Plague: Disease, Management, and Recognition of Act of Terrorism

Anthrax, brucellosis, and plague can result from a mucosal exposure, and each can produce a systemic disease. Next-generation vaccines have adopted mucosal approaches to protect against these diseases, particularly adopting homologous or heterologous vectors for vaccination. In fact, early vaccine development relied on live, attenuated pathogens. In this context, the development of live vaccines for anthrax, brucellosis, and plague are discussed. Some of the first vaccines developed in the mid- to late 19th century focused on the prevention of anthrax in livestock and the development of an immune antiserum for treating plague-infected patients. For each of these diseases, a historical perspective is provided, along with current work using live vector vaccines for mucosal and systemic prophylaxis. This discussion highlights the advantages of mucosal vaccination for protection against systemic diseases.

In the December 2002 issue of Clinical Pediatric Emergency Medicine, Andrew Kienstra and the author addressed the evaluation and management of children exposed to or infected with biological agents of terrorism. This topic had become particularly relevant to pediatricians, emergency physicians, and other front-line health care workers in the United States the previous year, when a child contracted cutaneous anthrax as part of the distribution of anthrax spores to prominent political and media figures via the US Postal Service. The ensuing 11 years have seen an enormous increase in bioterrorism research. This article reviews updates in the detection, diagnosis, and management of the organisms and toxins considered to be at highest risk for bioterrorist use.

In recent decades, the issue of emerging and re-emerging infectious diseases has become an increasingly important area of concern in public health. Today, like centuries ago, infectious diseases confront us with the fear of death and have heavily influenced social behaviors and policy decisions at local, national and international levels.

Remarkably, an infectious disease such as plague, which is disseminated from one country to another mainly by commercial transportation, remains today, as it was in the distant past, a threat for human societies. Throughout history, plague outbreaks prevailed on numerous occasions in Mediterranean harbors, including Marseille in the south of France. A few months ago, the municipal authorities of the city of Marseille, announced the archaeological discovery of the last remnants of a “lazaretto” or “lazaret” (http://20.minutes.fr, March 3th, 2012), a place equipped with an infirmary and destined to isolate ship passengers quarantined for health reasons. More recently, on September 16th, 2012, the anchor of the ship “Grand Saint Antoine” responsible for bringing the plague to Marseille in 1720, was recovered and it will be restored before being presented to the public in 2013 (http://www.libemarseille.fr/henry/2012/09/lancre-du-bateau-qui-amena-la-grande-peste-%C3%A0-marseille.html).

In the light of these recent archaeological discoveries, it is quite instructive to revisit the sequence of events and decisions that led to the outbreak of the Great Plague of Marseille between 1720 and 1723. It comes to the evidence that although the threat was known and health surveillance existed with quite effective preventive measures such as quarantine, the accumulation of small negligence led to one of the worst epidemics in the city (about 30% of casualties among the inhabitants). This is an excellent model to illustrate the issues we are facing with emerging and re-emerging infectious diseases today and to define how to improve biosurveillance and response tomorrow. Importantly, the risk of plague dissemination by transport trade is negligible between developed countries, however, this risk still persists in developing countries. In addition, the emergence of antibiotic resistant strains of Yersinia pestis, the infectious agent of plague, is raising serious concerns for public health.

The chemokine, lymphotactin (LTN), was tested as a molecular adjuvant using bicistronic DNA vaccines encoding the protective Yersinia capsular (F1) antigen and virulence antigen (V-Ag) as a F1-V fusion protein. The LTN-encoding F1-V or V-Ag vaccines were given by the intranasal (i.n.) or intramuscular (i.m.) routes, and although serum IgG and mucosal IgA antibodies (Abs) were induced, F1-Ag boosts were required for robust anti-F1-Ag Abs. Optimal efficacy against pneumonic plague was obtained in mice i.m.-, not i.n.-immunized with these DNA vaccines. These vaccines stimulated elevated Ag-specific Ab-forming cells and mixed Th cell responses, with Th17 cells markedly enhanced by i.m. immunization. These results show that LTN can be used as a molecular adjuvant to enhance protective immunity against plague.

Pneumonic plague remains problematic in endemic areas, and because it can be readily transmitted and has high mortality, the development of efficacious vaccines is warranted. To test whether stimulation of cell-mediated immunity with IL-12 will improve protective immunity against plague, we constructed two IL-12 DNA vaccines using a bicistronic plasmid encoding the protective plague epitopes, capsular (F1) antigen and virulence antigen (V-Ag) as F1-V fusion protein and V-Ag only, respectively. When applied intramuscularly, antibody responses to F1- and V-Ag were detectable beginning at week 6 after 3 weekly doses, and F1-Ag protein boosts were required to induce elevated Ab responses. These Ab responses were supported by mixed Th cell responses, and the IL-12/V-Ag DNA vaccine showed greater cell-mediated immune bias than IL-12/F1-V DNA vaccine. Following pneumonic challenge, both IL-12 DNA vaccines showed similar efficacy despite differences in Th cells simulated. These results show that IL-12 can be used as a molecular adjuvant to enhance protective immunity against pneumonic plague.

The terrorist attacks on the United States in 2001 and the anthrax release soon after brought the issue of bioterrorism to the forefront in the medical community. Bioterrorism is the use of a biologic weapon to create terror and panic. Biologic weapons, or bioweapons, can be bacteria, fungi, viruses, or biologic toxins. Because the emergency department represents the front line of defense for the recognition of agents of bioterrorism, it is essential that emergency physicians have the ability to quickly diagnose victims of bioterrorism. This review examines the most deadly and virulent category A agents of bioterrorism, that is, anthrax, smallpox, plague, botulism, hemorrhagic fever viruses, and tularemia. The focus is on epidemiology, transmission, clinical manifestations, diagnosis, and treatment.