The Fundamentals of Immunization
The major day-to-day function of the immune response is to protect the body from infection. Exposure to foreign antigens such as infectious agents results in the stimulation of either of two components of the immune system: the humoral (or antibody) immune response or the cellular immune response. Although no clear division exists between these two facets of the immune system, the antibody response deals primarily with organisms such as bacteria that live outside the cell. The cellular response deals primarily with microbes that live within a cell, such as intracellular bacteria or viruses.
A specialized class of white cells called B lymphocytes carries out the production of antibodies. Stimulation of these cells results from a complicated interaction between a variety of cells, including antigen-presenting cells (macrophage and dendritic cells) and both T and B lymphocytes. The response is specific in that each type of T or B cell can interact with only a single antigen. The B cell that produces antibodies against a particular characteristic or shape on the surface of a bacterium reacts only with that particular determinant. In turn, the antibodies secreted by that B cell can interact only with specific determinants.
Antibodies secreted by B cells are themselves inert proteins. A variety of effects can result, however, when an antibody binds to an antigen. The specific results depend on the nature of the antigen. For example, binding of an antibody to a toxin results in the neutralization of that substance. If the antigen is on the surface of a bacterial cell, then the antibody can act as a flag that attracts other chemicals circulating in the blood. The technical term for an antibody bound to a bacterium is opsonin. The antibody-bacterium complex becomes much more likely to be ingested and destroyed by a specialized cell called a phagocyte than if the antibody were not present. Likewise, if the antigen is an extracellular virus particle, binding of the antibody may inhibit the ability of the virus to infect a cell.
The cellular immune system also reacts in a specific manner. A subclass of T lymphocytes called cytotoxic T cells reacts with specific antigenic determinants on the surface of infected cells. When the T cells bind to a target, the result is the local release of toxic chemicals that ultimately kill the target.
The development of vaccines against specific infectious microbial agents resulted in the control or elimination of many diseases caused by these agents. The first formal vaccine developed for the prevention of disease was that used by Edward Jenner against smallpox during the 1790s. Another century passed before the molecular basis for vaccine function began to be understood.
Immunity to an antigen or disease may be induced using either of two methods. If preformed antibodies produced in another human or animal are inoculated into an individual, the result is passive immunity. Passive immunity can be advantageous in that the recipient achieves immunity in a short period of time. For example, if a person has been exposed to a toxin or has come into contact with an infectious agent, passive immunity can provide rapid, short-term protection. However, because the individual does not generate the capacity to produce that antibody, and the preformed antibodies are gradually removed from the body, no long-range protection is achieved.
The stimulation of antibody production through exposure to antigens, such as those found in a vaccine, results in active immunity. Development of effective active immunity requires a time span of several days to several weeks. The immunity is long term, however, often lasting for the life span of the individual. Furthermore, each additional exposure to that same antigen, either through a vaccine booster or through natural exposure, results in a more rapid, greater response than those achieved previously. This increased rate of reaction is referred to as an anamnestic response.
The actual material used in a vaccine is variable, depending on the form of antigen. The earliest vaccine, that used by Jenner against smallpox, consisted of a virus that caused a disease in cattle called cowpox. The word vaccination is itself derived from this use; vacca is the Latin word for cow. While cowpox is distinct from the disease smallpox, the viruses that cause the two diseases contain similar antigenic determinants. Jenner made this observation and exploited the fact that exposure to the cowpox virus results in active immunization against smallpox.
The use of attenuated strains of bacteria or viruses applies the same principle of cross-reaction. Attenuated organisms are mutants that have lost the ability to cause disease but that retain the antigenic character of the virulent strain. The most notable application of attenuation is the Sabin oral poliovirus vaccine (OPV). By testing hundreds of virus isolates for the ability to cause polio in monkeys, Albert Sabin was able to isolate certain strains that did not cause disease. These strains formed the basis for his vaccine. Similar testing resulted in the development of attenuated virus vaccines against a wide variety of agents, including measles, mumps, and rubella. Likewise, the Bacillus Calmette-Guérin (BCG) strain of Mycobacterium tuberculosis serves as a vaccine against the agent that causes tuberculosis. Unfortunately, the latter vaccine does not always result in immunity for the recipient. It generally is not used in the United States but is widely used in countries where tuberculosis is common.
In some cases, the isolation of attenuated strains of microorganisms has proved difficult. For this reason, inactivated or killed microorganisms often serve as the basis for vaccine production. The Salk inactivated poliovirus vaccine represents the best-known example. By treating poliovirus with a solution of the chemical formalin, Jonas Salk was able to inactivate the organism. The virus retained its antigenic potential and served as an effective vaccine. A similar process has resulted in vaccines to protect against other bacterial diseases, such as bubonic plague, cholera, and pertussis (whooping cough), and against viral influenza.
In some cases, the vaccine is directed not against the etiological agent itself but against toxic materials produced by the agent. This is the case with diphtheria and tetanus. The vaccines are produced by treating the diphtheria and tetanus toxins secreted by these bacteria with formalin. The toxoids that result are antigenically similar to the actual toxins and so are able to induce immunity. They are incapable, however, of causing the deleterious effects of the respective diseases.
Only those determinants of a virus or bacterium that stimulate neutralizing antibodies are necessary in most vaccines. For this reason, the use of genetically engineered vaccines was begun in the 1980s. The first example put into use was the production of a vaccine against the hepatitis B virus (HBV). The gene that encodes the surface antigen of HBV was isolated and inserted into a piece of genetic material within the yeast Saccharomyces. The HBV antigen produced by the yeast was purified and subsequently found to be as effective in a vaccine as the whole virus. Since no live virus is involved, there is no danger of an attenuated strain reverting to its virulent parent. Recently, similar technology has been applied to produce vaccines that protect against chickenpox and hepatitis A virus.
History and Major Successes
Since the first use of vaccination by Jenner in the 1790s for the prevention of smallpox, immunization techniques have been developed for protection against most major infectious illnesses. The term vaccination was originally applied to immunization against smallpox, but its definition has long been expanded to include most immunization techniques. The terms vaccination and immunization are used interchangeably, although there are technical differences in their definitions.
The nineteenth-century improvements in public health measures, combined with the passage of laws for compulsory vaccination, resulted in a steady decrease in the number of smallpox cases in the United States and most countries of Europe. Even as late as 1930, however, approximately 49,000 cases were reported in the United States. In the 1950s, large numbers of cases were still being reported in areas of Africa and Asia. At that time, the World Health Organization (WHO) of the United Nations decided on a plan for the elimination of smallpox based on the fact that humans served as the sole reservoir for the smallpox virus; animals are not naturally infected with smallpox. Through the use of mass immunization techniques, the plan was to isolate areas of infection into smaller and smaller pockets.
The plan for the elimination of smallpox developed by WHO ultimately proved completely successful. There are actually two different forms of smallpox. The last known natural case of variola major was reported in Bangladesh in 1974. The last known case of variola minor was reported in Somalia in 1976. Although an outbreak of smallpox resulting from a laboratory accident was reported in Great Britain, there were no additional naturally caused cases of smallpox. In 1978, WHO declared the world to be free of smallpox.
Ironically, the origins of the vaccine in use during this successful campaign are unknown. The original strain of cowpox used by Jenner was lost sometime during the nineteenth century. The strain used in the vaccine during the twentieth century, called vaccinia virus, may have originated from an isolate obtained during the Franco-Prussian War in the 1870s.
Although vaccination was effective in immunizing most persons against smallpox, use of the vaccine itself had some risk. Serious complications were rare but did occasionally occur. With the disappearance of the disease, the need for routine immunization lessened, and, in 1971, compulsory vaccination of children in the United States was discontinued. In 1976, the routine vaccination of hospital employees was discontinued as well. By the 1990s, the only known sites of existence of smallpox virus were freezers in four laboratories. The September 11, 2001, terrorist attacks at the World Trade Center in New York City and at the Pentagon introduced a new era in which the fear of terrorists’ use of biological agents has prompted renewed discussions about the reintroduction of the smallpox vaccine.
The use of vaccines for the elimination of poliomyelitis represents another success story. Although sporadic outbreaks of polio occurred in earlier centuries and probably as long ago as the time of ancient Egypt, the first epidemics appeared in the late nineteenth century. Ironically, this increase in the incidence of polio was caused by improvements in public health. Poliovirus is easily transmitted through a fecal-oral route, but the majority of cases, particularly in young children, are without symptoms, or asymptomatic. With improvements in sanitation, the first exposure to polio was often delayed until later childhood or, as in the case of President Franklin D. Roosevelt, in the adult years. Under these circumstances, the disease is often more severe.
In 1955, the inactivated poliovirus vaccine developed by Salk was introduced for general use; in 1961, Sabin’s oral poliovirus vaccine was licensed for use. By the 1990s, polio had been eliminated from the Western Hemisphere and from developed countries elsewhere. In 2003, WHO developed the Global Polio Eradication Initiative, the purpose of which is both to monitor outbreaks of polio and to address the means of preventing its transmission. Despite setbacks in portions of Asia and Africa, the number of reported cases of polio worldwide was reduced to 350 by 2014, according to WHO data. In 2014, southeast Asia was certified polio-free by the WHO, having reported no cases since 2011; this left Africa and the Middle East the only remaining strongholds of the virus. Since eradication of polio is not complete, the American Academy of Pediatrics (AAP) recommends that children receive immunizations at intervals during their first two years of life and again before starting school. Adults who plan to travel to areas of the world in which polio is found should also be immunized.
The most significant advancement in twentieth-century health care in the United States has been the elimination of most major childhood diseases. In addition to poliovirus immunization, children routinely receive a variety of early immunizations. Measles, mumps, and rubella (MMR) vaccines are first administered in a single preparation at twelve to fifteen months of age. All three contain live attenuated viruses. The measles vaccine was first introduced in 1966 and resulted in a decline in reported measles cases of nearly 99 percent by the 1980s. Beginning about 1986, however, increasing numbers of cases of measles were reported among young adults who had been previously immunized. For this reason, the AAP recommends that children receive a second dose of MMR vaccine prior to entering school, at approximately four to six years of age. Measles was judged to be eradicated in the United States in 2000, but growing antivaccination sentiment caused a resurgence in the disease in the 2010s; in 2014, a twenty-year high of 610 cases of measles was reported.
A series of the diphtheria, pertussis, and tetanus (DTaP) vaccine is administered at two, four, six, and fifteen to eighteen months, with tetanus and diphtheria boosters recommended at ten-year intervals throughout the remainder of a person’s life.
With the elimination of most other major childhood illnesses, Hemophilus influenzae type B infections moved into the dubious position of being among the most significant causes of illness and death among young children. In 1985, a vaccine developed from the outer coat of the bacterium was licensed for use. The vaccine worked poorly in children under the age of two, the major population at risk. Consequently, an improved vaccine was developed and licensed by 1987. The second vaccine consisted of a portion of the bacterial coat of H.
influenzae joined to diphtheria toxoid. Immunization with the vaccine is recommended at two, four, six, and twelve to fifteen months.
Understandings of immunity and immunization grew, and vaccine technology continued to evolve. For example, in 1986, a genetically engineered hepatitis B virus vaccine was developed and licensed. The gene that encodes the virus surface antigen was placed in a small piece of deoxyribonucleic acid (DNA), a plasmid, and inserted into the common baker’s yeast Saccharomyces cerevisiae. The antigen that is produced is used in a three-dose series to immunize individuals at risk for the disease: health care workers, institutional staff, and anyone else who is likely to come into contact with the virus. It is also recommended in all children in an effort to eradicate disease through universal immunization.
Other vaccines developed during the late twentieth century include pneumococcal vaccine, meningococcal vaccine, hepatitis A vaccine, rotavirus vaccine, and varicella (chickenpox) vaccine. All of these have become part of routine immunization in children and adolescents.
Additionally, preparations of some long-standing vaccines have been improved through new technology. For example, live polio virus vaccine (Sabin) proved more effective than the original injectable vaccine (Salk). However, even the attenuated virus rarely caused disease in some vaccine recipients, and successful efforts were undertaken to improve the effectiveness of vaccine made from killed (inactivated) virus; this enhanced inactivated preparation is now in use in the United States. Likewise, pertussis vaccine, which was poorly tolerated in a significant number of children and adults, has been improved, and the new acellular pertussis vaccine preparation is now recommended for both children and adults.
Although routine vaccination of children has virtually eliminated most health-threatening infectious disease from that population, immunization of adults against preventable diseases has not been as successful. It was estimated that in the late twentieth century, between fifty thousand and seventy thousand adults died yearly from diseases that were preventable through immunization, such as pneumococcal pneumonia, influenza, and hepatitis B.
Historically, pneumococcal
pneumonia, caused by the bacterium Streptococcus pneumonia
, has been a killer of adults. In the 1990s, an estimated forty thousand persons, primarily the elderly, died from this disease. The available vaccine is a polysaccharide vaccine, representing serotypes for twenty-three of the major strains of the bacterium. When administered by the age of fifty, the vaccine provides a significant degree of protection against the organism.
Between 1957 and 2005, seasonal influenza outbreaks averaged between ten thousand to twenty-five thousand deaths per year in the United States alone. Two of the epidemics each resulted in more than forty thousand deaths. Most of these deaths were in elderly adults. Although the usefulness of vaccination among the elderly is limited, immunization against influenza will often lessen the severity of the disease, even if it fails to prevent infection. Furthermore, vaccination of large segments of the population, including health care workers, limits the spread of disease within the population and therefore reduces the exposure to susceptible elderly persons and others at risk for complications from influenza.
Shingles is a blistering skin condition caused by a reactivation of the chickenpox virus (varicella zoster, or herpes zoster) that occurs primarily among the elderly. Although it rarely causes death, it can be extremely painful, and the pain may persist long after the lesions heal. When the condition involves the area around they eye, blindness may result. A vaccine against this disease has been developed and is recommended for adults sixty years and older..
Some specialized vaccines are recommended only for international travelers. Both killed injectable and live attenuated oral vaccines against typhoid are licensed. The ease of administration of an oral vaccine has made this form the preferred choice. In addition, vaccines against cholera and yellow fever may be used in appropriate circumstances.
Although active immunization in most circumstances remains the preferred method of protection through vaccination, there are situations in which passive immunization may provide temporary protection. Individuals may be immunosuppressed or lack a functional immune system. This condition may result from infection (acquired immunodeficiency syndrome, or AIDS), medical intervention (chemotherapy), or congenital reasons (severe combined immunodeficiency disease, or SCID). Whatever the cause, active immunization does not develop. In addition, there are circumstances in which the necessary time for the development of immunity through active immunization is not available, such as with exposure to tetanus, hepatitis A or B, or rabies. For passive immunization or replacement therapy in immunodeficiency disorders , immunoglobulin is usually prepared from pools of plasma obtained from large numbers of blood donors. Specific immunoglobulins, directed against specific targets such as rabies or tetanus, are prepared from plasma containing high concentrations of these antibodies.
Perspective and Prospects
The elimination of smallpox represents the classic example in which the efficacy of a vaccine resulted in the eradication of disease. Smallpox was an ancient disease, with origins as early as the twelfth century BCE. It appeared in the Middle East in the sixth century CE, with subsequent dissemination into northern Africa and southern Europe as a result of the Arab invasions from the sixth to the eighth centuries. The disease spread throughout Europe during the Crusades of the eleventh and twelfth centuries and reached the Americas early in the colonial period. It has been estimated that at its peak during the eighteenth century, smallpox killed 400,000 persons each year and caused more than one-third of all cases of blindness. It has also been estimated that smallpox or other diseases that traveled to the Americas with settlers killed approximately 85 percent of the American Indians who died during colonial periods.
The principle of immunization in prevention did not originate with Jenner, the English physician credited with development of the smallpox vaccine in the 1790s. A practice called variolation was well known in China and parts of the Middle East for centuries prior to Jenner. Variolation consisted of the inhalation of dried crust prepared from the pocks obtained from individuals suffering from mild cases of smallpox. A variation involved removing small amounts of fluid from an active smallpox pustule and scratching the liquid into the skin of children. Lady Mary Wortley Montagu, wife of the British ambassador to the Ottoman Empire, introduced the practice of variolation into Great Britain during the early eighteenth century. Use of variolation was empirical; the practice was often successful. The possibility remained, however, that immunization might actually introduce the disease.
Born in 1749, Jenner first became aware of the protective effects of cowpox from the story of a local dairymaid who had been exposed to the disease. After years of study and observation, he became convinced of the story’s validity. In 1796, he immunized an eight-year-old boy with material from a cowpox lesion. No ill effects were seen. Further immunizations supported the theory that cowpox protected against smallpox. Jenner called this material variolae vaccinae. Richard Dunning, a Plymouth physician, in an 1800 analysis of the procedure, was the first to use the term vaccination.
Wider application of the principle of vaccination followed from Louis Pasteur’s studies during the 1870s and 1880s. With his attenuation of the bacterium that caused chicken cholera, Pasteur demonstrated that one could manipulate the virulence of a microorganism. This practice soon led to his development of vaccines against both anthrax and rabies.
The twentieth century saw the development of effective vaccines against most major childhood diseases. Use of the DPT toxoid became routine in the United States about 1945. Development of the oral Sabin vaccine and inactivated Salk vaccines during the 1950s resulted in the complete elimination of poliomyelitis from the Western Hemisphere by the 1990s. The use of genetic engineering, in which only the genes necessary to synthesize specific antigens are used, was first applied to the hepatitis B vaccine. It has also been applied successfully to create vaccines against chickenpox and hepatitis A virus. A vaccine against hepatitis C virus is under development. This technology provides the potential for manufacturing vaccine “cocktails,” or combinations of such genes from a variety of infectious agents in a single vaccine.
Some vaccines have more wide-ranging impact than prevention of infection, as some long-standing viral infections have been shown to cause cancer. This is true of both hepatitis B and hepatitis C, which are implicated in the development of primary hepatocellular carcinoma, the most common form of cancer worldwide.
Another such vaccine is directed against infection by certain strains of the Human papillomavirus (HPV). HPV is most commonly associated with genital warts and is usually transmitted sexually, but it may be spread by hand contact as well. Infection by some strains may lead to the development of cervical cancer. According to WHO, more than 500,000 new cases of cervical cancer are diagnosed annually, and more than 250,000 women die of the disease each year. In 2006, a vaccine called Gardasil, directed against the four most common types of HPV, was licensed. A three-dose regimen is recommended for girls and boys aged eleven and twelve, and may also be given to people aged thirteen through twenty-six who did not receive any or all of the doses when younger.
Several infections that cause a huge burden of illness and death worldwide have so far eluded efforts to create a successful vaccine. Malaria is one example; ebola is another, although following the 2014 epidemic in West Africa, efforts to develop a vaccine were expedited. Attempts to develop a vaccine against AIDS also have proven largely unsuccessful. The mechanism that has been exploited by other vaccines, namely the stimulation of T cells to produce antibodies that protect a recipient, is nonfunctional in AIDS, and successful development of a vaccine against AIDS will require scientific ingenuity.
New infections also have attracted the attention of vaccine researchers. The appearance of a new outbreak of avian influenza in 2003, usually referred to simply as the bird flu, raised new concerns about particularly virulent strains of influenza. The emergence in 2009 of a new strain of influenza, the novel H1N1 strain, raised fears of a pandemic (a worldwide epidemic) and challenged the capacity of the pharmaceutical industry to develop an effective vaccine and to produce enough of it in a short time to immunize the world’s population against an imminent threat. Following these scares, yearly vaccination against emerging strains of influenza began to be encouraged for all individuals over the age of six months, though the success of these vaccinations in preventing flu outbreaks has been variable, as the virus mutates quickly. The emergence of new infections, the threat of bioterrorism, and the unique difficulties posed by some microorganisms remain areas of active investigation in the field of vaccine research and development.
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