Challenges in the Development of Vaccines for Pneumonic Plague
Inhalation of Yersinia pestis bacilli causes pneumonic plague, a rapidly progressing and exceptionally virulent disease. Extensively antibiotic-resistant Y. pestis strains exist and we currently lack a safe and effective pneumonic plague vaccine. These facts raise concern that Y. pestis may be exploited as a bioweapon. Here, I review the history and status of plague vaccine research and advocate that pneumonic plague vaccines should strive to prime both humoral and cellular immunity.

Plague is an exceptionally virulent, zoonotic infection transmitted naturally from rodent reservoirs to humans via fleas.Yersinia pestis, the disease-causing agent, was first identified by Alexander Yersin in 1894. This Gram-negative, nonmotile bacterium evolved recently from Yersinia pseudotuberculosis, an enteropathogen. Evolution selected for traits that enable Y. pestis to achieve high titers within the mammalian bloodstream, thereby facilitating vector-borne transmission. The spread of Y. pestis is also facilitated by the death of its mammalian hosts, which compels infected fleas to seek new hosts. In endemic areas, plague epizootics periodically decimate susceptible rodent populations. Humans are incidental victims in these deadly cycles.

Flea-borne human infections usually cause bubonic plague. The disease-defining symptom is the bubo, a painful swelling of the lymph nodes draining the fleabite. Without prompt antibiotic treatment, approximately 50% of bubonic plague cases progress to sepsis and death. Up to 30% of fleabites lead directly to sepsis, without prior evidence of a bubo.

Occasionally, bubonic and septicemic infections progress to secondary pneumonic infections. Pneumonic plague allows for direct person-to-person transmission via infectious respiratory droplets. The course of plague in individiuals infected directly by airborne Y. pestis is even more virulent than that which ensues after fleabite. Following an incubation period of 1-6 days, primary pneumonic plague develops very rapidly. Symptoms begin with rigor, severe headache, nausea and malaise. They quickly advance to fever, cough and difficulty breathing. The cough becomes increasingly productive, eventually yielding frothy, infectious, bright red sputum teeming with bacilli. Deaths result from respiratory failure and/or sequelae of severe sepsis, including circulatory collapse, coagulopathy and hemorrhage. Pneumonic plague is nearly always fatal unless treated with antibiotics within 20 h of symptom onset.