The bubonic plague, caused by the bacterium Yersinia pestis, is a disease with profound historical significance, having triggered the devastating Black Death pandemic in the 14th century. While modern antibiotics like streptomycin and gentamicin have dramatically reduced the mortality rate of plague cases today, the question of a vaccine remains complex. The initial development of vaccines for plague began over a century ago, yet a universally safe and effective option for general public use has proved elusive. The landscape involves older, imperfect vaccines and new research efforts driven by both public health and national security concerns.
Defining the Modern Need for a Plague Vaccine
Despite effective antibiotic treatment, the need for a protective plague vaccine persists due to several modern threats. The bacteria Yersinia pestis remains endemic in natural reservoirs across multiple continents, including parts of Africa, Asia, the Americas, and the Indian subcontinent. Countries like Madagascar, the Democratic Republic of Congo, and Peru regularly report human cases, demonstrating the ongoing public health challenge in these areas.
The specter of antibiotic resistance also creates a demand for prophylaxis, as drug-resistant strains of Yersinia pestis have been isolated, raising concerns about treatment failure. Furthermore, plague is classified as a Tier 1 biological agent by health authorities because of its potential for weaponization. An intentional aerosol release could cause pneumonic plague, which is highly contagious and rapidly fatal, making a protective vaccine a significant biodefense measure.
The History of Early Vaccine Development
The first widely used plague vaccine was developed by Waldemar Haffkine in 1897, consisting of a heat-killed whole-cell preparation of Yersinia pestis. This early vaccine was utilized in mass inoculation campaigns and was estimated to reduce mortality from bubonic plague by a significant percentage. However, the Haffkine vaccine came with considerable drawbacks, including severe adverse reactions such as fever and malaise in a majority of recipients.
Later, a more refined killed whole-cell vaccine, using formalin to inactivate the bacteria, was licensed and became the standard in the mid-20th century. This vaccine showed evidence of protecting against the bubonic form of the disease. A major limitation of all these early killed-cell vaccines was their poor efficacy against the rapidly progressing pneumonic plague, the form that spreads easily from person to person.
The severe side effects, which included headache, fever, and significant pain at the injection site, led to a decline in their acceptance and use. Separately, live-attenuated vaccines, which use a weakened form of the bacteria, were developed and used in countries like the former Soviet Union and China. Although some live vaccines demonstrated high efficacy, they also posed safety concerns, including the potential for severe reactions and, in some animal models, lethality, which limited their international adoption.
Current Status and Usage of Licensed Vaccines
Currently, there is no plague vaccine licensed by the Food and Drug Administration (FDA) for general public use in the United States. The killed whole-cell vaccine previously used in the US was discontinued and is no longer available. Certain older vaccines, often of the live-attenuated type, are still used in specific plague-endemic regions, such as parts of Asia and the former Soviet Union.
These remaining licensed vaccines are generally reserved for populations at extremely high risk of exposure. Such groups include laboratory personnel who regularly work with the Yersinia pestis bacterium, and military personnel deploying to regions where plague is highly endemic. Even where these older vaccines are used, they are known to have limitations, including the need for multiple booster shots to maintain protection.
New Directions in Plague Vaccine Research
Modern plague vaccine development has shifted away from the reactogenic whole-cell preparations toward subunit vaccines. This approach focuses on using only specific, highly protective protein components of the bacterium, primarily the Fraction 1 (F1) capsular antigen and the V antigen (LcrV). The goal is to create a vaccine that induces a strong immune response with significantly fewer side effects.
Combining the F1 and V antigens, often as a recombinant fusion protein (rF1-V), has shown promise in animal models by providing protection against both bubonic and pneumonic plague. Additionally, researchers are exploring the development of new live-attenuated strains using precise genetic engineering to remove virulence factors, aiming for a safer and more stable product. Some candidates involve using an established vaccine vector, such as an attenuated typhoid strain, to deliver the plague antigens. These next-generation vaccines are designed to elicit a stronger cellular immune response, which is considered necessary for robust protection against the respiratory form of the disease.