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Principles of Vaccination
Immunology and Vaccine-Preventable
Diseases
Immunology is a complicated subject, and a detailed discussion of it is beyond the scope of this text. However, an understanding of the basic function of the immune system is useful in order to understand both how vaccines work and the basis of recommendations for their use. The description that follows is simplified. Many excellent immunology textbooks are available to provide additional detail.
Immunity is the ability of the human body to tolerate the presence of material indigenous to the body (“self”), and to eliminate foreign (“nonself”) material. This discriminatory ability provides protection from infectious disease, since most microbes are identified as foreign by the immune system. Immunity to a microbe is usually indicated by the presence of antibody to that organism. Immunity is generally very specific to a single organism or group of closely related organisms. There are two basic mechanisms for acquiring immunity, active and passive.
Active immunity is protection that is produced by the person’s own immune system. This type of immunity is usually permanent.
Passive immunity is protection by products produced by an animal or human and transferred to another human, usually by injection. Passive immunity often provides effective protection, but this protection wanes (disappears) with time, usually within a few weeks or months.
The immune system is a complex system of interacting cells whose primary purpose is to identify foreign (“nonself”) substances referred to as antigens. Antigens can be either live (such as viruses and bacteria) or inactivated. The immune system develops a defense against the antigen. This defense is known as the immune response and usually involves the production of protein molecules, called antibodies (or immunoglobulins), and of specific cells (also known as cell-mediated immunity ) whose purpose is to facilitate the elimination of foreign substances.
The most effective immune responses are generally produced in response to a live antigen. However, an antigen does not necessarily have to be alive, as occurs with infection with a virus or bacterium, to produce an immune response. Some proteins, such as hepatitis B surface antigen, are easily recognized by the immune system. Other material, such as polysaccharide (long chains of sugar molecules that make up the cell wall of certain bacteria) are less effective antigens, and the immune response may not provide as good protection.
1 Passive Immunity
Passive immunity is the transfer of antibody produced by one human or other animal to another. Passive immunity provides protection against some infections, but this protection is temporary. The antibodies will degrade during a period of weeks to months, and the recipient will no longer be protected.
The most common form of passive immunity is that which an infant receives from its mother. Antibodies are transported across the placenta during the last 1–2 months of pregnancy. As a result, a full-term infant will have the same antibodies as its mother. These antibodies will protect the infant from certain diseases for up to a year. Protection is better against some diseases (e.g., measles, rubella, tetanus) than others (e.g., polio, pertussis).
Virtually all types of blood products contain antibody. Some products (e.g., washed or reconstituted red blood cells) contain a relatively small amount of antibody, and some (e.g., intravenous immune globulin and plasma products) contain a large amount.
In addition to blood products used for transfusion (e.g., whole blood, red cells, and platelets) there are three major sources of antibody used in human medicine. These are homologous pooled human antibody, homologous human hyperimmune globulin, and heterologous hyperimmune serum.
Homologous pooled human antibody is also known as immune globulin. It is produced by combining (pooling) the IgG antibody fraction from thousands of adult donors in the United States. Because it comes from many different donors, it contains antibody to many different antigens. It is used primarily for postexposure prophylaxis for hepatitis A and measles.
Homologous human hyperimmune globulins are antibody products that contain high titers of specific antibody. These products are made from the donated plasma of humans with high levels of the antibody of interest. However, since hyperimmune globulins are from humans, they also contain other antibodies in lesser quantities. Hyperimmune globulins are used for postexposure prophylaxis for several diseases, including hepatitis B, rabies, tetanus, and varicella.
Heterologous hyperimmune serum is also known as antitoxin. This product is produced in animals, usually horses (equine), and contains antibodies against only one antigen. In the United States, antitoxin is available for treatment of botulism and diphtheria. A problem with this product is serum sickness, a reaction to the horse protein.
Many factors may influence the immune response to vaccination. These include the presence of maternal antibody, nature and dose of antigen, route of administration, and the presence of adjuvants (e.g., aluminum-containing materials added to improve the immunogenicity of the vaccine). Host factors such as age, nutritional factors, genetics, and coexisting disease, may also affect the response.
Classification of Vaccines
There are two basic types of vaccines: live attenuated and inactivated. The characteristics of live and inactivated vaccines are different, and these characteristics determine how the vaccine is used.
Live attenuated vaccines are produced by modifying a disease-producing (“wild”) virus or bacterium in a laboratory. The resulting vaccine organism retains the ability to replicate (grow) and produce immunity, but usually does not cause illness. The majority of live attenuated vaccines available in the United States contain live viruses. However, two live attenuated bacterial vaccines are also available.
Inactivated vaccines can be composed of either whole viruses or bacteria, or fractions of either. Fractional vaccines are either protein-based or polysaccharide-based. Protein- based vaccines include toxoids (inactivated bacterial toxin) and subunit or subvirion products. Most polysaccharide-based vaccines are composed of pure cell wall polysaccharide from bacteria. Conjugate polysaccharide vaccines are those in which the polysaccharide is chemically linked to a protein. This linkage makes the polysaccharide a more potent vaccine.
Live Attenuated Vaccines Live vaccines are derived from “wild,” or disease-causing, viruses or bacteria. These wild viruses or bacteria are attenuated, or weakened, in a laboratory, usually by repeated culturing. For example, the measles vaccine used today was isolated from a child with measles disease in 1954. Almost 10 years of serial passage using tissue culture media was required to transform the wild virus into vaccine virus.
The more similar a vaccine is to the disease-
causing form of the organism, the better the
immune response to the vaccine.
General Rule
To produce an immune response, live attenuated vaccines must replicate (grow) in the vaccinated person. A relativ ely small dose of virus or bacteria is administered, which replicates in the body and creates enough of the organism to stimulate an immune response. Anything that either damages the live organism in the vial (e.g., heat, light) or interferes with replication of the organism in the body (circulating antibody) can cause the vaccine to be ineffective.
Although live attenuated vaccines replicate, they usually do not cause disease such as may occur with the “wild” form of the organism. When a live attenuated vaccine does cause “disease,” it is usually much milder than the natural disease and is referred to as an adverse reaction.
The immune response to a live attenuated vaccine is virtually identical to that produced by a natural infection. The immune system does not differentiate between an infection with a weakened vaccine virus and an infection with a wild virus. Live attenuated vaccines are usually effective with one dose, except those administered orally.
Live attenuated vaccines may cause severe or fatal reactions as a result of uncontrolled replication (growth) of the vaccine virus. This only occurs in persons with immunodeficiency (e.g., from leukemia, treatment with certain drugs, or human immunodeficiency virus (HIV) infection).
A live attenuated vaccine virus could theoretically revert to its original pathogenic (disease-causing) form. This is known to happen only with live (oral) polio vaccine.
Active immunity from a live attenuated vaccine may not develop because of interference from circulating antibody to the vaccine virus. Antibody from any source (e.g., transplacental, transfusion) can interfere with growth of the vaccine organism and lead to poor response or no response to the vaccine (also known as vaccine failure). Measles vaccine virus seems to be most sensitive to circulating antibody. Polio and rotavirus vaccine viruses are least affected.
Live attenuated vaccines are fragile and can be damaged or destroyed by heat and light. They must be handled and stored carefully.
Currently available live attenuated viral vaccines are measles, mumps, rubella, vaccinia, varicella, yellow fever, and influenza (intranasal). Oral polio vaccine is a live viral vaccine but is no longer available in the United States. A new live recombinant rotavirus vaccine may be licensed in the future. Live attenuated bacterial vaccines are bacille Calmette-Guérin (BCG) and oral typhoid vaccine.
The immune response to a pure polysaccharide vaccine is typically T-cell independent, which means that these vaccines are able to stimulate B cells without the assistance of T-helper cells. T-cell–independent antigens, including polysaccharide vaccines, are not consistently immunogenic in children younger than 2 years of age. Young children do not respond consistently to polysaccharide antigens, probably because of immaturity of the immune system.
Repeated doses of most inactivated protein vaccines cause the antibody titer to go progressively higher, or “boost.” This is not seen with polysaccharide antigens; repeat doses of polysaccharide vaccines do not cause a booster response. Antibody induced with polysaccharide vaccines has less functional activity than that induced by protein antigens. This is because the predominant antibody produced in response to most polysaccharide vaccines is IgM, and little IgG is produced.
In the late 1980s, it was discovered that the problems noted above could be overcome through a process called conjugation, in which the polysaccharide is chemically combined with a protein molecule. Conjugation changes the immune response from T-cell independent to T-cell dependent, leading to increased immunogenicity in infants and antibody booster response to multiple doses of vaccine.
The first conjugated polysaccharide vaccine was for Hib. A conjugate vaccine for pneumococcal disease was licensed in 2000. A meningococcal conjugate vaccine was licensed in 2005.
Recombinant Vaccines
Vaccine antigens may also be produced by genetic engineering technology. These products are sometimes referred to as recombinant vaccines. Three genetically engineered vaccines are currently available in the United States. Hepatitis B vaccines are produced by insertion of a segment of the hepatitis B virus gene into the gene of a yeast cell. The modified yeast cell produces pure hepatitis B surface antigen when it grows. Live typhoid vaccine (Ty21a) is Salmonella Typhi bacteria that have been genetically modified to not cause illness. Live attenuated influenza vaccine has been engineered to replicate effectively in the mucosa of the nasopharynx but not in the lungs.
1 Selected References
Ada G. The immunology of vaccination. In: Plotkin SA, Orenstein WA. Vaccines. 4th ed. Philadelphia, PA: Saunders, 2003:31–45.
