factors, F1 and V antigens, are located on the surface of the bacterium. The F1 antigen is a capsular protein with anti-phagocytic properties; the V antigen mediates the delivery of toxins called Yops into the host cells. Yops are involved in capsase activation and macrophage apoptosis (Mota et al., 2005). Once the Yops are injected into the host’s cytoplasm, cytoskeleton functions are disrupted and cellular signals are corrupted. The V antigen has also demonstrated immuno-suppressive properties through the production of interleukin-10. Yersina pestis is primarily encountered by the host immune system’s macrophages; these cells are thought to be potentially important as a site of action for anti-Lcr V antibodies (Philipovski et al. 2005). The F1 and V antigens provide a protective response when used individually. When a combination of these proteins was used, an additive protective effect was noted with immunized mice in challenges with Y. pestis (Titball et al. 2001).

In an animal trial conducted by Williamson et al. (2001), a single dose transcutaneous injection of the combined subunit provided a response at 60 days with high serum titers of IgG, a systemic immune response, increasing until day 89. In a comparative study, animals given a single dose of killed whole-cell vaccine produced a lower anti-F1 IgG titer with no detection of V antibody titers. Subcutaneous and aerosol challenges using an alhydrogel adjuvant system have demonstrated a protective capacity against Y. pestis in the mouse model. Aerosol protection contributed to the induction of the systemic IgG which transudates into the lungs. The presence of F1+V specific IgA in the upper respiratory tract could induce protection from inhalation exposure through a mucosal delivery system (Titball et. al. 2001).

Williamson et al. (2001) reported the first effective microencapsulating vaccine delivery. Individual encapsulations of F1+V antigens were developed into microspheres of a low molecular weight using poly-L-lactide enhanced with mucosal adjuvant cholera toxin B subunit (CTB). The microsphere subunits were immunogenic in mice, inducing both systemic and mucosal immunity at 2 x 105 median lethal dose. Further modifications on the delivery system have developed a microsphere preparation suitable for nasal administration that does not contain CTB.

The principle of the transcutaneous delivery system is that it primes the immune effector cells at the mucosal surface followed by movement of the primed cells via the lymphatic system to “seed” a secondary surface which then induces a protective immune response. Once the microspheres reach the mucosal surface they cross the epithelium by both active sampling and passive diffusion. The active sampling is conducted by M-cells in the nasal and gut mucosas that are linked to local lymph nodes. Soluble antigens in the lumens of the gut and nasal passages will diffuse across the epithelial surface and be phagocytosed by intra-epithelial dendritic cells and transported to draining lymph nodes to induce an immune response (Titball et al. 2001).

Transcutaneous vaccine delivery of Y. pestis vaccine has long-term advantages, reducing the need for intense intervention by medical personnel, and improving the public’s acceptability of the vaccine with the method of the delivery that is needle free. The transcutaneous method of immunization may also be used in conjunction with hypodermal methods as a replacement for one or more booster injections in an immunization regimen (Eyles 2004).

Plague, once a pandemic killer that was feared throughout the Old World, is now only a minor player in world health problems because of modern medical techniques and strict containment and reporting methods of cooperating countries’ public health programs. Continuing developments and advances in modern medicine using immuno-response concepts along with modified delivery systems will further reduce the natural occurrence of plague within human populations as well as reduce the severity of bioterrorism acts on modern society.

References Cited

  1. Eyles, J. E., Elevin, S. J., Westwood, A., Le Butt C. S., Alpar H. O., Somavarapu S., Williamson E. D. 2004. Immunization against plague by transcutaneous and intradermal applications of subunit antigens. Vaccine 22:4356-4373.
  2. Mota, L. J., Journet, L., Sorg, I., Agrain, C., Cornelis, G. 2005. Bacterial injectosomes: needle length does matter. Science 307:1278.
  3. Philipovski, A. V., Cowan, C., Wulff-Strobel, C. R., Burnett, S. H., Kershen, E. J., Cohen, D. A., Kaplan, A. M., Straley, S. C. 2005. Antibody against V antigen prevents yop-dependent growth of Yersina pestis. Infection and Immunity 73:1532-1542.
  4. Titball, R. W., Williamson, E. D. 2001. Vaccination against bubonic and pneumonic plague. Vaccine 19:4175-4184.
  5. Williamson E. D., Eley S. M., Stagg, A. J., Green M., Russel P., Titball, R. W. 2001. A single dose sub-unit vaccine protects against pneumonic plague. Vaccine 19:566-571.