“With the exception of safe water, no other modality, not even antibiotics, has had such a major effect on mortality reduction…” (Plotkin)
Immunization is the process whereby a person is made immune or resistant to an infection, typically by the administration of a vaccine. Vaccines are highly regulated, complex biologic products designed to induce a protective immune response both effectively and safely.
Vaccination is the administration of a vaccine to stimulate a protective immune response that will prevent disease in the vaccinated person if contact with the corresponding infectious agent occurs subsequently. Thus vaccination, if successful, results in immunization: the vaccinated person has been immunized. In practice, the terms “vaccination” and “immunization” are often used interchangeably. Immunization is a proven tool for controlling and eliminating and eradicating life threatening infectious diseases and is estimated to avert over 2 million deaths each year. It is considered as one of the most cost-effective health investments. The word “vaccine” comes from the Latin word vaccinus, which means “pertaining to cows.” What do cows have to do with vaccines? The first vaccine was based on the relatively mild cowpox virus, which infected cows as well as people. This vaccine protected people against the related, but much more dangerous, smallpox virus. More than 200 years ago, Edward Jenner, a country physician practicing in England, noticed that milkmaids rarely suffered from smallpox. The milkmaids often did get cowpox, a related but far less serious disease, and they never became ill with smallpox. In an experiment that laid the foundation for modern vaccines, Jenner took a few drops of fluid from a skin sore of a woman who had cowpox and injected the fluid into the arm of a healthy young boy who had never had cowpox or smallpox. Six weeks later, Jenner injected the boy with fluid from a smallpox sore, but the boy remained free of smallpox. Dr. Jenner had discovered one of the fundamental principles of immunization. He had used a relatively harmless foreign substance to evoke an immune response that protected someone from an infectious disease. His discovery eased the suffering of people around the world and eventually led to eradication of small pox, a disease that killed a million people, mostly children. By the beginning of the 20th century, vaccines were in use for diseases that had nothing to do with cows [rabies, diphtheria, typhoid fever, and plague] but the name stuck.
Today, there are many vaccines available to prevent nearly 30 communicable diseases. Indeed, vaccination has become one of the most important preventive health care interventions of all time. Every year millions of children and adults receive vaccinations that protect them from a host of infectious diseases; meanwhile, the arsenal of vaccines is growing rapidly through bio-medical research.
Today all countries have national immunization programmes, and in most developing countries, children under five years are immunized with the standard WHO recommended vaccines that protect against eight diseases – tuberculosis, diphtheria, tetanus (including neonatal tetanus through immunization of mothers), pertussis, polio, measles, hepatitis B, and Hib. These vaccines are preventing more than 2.5 million child deaths globally each year.
A large number of new vaccine products are currently in the pipeline and are expected to become available in coming years. According to recent unpublished data, more than 80 candidate vaccines are in the late stages of clinical testing. About 30 of these candidate vaccines aim to protect against major diseases for which no licensed vaccines exist, such as malaria. If successful, malaria vaccine would be the first vaccine against a parasite that causes disease in humans. About 50 candidate vaccines target diseases for which vaccines already exist, such as pneumococcal disease, Japanese encephalitis, hepatitis A, and cholera: however, these candidates hold the promise of being more effective, more easily administered, and more affordable than the existing vaccines.
Immunity is the ability of the human body to tolerate the presence of material indigenous to the body (“self”), and to eliminate foreign (“non-self”) 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 stimulation of the immune system to produce antigen-specific humoral (antibody) and cellular immunity. Unlike passive immunity, which is temporary, active immunity usually lasts for many years, often for a lifetime. One way to acquire active immunity is to survive infection with the disease-causing form of the organism. In general, once persons recover from infectious diseases, they will have lifelong immunity to that disease. Following exposure of the immune system to an antigen, certain cells (memory B cells) continue to circulate in the blood (and also reside in the bone marrow) for many years. Upon re-exposure to the same antigen, these memory cells begin to replicate and produce antibody very rapidly to re-establish protection.
Another way to produce active immunity is by vaccination. Vaccines interact with the immune system and often produce an immune response similar to that produced by the natural infection, but they do not subject the recipient to the disease and its potential complications. Many vaccines also produce immunologic memory similar to that acquired by having the natural disease.
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 an adjuvant (e.g. aluminum-containing material) added to improve the immunogenicity of the vaccine. Host factors such as age, nutritional factors, genetics, and coexisting disease, may also affect the response.
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 over the time. 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 one year. This type of protection is better against some diseases (e.g. measles, rubella, tetanus) than others (e.g. polio, pertussis).
How does immunization work
There are many types of vaccines, but they all work in the same general way, by preparing the immune system to attack the infection. Basically vaccine contains components that are more or less similar to the infecting organism, and so the immune system responds as it would to an infection with that organism. The most important consequence of successful vaccination is that long lived memory lymphocytes are produced. These respond more quickly and in a more cocoordinated way to subsequent infections so that the infectious microbe is destroyed more quickly. Protection is not always complete, infection may not be prevented but the severity of the illness is usually reduced.
The first exposure to a vaccine stimulates the immune response (known as priming). The immune system takes time to respond to the antigen by producing antibodies and immune cells. Initially immunoglobulin M (IgM) antibody is produced but this is in small amounts and does not bind very strongly to the antigen. After a few days the immune response begins to make immunoglobulin G (IgG) antibody, which is more specific to the microbe. Priming may need more than one dose.
Subsequent administration of the same vaccine stimulates the secondary response. The secondary response is much faster than the primary response and produces predominantly IgG rather than IgM. The aim is to generate enough immune cells and antibodies, specific to the infectious microbe, to provide long lasting protection against the disease.
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
Live vaccines are derived from “wild,” or disease-causing, virus or bacteria. These wild viruses or bacteria are attenuated, or weakened, in a laboratory, usually by repeated culturing. The resulting vaccine organism retains the ability to replicate (grow) in the vaccinated person and produce immunity, but usually does not cause illness. The immune response to a live attenuated vaccine is virtually identical to that produced by a natural infection.
For live vaccines, the first dose usually provides protection. An additional dose is given to ensure seroconversion. For instance, 95% to 98% of recipients will respond to a single dose of measles vaccine. The second dose is given to assure that nearly 100% of persons are immune (i.e., the second dose is “insurance”). Immunity following live vaccines is long-lasting, and booster doses are not necessary, with the exception of oral polio vaccine, which requires multiple doses.
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 HIV infection). Live attenuated vaccines are labile, and can be damaged or destroyed by heat and light. They must be handled and stored carefully.
Currently available live attenuated viral vaccines include measles, mumps, rubella, varicella, yellow fever, oral polio and influenza (intranasal). Live attenuated bacterial vaccines include BCG and oral typhoid vaccine.
Inactivated vaccines are produced by growing viruses or bacteria in culture media and then inactivating them with heat or chemicals (usually formalin). Because they are not alive, they cannot grow in a vaccinated individual and therefore cannot cause the disease, even in an immunodeficient person. Unlike live antigens, inactivated antigens are usually not affected by circulating antibody.
Whole cell, toxoid, subunit, recombinant and conjugate vaccines all come under the category of inactivated vaccines, in that they are non-infectious but retain the ability to stimulate the immune system.
Whole cell vaccines
Growing whole bacteria or viruses (e. g. inactivated influenza or inactivated polio vaccine) in culture media, then treating them with heat and/or chemicals, produces an inactivated, non-viable vaccine.
In some bacterial infections (e.g. diphtheria, tetanus) the clinical manifestations of disease are caused not by the bacteria themselves but by the toxins they secrete. Toxoid vaccines are produced by purifying the toxin and altering it chemically (usually with formaldehyde). While no longer toxic, the toxoid is still capable of inducing a specific immune response protective against the effects of the toxin.
The whole organism is grown in culture media and then the organism is further treated to purify only those components to be included in the vaccine (e.g. acellular pertussis and the meningococcal B vaccine).
For example, the hepatitis B vaccine is made by inserting a segment of the hepatitis B virus gene into a yeast cell. The modified yeast cell produces large amounts of hepatitis B surface antigen, which is purified and harvested and used to produce the vaccine. The recombinant hepatitis B vaccine is identical to the natural hepatitis B surface antigen, but does not contain virus DNA, and is therefore unable to produce infection.
Children under two years of age do not respond well to antigens such as polysaccharides, which produce antibodies via a T-cell independent mechanism. If these polysaccharide antigens are chemically linked (conjugated) to a protein that T-cells recognize, then these conjugate vaccines can elicit strong immune responses and immune memory in young children.
Inactivated vaccines always require multiple doses. In general, the first dose does not produce protective immunity, but only “primes” the immune system. A protective immune response develops after subsequent multiple doses.
In contrast to live vaccines, in which the immune response closely resembles natural infection, the immune response to an inactivated vaccine is mostly humoral. Little or no cellular immunity results. Antibody titers against inactivated antigens diminish with time. As a result, some inactivated vaccines may require periodic supplemental doses to increase, or “boost,” antibody titres. Currently available inactivated vaccines are limited to inactivated whole viral vaccines (influenza, polio, rabies, and hepatitis A), inactivated whole bacterial vaccines (pertussis, typhoid, cholera, and plague), “Fractional” vaccines include subunit,( influenza, acellular pertussis), recombinant (hepatitis B) and toxoids (diphtheria, tetanus).
Other components in vaccines - Excipients
A substance added to a vaccine to enhance the immune response by degree and/ or duration, making it possible to reduce the amount of immunogen per dose or the total number of doses needed to achieve immunity. The commonly used adjuvant are aluminum salts (aluminum hydroxide, aluminum phosphate or potassium aluminum sulfate), which primarily enhance the immune response to proteins. They have been shown to be safe over seven decades of use. Rarely, they may cause injection site reactions, including subcutaneous nodules, sterile abscess, granulomatous inflammation or contact hypersensitivity.
Chemicals (e.g. thimerosal, phenol, 2 phenoxy ethanol) are added to multidose, killed or subunit vaccines in order to prevent serious secondary infections as a result of bacterial or fungal contamination.
Substances other than those already mentioned may be added to vaccines for different purposes such as:
- to support the growth and purification of specific immunogens and/or the inactivation of toxins. These include antibiotics added to prevent contamination during viral cell culture; substances needed for the growth of viruses, such as egg or yeast proteins, glycerol, serum, amino acids and enzymes; and formaldehyde used to inactivate viruses and protein toxins. Most of these reagents are removed in subsequent manufacturing steps, but minute “trace” amounts may remain in the final product. The amounts present are only of consequence for individuals who are allergic to them.
- to confirm product quality or stability, compounds may be added to vaccines for a variety of manufacture-related issues: controlling acidity (pH); stabilizing immunogens through necessary steps in the manufacturing process, such as freeze drying; and preventing immunogens from adhering to the sides of glass vials with a resultant loss in immunogenicity. Examples of such additives include potassium or sodium salts, lactose, polysorbate 20 or 80, human serum albumin and a variety of animal proteins, such as gelatin and bovine serum albumin.
Optimal response to a vaccine depends on multiple factors, including the nature of the vaccine and the age and immune status of the recipient. Recommendations for the age at which vaccines are administered are influenced by age-specific risks for disease, age-specific risks for complications, ability of persons of a certain age to respond to the vaccine, and potential interference with the immune response by passively transferred maternal antibody.
Certain products, including inactivated vaccines, toxoids, recombinant subunit, and polysaccharide conjugate vaccines, require administration of 2 or more doses for development of an adequate and persisting antibody response. Tetanus and diphtheria toxoids require periodic reinforcement or booster doses to maintain protective antibody concentrations.
The simultaneous administration of the most widely used live and inactivated vaccines does not result in decreased antibody responses or increased rates of adverse reaction. Simultaneous administration of all vaccines for which a child is eligible can be very important in childhood vaccination programmes because it increases the probability that a child will be fully immunized at the appropriate age.
Live parenteral (injected) vaccines (measles, rubella, MMR, varicella, and yellow fever) that are not administered simultaneously should be separated by at least 4weeks. This precaution is intended to reduce or eliminate interference from the vaccine given first on the vaccine given later.
Live vaccines administered by a nonparenteral route (OPV, oral typhoid, live attenuated influenza) are not believed to interfere with each other if not given simultaneously. These vaccines may be given at any time before or after each other. All other combinations of two inactivated vaccines or live and inactivated vaccines may be given at any time before or after each other.
Most vaccines in the childhood immunization schedule require two or more doses for stimulation of an adequate and persisting antibody response. Studies have demonstrated that recommended ages and intervals between doses of the same antigen(s) provide optimal protection or have the best evidence of efficacy. Administering doses of a multidose vaccine at shorter than the recommended intervals may interfere with optimal antibody response and protection. Vaccine doses should not be administered at intervals less than the recommended minimal intervals or earlier than the minimal ages.
However, available data indicate that intervals between doses longer than those routinely recommended do not affect seroconversion rate or titre when the schedule was completed. Consequently, it is not necessary to restart the series or add doses of any vaccine due to an extended interval between doses.
Herd immunity (or community immunity) describes a type of immunity that occurs when the vaccination of a portion of the population (or herd) provides protection to unprotected individuals. Herd immunity theory proposes that, in diseases passed from individual to individual, it is more difficult to maintain a chain of infection when large numbers of a population are immune. The higher the proportion of individuals who are immune, the lower the likelihood that a susceptible person will come into contact with an infectious agent. From both theoretical and practical perspectives, disease usually disappears before immunization levels reach 100%, as has been seen with smallpox and poliomyelitis. The proportion of immune individuals in a population above which a disease may no longer persist is the herd immunity threshold. Its value varies with the virulence of the disease, the efficacy of the vaccine, and the contact parameter for the population.
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