Vaccines

█ JULI BERWALD

A vaccine is a medical preparation given to a person to provide immunity from a disease. Vaccines use a variety of different substances ranging from dead microorganisms to genetically engineered antigens to defend the body against potentially harmful antigens. Effective vaccines change the immune system by promoting the development of antibodies that can quickly and effectively attack disease causing microorganisms or viruses when they enter the body, preventing disease development.

Vaccine Development

The development of vaccines against diseases including polio, smallpox, tetanus, and measles is considered among one of the great accomplishments of medical science. Researchers are continually attempting to develop new vaccinations against other diseases. In particular, vigorous research into vaccines for Acquired Immune Deficiency Syndrome (AIDS), cancer and Severe Acute Respiratory Syndrome (SARS) is currently underway.

The first successful vaccine was developed from cowpox as a treatment for smallpox. Coined by Louis Pasteur (1822–1895), the etymology of the term vaccine reflects this achievement. It is taken from the Latin for cow ( vacca ) and the word vaccinia, the virus that causes cowpox.

Smallpox. The first effective vaccine developed treated smallpox, a virulent disease that killed thousands of its victims and left thousands of others disfigured. In one of the first forms of inoculation, the ancient Chinese developed a snuff made from powdered smallpox scabs that was blown into the nostrils of uninfected individuals. Some individuals died from the therapy; however, in most cases, the mild infection produced offered protection from later, more serious infection.

In the late 1600s, European peasants employed a similar method of immunizing themselves against smallpox. In a practice referred to as "buying the smallpox," peasants in Poland, Scotland, and Denmark reportedly injected the smallpox virus under the skin to obtain immunity.

Lady Mary Wortley Montague, the wife of the British ambassador to Turkey brought information on immunization back to Europe in the early 1700s. Montague reported that the Turks injected a preparation of smallpox scabs into the veins of susceptible individuals. Those injected generally developed a mild case of smallpox from which they recovered rapidly. Montague convinced King George I to allow trials of the technique on inmates in Newgate Prison. Although some individuals died after receiving the injections, the trials were successful enough that variolation, or the direct injection of smallpox, became accepted medical practice. Variolation also was credited with protecting United States soldiers from smallpox during the Revolutionary War.

Edward Jenner (1749–1823), an English country physician, observed that people who were in contact with cows often developed cowpox, which caused pox sores but was not life threatening. Those people never developed smallpox. In 1796, Jenner tested the hypothesis that cowpox could be used to protect humans against smallpox. He injected a healthy eight-year-old boy with cowpox obtained from a milkmaid's sore. The boy was moderately ill and recovered. Jenner then injected the boy twice with the smallpox virus, and the boy did not get sick.

Modern knowledge of the immune system suggests that the virus that causes cowpox is similar enough to the virus that causes smallpox that the vaccine simulated an immune response to smallpox. Exposure to cowpox antigen stimulated the boy's immune system, producing cells that attacked the original antigen as well as the smallpox antigen. The vaccine also conditioned the immune system to produce antibodies more quickly and more efficiently against future infection by smallpox.

During the two centuries since its development, the smallpox vaccine gained popularity, protecting millions from contracting the disease. In 1979, following a major cooperative effort between nations and several international organizations, world health authorities declared smallpox the only infectious disease to be eradicated from the planet.

Rabies. In 1885 Louis Pasteur (1822–1895) saved the life of Joseph Meister, a nine year old who had been attacked by a rabid dog. Pasteur's series of experimental rabies vaccinations on the boy proved the effectiveness of the new vaccine.

Pasteur's rabies vaccine, the first human vaccine created in a laboratory, was made of an extract gathered from the spinal cords of rabies-infected rabbits. The live virus was weakened by drying over potash. The new vaccination was far from perfect, causing occasional fatalities and temporary paralysis. Individuals had to be injected 14 to 21 times.

The rabies vaccine has been refined many times. In the 1950s, a vaccine grown in duck embryos replaced the use of live virus, and in 1980, a vaccine developed in cultured human cells was produced. In 1998, the newest vaccine technology—genetically engineered vaccines—was applied to rabies. The new DNA vaccine cost a fraction of the regular vaccine. While only a few people die of rabies each year in the United States, more than 40,000 die worldwide, particularly in Asia and Africa. The less expensive vaccine will make vaccination far more available to people in less developed nations.

Polio. In the early 1900s polio was extremely virulent in the United States. At the peak of the epidemic, in 1952, polio killed 3,000 Americans, and 58,000 new cases of polio were reported.

In 1955 Jonas Salk (1914–1995) developed a vaccine for poliomyelitis. The Salk vaccine, a killed virus type, contained the three types of poliovirus that had been identified in the 1940s. In the first year the vaccine was distributed, dozens of cases of polio were reported in individuals who had received the vaccine or had contact with individuals who had been vaccinated. This resulted from an impure batch of vaccine that had not been completely inactivated. By the end of the incident, more than 200 cases had developed and 11 people had died.

In 1961, an oral polio vaccine developed by Albert B. Sabin (1906–1993) was licensed in the United States. The Sabin vaccine, which uses weakened, live polio viruses, quickly overtook the Salk vaccine in popularity in the United States, and is currently administered to all healthy children. Because it is taken orally, the Sabin vaccine is more convenient and less expensive to administer than the Salk vaccine.

Advocates of the Salk vaccine, which is still used extensively in Canada and many other countries, contend that it is safer than the Sabin oral vaccine. No individuals have developed polio from the Salk vaccine since the 1955 incident. In contrast, the Sabin vaccine has a very small but significant rate of complications, including the development of polio. However, there has not been one new case of polio in the United States since 1975, or in the Western Hemisphere since 1991. Though polio has not been completely eradicated, there were only 144 confirmed cases worldwide in 1999.

Influenza. Developing a vaccine against the influenza virus is problematic because the viruses that cause the flu constantly evolve. Scientists grapple with predicting what particular influenza strain will predominate in a given year. When the prediction is accurate, the vaccine is effective. When they are not, the vaccine is often of little help. However, the flu shot has had enough success that pediatricians are now recommending the vaccine for children older than 6 months.

AIDS Vaccine Research

Since the emergence of AIDS in the early 1980s, research for a treatment for the disease has resulted in clinical trials for more than 25 experimental vaccines. These range from whole-inactivated viruses to genetically engineered types. Some have focused on a therapeutic approach to help infected individuals to fend off further illness by stimulating components of the immune system; others have genetically engineered a protein on the surface of HIV to prompt immune response against the virus; and yet others attempted to protect uninfected individuals. The challenges in developing a protective vaccine include the fact that HIV appears to have multiple viral strains and mutates quickly.

In January 1999, a promising study was reported in Science magazine of a new AIDS vaccine created by injecting a healthy cell with DNA from a protein in the AIDS virus that is involved in the infection process. This cell was then injected with genetic material from cells involved in the immune response. Once injected into the individual, this vaccine "catches the AIDS virus in the act," exposing it to the immune system and triggering an immune response. This discovery offers considerable hope for development of an effective vaccine. As of April, 2003, a vaccine for AIDS had not been proven in clinical trials.

Cancer Vaccine Research

Stimulating the immune system is considered key by many researchers seeking a vaccine for cancer. Currently numerous clinical trials for cancer vaccines are in progress, with researchers developing experimental vaccines against cancer of the breast, colon, and lung, among others. Promising studies of vaccines made from the patient's own tumor cells and genetically engineered vaccines have been reported. Other experimental techniques attempt to penetrate the body in ways that could stimulate vigorous immune responses. These include using bacteria or viruses, both known to efficiently circulate through the body, as carriers of vaccine antigens. These bacteria or viruses could be treated or engineered to make them incapable of causing illness.

Vaccine Production

The classic methods for producing vaccines use biological products obtained directly from a virus or a bacteria. Depending on the vaccination, the virus or bacteria is either used in a weakened form, as in the Sabin oral polio vaccine; killed, as in the Salk polio vaccine; or taken apart so that a piece of the microorganism can be used. For example, the vaccine for Streptococcus pneumoniae , which causes pneumonia, uses bacterial polysaccharides, carbohydrates found in bacteria which contain large numbers of monosaccharides, a simple sugar. The different methods for producing vaccines vary in safety and efficiency. In general, vaccines that use live bacterial or viral products are extremely effective when they work, but carry a greater risk of causing disease. This is most threatening to individuals whose immune systems are weakened, such as individuals with leukemia. Children with leukemia are advised not to take the oral polio vaccine because they are at greater risk of developing the disease. Vaccines which do not include a live virus or bacteria tend to be safer, but their protection may not be as great.

The classic types of vaccines are all limited in their dependence on biological products, which often must be kept cold, may have a limited life, and can be difficult to produce. The development of recombinant vaccines—those using chromosomal parts (or DNA) from a different organism—has generated hope for a new generation of man-made vaccines. The hepatitis B vaccine, one of the first recombinant vaccines to be approved for human use, is made using recombinant yeast cells genetically engineered to include the gene coding for the hepatitis B antigen. Because the vaccine contains the antigen, it is capable of stimulating antibody production against hepatitis B without the risk that live hepatitis B vaccine carries by introducing the virus into the blood stream.

DNA vaccines. As medical knowledge has increased—particularly in the field of DNA vaccines—researchers are working towards developing new vaccines for cancer, melanoma, AIDS, influenza, and numerous others. Since 1980, many improved vaccines have been approved, including several genetically engineered (recombinant) types which first developed during an experiment in 1990. These recombinant vaccines involve the use of so-called "naked DNA." Microscopic portions of a virus's DNA are injected into the patient. The patient's own cells then adopt that DNA, which is then duplicated when the cell divides, becoming part of each new cell. Researchers have reported success using this method in laboratory trials against influenza and malaria. These DNA vaccines work from inside the cell, not just from the cell's surface, as other vaccines do, allowing a stronger cell-mediated fight against the disease. Also, because the influenza virus constantly changes its surface proteins, the immune system or vaccines cannot change quickly enough to fight each new strain. However, DNA vaccines work on a core protein, which researchers believe should not be affected by these surface changes.

Vaccination programs. The Children's Vaccine Initiative, supported by the World Health Organization, the United Nations' Children's Fund, and other organizations, are working diligently to make vaccines easier to distribute in developing countries. More than four million people, mostly children, die every year from preventable diseases. Annually, measles kills 1.1 million children worldwide; whooping cough (pertussis) kills 350,000; hepatitis B 800,000; Haemophilus influenzae type b (Hib) 500,000; tetanus 500,000; rubella 300,000; and yellow fever 30,000. Another 8 million die from diseases for which vaccines are still being developed. These include pneumococcal pneumonia (1.2 million); acute respiratory virus infections (400,000), malaria (2 million); AIDS (2.3 million); and rotavirus (800,000). In August 1998, the Food and Drug Administration approved the first vaccine to prevent rotavirus—a severe diarrhea and vomiting infection.

Effective vaccines have limited many of the life-threatening infectious diseases. In the United States, children starting kindergarten are required to be immunized against polio, diphtheria, tetanus, and several other diseases. Other vaccinations are used only by populations at risk, individuals exposed to disease, or when exposure to a disease is likely to occur due to travel to an area where the disease is common. These include influenza, yellow fever, typhoid, cholera, and Hepatitis A and B.

The measles epidemic of 1989 was a graphic display of the failure of many Americans to be properly immunized. A total of 18,000 people were infected, including 41 children who died after developing measles, an infectious, viral illness whose complications include pneumonia and encephalitis. The epidemic was particularly troubling because an effective, safe vaccine against measles has been widely distributed in the United States since the late 1960s. By 1991, the number of new measles cases had started to decrease, but health officials warned that measles remained a threat.

This outbreak reflected the limited reach of vaccination programs. Only 15% of the children between the ages of 16 and 59 months who developed measles between 1989 and 1991 had received the recommended measles vaccination. In many cases parents erroneously reasoned that they could avoid even the minimal risk of vaccine side effects "because all other children were vaccinated."

Nearly all children are immunized properly by the time they start school. However, very young children are far less likely to receive the proper vaccinations. Problems behind the lack of immunization range from the limited health care received by many Americans to the increasing cost of vaccinations. Health experts also contend that keeping up with a vaccine schedule, which requires repeated visits, may be too challenging for Americans who do not have a regular doctor or health provider.

Internationally, the challenge of vaccinating large numbers of people has also proven to be immense. Also, the reluctance of some parents to vaccinate their children due to potential side effects has limited vaccination use. Parents in the United States and several European countries have balked at vaccinating their children with the pertussis vaccine due to the development of neurological complications in a small number of children given the vaccine. Because of incomplete immunization, whooping cough remains common in the United States, with 30,000 cases and about 25 deaths due to complications annually. One response to such concerns has been testing in the United States of a new pertussis vaccine that has fewer side effects.

Vaccines against biological weapons. The United States Centers for Disease Control have identified six diseases that are the most likely to be used in biological weapons. They are smallpox, anthrax, plague, botulism, tularemia and viral hemorrhagic fevers. Vaccines against these diseases are in various stages of development and dissemination.

After smallpox was eradicated from the United States in 1972, vaccination against the disease was discontinued. As a result, there are a substantial number of people in the United States that have never been exposed to the virus. A majority of those vaccinated may have waning immunity because the smallpox vaccine provides a high level of immunity for approximately five years, with declining immunity thereafter. The United States has recently stockpiled enough vaccine to control an outbreak in case of a crisis, and plans are underway to increase vaccine production until stockpiles include enough vaccine to inoculate the entire U.S. population against smallpox.

Anthrax is of particular note as a biological weapon because it is an airborne pathogen that can be used in conjunction with traditional weapons. A vaccine against anthrax has recently been developed and it consists of a series of six subcutaneous injections. Because antibiotics are effective against the disease, the vaccine is currently only administered to populations at high risk, such as military personnel and researchers who handle the bacterium that causes anthrax.

Tularemia is caused by the bacterium Francisella tularensis , which is an extremely infectious airborne pathogen. Tularemia is usually treated with antibiotics, but a vaccine has been developed and the Food and Drug Administration is currently testing it. To date the vaccine has only been administered to laboratory workers who contact the pathogen on a regular basis.

Vaccines against several diseases that are of concern as biological weapons have not yet been developed. Plague is caused by a bacterium Yersina pestis that is often carried by rat mites. Although research is ongoing, there is no vaccine against this disease and one is unlikely to be developed for several years. Botulism is caused by a toxin produced by the bacterium Clostridium botulinum . Although an antitoxin that reduces the severity of the symptoms is available, there is no vaccine against botulism. Viral hemorrhagic fevers are caused by any one of several viruses including Ebola, Marburg, Lassa and Machupo. No vaccine against these pathogens is currently available.

█ FURTHER READING:

BOOKS:

Joellenbeck, L. M., L. L. Zwanziger, J. S. Durch, et al. The Anthrax Vaccine: Is It Safe? Does It Work? Washington, DC: National Academies Press, 2002.

Preston, R. The Demon in the Freezer. New York: Random House, 2002.

PERIODICALS:

Bradley, K. A., J. Mogridge, M. Mourey, et al. "Identification of the Cellular Receptor for Anthrax Toxin." Nature no. 414 (2001): 225–29.

Friedlander, A. M. "Tackling Anthrax." Nature no. 414 (2001): 160–61.

Henderson, D. A. "Smallpox: Clinical and Epidemiologic Features." Emerging Infectious Diseases no. 5 (1999): 537–39.

Rosenthal, S. R., M. Merchlinsky, C. Kleppinger, et al. "Developing New Smallpox Vaccines." Emerging Infectious Diseases no. 7 (2001): 920–26.

ELECTRONIC:

Centers for Disease Control and Prevention. "Smallpox Factsheet: Vaccine Overview." Public Health Emergency Preparedness and Response. December 9, 2002. < http://www.bt.cdc.gov/agent/smallpox/vaccination/facts.asp >(31 December 2002).

Rhode Island Department of Health: Bioterrorism Preparedness Program "History of Biological Warfare and Current Threat." < http://www.healthri.org/environment/biot/history.htm > (March 12, 2003).

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