Plague

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Vaccines Have Serious Side Effects

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References to the plague in human history date back to at least 500 B.C., although we don't really know if that plague was the same as the three pandemics that swept Europe and Asia in the Middle Ages, which is what we recognize as plague today. There were several major and many minor pandemics in Europe in the fourteenth through eighteenth centuries. They were deadly. Although we have no precise figures, as many as 200 million people are estimated to have died.

The non-spore-forming bacterium Yersinia pestis has been associated with the European outbreaks, and Y. pestis DNA has actually been extracted from dental remains found in graves of persons dying from the plague. We still see occasional incidents of Y. pestis plague, with several thousand new cases arising annually throughout the world. There have been about 400 cases in the United States since 1950, mostly in the southwest.

Y. pestis can cause several types of disease in humans, depending on how the infection is acquired. Bubonic plague results when a human is bitten by an insect, usually a flea, carrying Y. pestis, which it acquired from previously biting an infected animal. In urban areas, the most common animal carriers are rats and squirrels and the occasional house cat. Y. Pestis can also jump from animal fleas into fleas more at home in humans, which greatly aids human-to-human spread of the disease. In the middle ages, most people had fleas in abundance. Prior to the introduction of antibiotics in the 1940s and 1950s, fatality rates of 50% or more for bubonic plague were not uncommon.

After transmission through a bite, Yersinia bacteria begin to replicate and are swept along to nearby lymph nodes in lymph fluid. At various stages in this journey they may be engulfed by macrophages, but are relatively resistant to being digested by them. A few days later the typical symptoms of a microbial infection set in: fever, chills, and general achiness, byproducts of activation of the innate immune system.

As the bacteria continue to replicate inside the lymph nodes, the nodes become greatly enlarged ("buboes") and very tender. They can grow as much as four inches across. If the bite occurs in the lower part of the body, lymph nodes in the groin are preferentially affected. Bites in the upper body regions tend to deliver bacteria to lymph nodes in the armpit and neck. Untreated mortality rates are around 50% of those infected.

If the bacteria spill out of the lymph nodes and enter the general blood circulation, numerous other tissue compartments become involved and the infection is even more lethal ("septicemic plague"). Blood vessels are destroyed, resulting in gangrene in the extremities. This is probably the origin of the term "Black Death" for plague. Prolonged infection can also trigger shock, a common cause of plague death. If the bacteria invade the lungs (secondary pneumonic plague), the infection is almost always fatal and the bacteria spread more readily from person to person through sneezing and coughing.

Primary pneumonic plague, the second major form of plague, is particularly deadly. It occurs when Y. pestis is taken in directly through the respiratory system as opposed to an insect bite. Untreated mortality rates approach 100%. Symptoms set in within a day or two after inhalation of infectious Y. pestis and are initially indistinguishable from other forms of aggressive pneumonia. Aerosolized Y. pestis and the pneumonic plague that results would likely be the choice of terrorists. Bubonic plague carried by fleas is difficult to spread over a large area and does not pass easily from person to person. Experience in diagnosing and treating pneumonic plague is very limited in the United States. Moreover, many currently used antibiotics have never really been tested against Y. pestis in humans.

The only modern-day use of plague for biological warfare was by the Japanese during occupation of China in World War II, when they released plague-infected fleas onto civilian populations. Both the United States and the Soviet Union pursued development of aerosolized Y. pestis, but these appear never to have been used. Aerosols of course would induce pneumonic plague and could be unbelievably deadly. The WHO estimates that 50 kg of aerosolized Y. pestis spread over an urban population of 5 million would infect at least 150,000 people, causing at least 36,000 deaths.

There have been no documented attempts to use Y. pestis as a bioterrorism agent. However, in 1995, a microbiologist was arrested for fraudulently obtaining large amounts of plague bacteria, with no obvious legitimate scientific purpose. And in 2004, a respected physician-scientist at Texas Tech University was sentenced to two years in prison for grossly mishandling and illegally shipping to Tanzania vials containing infectious Y. pestis—on a commercial airliner, no less! No connection with bioterrorism was alleged or proved.

We know few details of the human immune response to Y. pestis, especially primary pneumonic plague infections, because of the scarcity of cases. Most of our recent insights into human immune responses have never been examined in plague patients. The standard vaccine for many years, based on a whole-cell, killed form of Y. pestis, is no longer used. A second vaccine based on a live but attenuated form of the bacterium induces good protection against bubonic plague but unfortunately little or no protection against pneumonic plague. Producing an effective vaccine for pneumonic plague is an active area of research, driven largely by concern about use of plague for terrorism.

From animal studies we know that in bubonic plague (and we assume in pneumonic plague as well), plague bacteria quickly make contact with host macrophages, dendritic cells, and neutro-phils. But immediately upon contact, the bacteria inject substances into the cells that greatly reduce their phagocytic function. Even for those bacilli that are successfully engulfed, additional substances released inside the cell inhibit degradation of the bacilli and allow them to replicate. Another chemical released while the bacilli are still outside the cell kills off nearby NK cells, a vital component of the early response to viruses. So right off the bat, crucial elements of the innate immune system that otherwise would ordinarily slow the infection, and help kick off an adaptive response, are seriously disabled.

The B-cell response to Y. pestis requires CD4 T-cell help, and CD4 T cells also produce numerous cytokines that help fight the infection. Little is known about the role of CD8 cells in the response. Many Y. pestis bacteria remain extracellular during an infection, but many also manage to replicate within macrophages and perhaps dendritic cells. Whether these intracellular bacteria elicit a protective CD8 response is not known. Many people die without ever mounting an effective antibody or T-cell response

As noted above, currently available vaccines induce a good antibody response that can control bubonic plague but offer little protection against pneumonic plague, which we expect would be the form we would encounter in a terrorist attack. Moreover, these vaccines require multiple injections to be effective, do not give long-lasting immunity without booster shots, and can have numerous undesirable side effects. There is currently an intensive laboratory campaign to develop vaccines effective against pneumonic plague. Hopefully one can be found that acts quickly enough to be of some use during an attack while having acceptable side effects. Several are based on recombinant DNA. Tests on animals look promising, and one of these has recently received Food and Drug Administration (FDA) fast-track approval for human clinical trials.

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