Immunization

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Dr. Schreiber of San Augustine giving a typhoid inoculation at a rural school, San Augustine County, Texas. Transfer from U.S. Office of War Information, 1944. Typhoid inoculation2.jpg
Dr. Schreiber of San Augustine giving a typhoid inoculation at a rural school, San Augustine County, Texas. Transfer from U.S. Office of War Information, 1944.
A child being immunized against polio. Poliodrops.jpg
A child being immunized against polio.

Immunization, or immunisation, is the process by which an individual's immune system becomes fortified against an agent (known as the immunogen).

Immune system A biological system that protects an organism against disease

The immune system is a host defense system comprising many biological structures and processes within an organism that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from the organism's own healthy tissue. In many species, the immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity. In humans, the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–brain barriers separate the peripheral immune system from the neuroimmune system, which protects the brain.

Antigen molecule capable of inducing an immune response (to produce an antibody) in the host organism

In immunology, antigens (Ag) are structures specifically bound by antibodies (Ab) or a cell surface version of Ab ~ B cell antigen receptor (BCR). The terms antigen originally described a structural molecule that binds specifically to an antibody only in the form of native antigen. It was expanded later to refer to any molecule or a linear molecular fragment after processing the native antigen that can be recognized by T-cell receptor (TCR). BCR and TCR are both highly variable antigen receptors diversified by somatic V(D)J recombination. Both T cells and B cells are cellular components of adaptive immunity. The Ag abbreviation stands for an antibody generator.

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When this system is exposed to molecules that are foreign to the body, called non-self, it will orchestrate an immune response, and it will also develop the ability to quickly respond to a subsequent encounter because of immunological memory. This is a function of the adaptive immune system. Therefore, by exposing an animal to an immunogen in a controlled way, its body can learn to protect itself: this is called active immunization.

Molecule Electrically neutral entity consisting of more than one atom (n > 1); rigorously, a molecule, in which n > 1 must correspond to a depression on the potential energy surface that is deep enough to confine at least one vibrational state

A molecule is an electrically neutral group of two or more atoms held together by chemical bonds. Molecules are distinguished from ions by their lack of electrical charge. However, in quantum physics, organic chemistry, and biochemistry, the term molecule is often used less strictly, also being applied to polyatomic ions.

Immunological memory is the ability of the immune system to quickly and specifically recognize an antigen that the body has previously encountered and initiate a corresponding immune response. Generally these are secondary, tertiary and other subsequent immune responses to the same antigen. Immunological memory is responsible for the adaptive component of the immune system, special T and B cells — the so-called memory T and B cells. Immunological memory is the basis of vaccination.

Adaptive immune system subsystem of the overall immune system that is composed of highly specialized, systemic cells and processes that eliminate pathogens or prevent their growth

The adaptive immune system, also known as the acquired immune system or, more rarely, as the specific immune system, is a subsystem of the overall immune system that is composed of highly specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates. Acquired immunity creates immunological memory after an initial response to a specific pathogen, and leads to an enhanced response to subsequent encounters with that pathogen. This process of acquired immunity is the basis of vaccination. Like the innate system, the acquired system includes both humoral immunity components and cell-mediated immunity components.

The most important elements of the immune system that are improved by immunization are the T cells, B cells, and the antibodies B cells produce. Memory B cells and memory T cells are responsible for a swift response to a second encounter with a foreign molecule. Passive immunization is direct introduction of these elements into the body, instead of production of these elements by the body itself.

T cell Type of lymphocyte.

A T cell, or T lymphocyte, is a type of lymphocyte that plays a central role in cell-mediated immunity. T cells can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T-cell receptor on the cell surface. They are called T cells because they mature in the thymus from thymocytes. The several subsets of T cells each have a distinct function. The majority of human T cells, termed alpha beta T cells, rearrange their alpha and beta chains on the cell receptor and are part of the adaptive immune system. Specialized gamma delta T cells,, have invariant T-cell receptors with limited diversity, that can effectively present antigens to other T cells and are considered to be part of the innate immune system.

B cell Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Additionally, B cells present antigen and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ..

Antibody large Y-shaped protein produced by B-cells, used by the immune system; large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein produced mainly by plasma cells that is used by the immune system to neutralize pathogens such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen, via the fragment antigen-binding (Fab) variable region. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize its target directly. Depending on the antigen, the binding may impede the biological process causing the disease or may activate macrophages to destroy the foreign substance. The ability of an antibody to communicate with the other components of the immune system is mediated via its Fc region, which contains a conserved glycosylation site involved in these interactions. The production of antibodies is the main function of the humoral immune system.

Immunization is done through various techniques, most commonly vaccination. Vaccines against microorganisms that cause diseases can prepare the body's immune system, thus helping to fight or prevent an infection. The fact that mutations can cause cancer cells to produce proteins or other molecules that are known to the body forms the theoretical basis for therapeutic cancer vaccines. Other molecules can be used for immunization as well, for example in experimental vaccines against nicotine (NicVAX) or the hormone ghrelin in experiments to create an obesity vaccine.

Vaccination administration of a vaccine to protect against disease

Vaccination is the administration of a vaccine to help the immune system develop protection from a disease. Vaccines contain a microorganism in a weakened or killed state, or proteins or toxins from the organism. In stimulating the body's adaptive immunity, they help prevent sickness from an infectious disease. When a sufficiently large percentage of a population has been vaccinated, herd immunity results. The effectiveness of vaccination has been widely studied and verified. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the elimination of diseases such as polio, measles, and tetanus from much of the world.

Microorganism microscopic living organism

A microorganism, or microbe, is a microscopic organism, which may exist in its single-celled form or in a colony of cells.

Disease abnormal condition negatively affecting organisms

A disease is a particular abnormal condition that negatively affects the structure or function of part or all of an organism, and that is not due to any external injury. Diseases are often construed as medical conditions that are associated with specific symptoms and signs. A disease may be caused by external factors such as pathogens or by internal dysfunctions. For example, internal dysfunctions of the immune system can produce a variety of different diseases, including various forms of immunodeficiency, hypersensitivity, allergies and autoimmune disorders.

Immunizations are often widely stated as less risky and an easier way to become immune to a particular disease than risking a milder form of the disease itself. They are important for both adults and children in that they can protect us from the many diseases out there. Immunization not only protects children against deadly diseases but also helps in developing children's immune systems. [1] Through the use of immunizations, some infections and diseases have almost completely been eradicated throughout the United States and the World. One example is polio. Thanks to dedicated health care professionals and the parents of children who vaccinated on schedule, polio has been eliminated in the U.S. since 1979. Polio is still found in other parts of the world so certain people could still be at risk of getting it. This includes those people who have never had the vaccine, those who didn't receive all doses of the vaccine, or those traveling to areas of the world where polio is still prevalent.

Active immunization/vaccination has been named one of the "Ten Great Public Health Achievements in the 20th Century".

History

Before the introduction of vaccines, people could only become immune to an infectious disease by contracting the disease and surviving it. Smallpox (variola) was prevented in this way by inoculation, which produced a milder effect than the natural disease. The first clear reference to smallpox inoculation was made by the Chinese author Wan Quan (1499–1582) in his Douzhen xinfa (痘疹心法) published in 1549. [2] In China, powdered smallpox scabs were blown up the noses of the healthy. The patients would then develop a mild case of the disease and from then on were immune to it. The technique did have a 0.5–2.0% mortality rate, but that was considerably less than the 20–30% mortality rate of the disease itself. Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Dr. Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. [3] According to Voltaire (1742), the Turks derived their use of inoculation from neighbouring Circassia. Voltaire does not speculate on where the Circassians derived their technique from, though he reports that the Chinese have practiced it "these hundred years". [4] It was introduced into England from Turkey by Lady Mary Wortley Montagu in 1721 and used by Zabdiel Boylston in Boston the same year. In 1798 Edward Jenner introduced inoculation with cowpox (smallpox vaccine), a much safer procedure. This procedure, referred to as vaccination, gradually replaced smallpox inoculation, now called variolation to distinguish it from vaccination. Until the 1880s vaccine/vaccination referred only to smallpox, but Louis Pasteur developed immunization methods for chicken cholera and anthrax in animals and for human rabies, and suggested that the terms vaccine/vaccination should be extended to cover the new procedures. This can cause confusion if care is not taken to specify which vaccine is used e.g. measles vaccine or influenza vaccine.

The terms inoculation, vaccination, and immunization are often used synonymously to refer to artificial induction of immunity against various infectious diseases. However, there are some important historical and current differences. In English medicine, inoculation referred only to the practice of variolation until the very early 1800s. When Edward Jenner introduced smallpox vaccine in 1798, this was initially called cowpox inoculation or vaccine inoculation. Soon, to avoid confusion, smallpox inoculation continued to be referred to as variolation and cowpox inoculation was referred to as vaccination. Then, in 1891, Louis Pasteur proposed that the terms vaccine and vaccination should be extended to include the new protective procedures being developed. Immunization refers to the use of all vaccines but also extends to the use of antitoxin, which contains preformed antibody such as to diphtheria or tetanus exotoxins. Inoculation is now more or less synonymous in nontechnical usage with injection and the like, and questions along the lines of "Have you had your flu injection/vaccination/inoculation/immunization?" should not cause confusion. The focus is on what is being given and why, not the literal meaning of the technique used.

Wan Quan, also known as Wan Mizhai, was a Ming dynasty pediatrician. He was the third in his family to practice medicine. He advocated that children be frequently exposed to sunlight and fresh air and trained to resist cold. He also believed that frightening a child was harmful to him or her, as was overfeeding or overmedicating.

Royal Society English learned society for science

The President, Council and Fellows of the Royal Society of London for Improving Natural Knowledge, commonly known as the Royal Society, is a learned society. Founded on 28 November 1660, it was granted a royal charter by King Charles II as "The Royal Society". It is the oldest national scientific institution in the world. The society is the United Kingdom's and Commonwealth of Nations' Academy of Sciences and fulfils a number of roles: promoting science and its benefits, recognising excellence in science, supporting outstanding science, providing scientific advice for policy, fostering international and global co-operation, education and public engagement.

Passive and active immunization

Medical student participating in a polio vaccine campaign in Mexico National Immunization Campaign in "San Miguel Topilejo".JPG
Medical student participating in a polio vaccine campaign in Mexico

Immunization can be achieved in an active or passive manner: vaccination is an active form of immunization.

Active immunization

Active immunization can occur naturally when a person comes in contact with, for example, a microbe. The immune system will eventually create antibodies and other defenses against the microbe. The next time, the immune response against this microbe can be very efficient; this is the case in many of the childhood infections that a person only contracts once, but then is immune.

Artificial active immunization is where the microbe, or parts of it, are injected into the person before they are able to take it in naturally. If whole microbes are used, they are pre-treated.

The importance of immunization is so great that the American Centers for Disease Control and Prevention has named it one of the "Ten Great Public Health Achievements in the 20th Century". [5] Live attenuated vaccines have decreased pathogenicity. Their effectiveness depends on the immune systems ability to replicate and elicits a response similar to natural infection. It is usually effective with a single dose. Examples of live, attenuated vaccines include measles, mumps, rubella, MMR, yellow fever, varicella, rotavirus, and influenza (LAIV).

Passive immunization

Passive immunization is where pre-synthesized elements of the immune system are transferred to a person so that the body does not need to produce these elements itself. Currently, antibodies can be used for passive immunization. This method of immunization begins to work very quickly, but it is short lasting, because the antibodies are naturally broken down, and if there are no B cells to produce more antibodies, they will disappear.

Passive immunization occurs physiologically, when antibodies are transferred from mother to fetus during pregnancy, to protect the fetus before and shortly after birth.

Artificial passive immunization is normally administered by injection and is used if there has been a recent outbreak of a particular disease or as an emergency treatment for toxicity, as in for tetanus. The antibodies can be produced in animals, called "serum therapy," although there is a high chance of anaphylactic shock because of immunity against animal serum itself. Thus, humanized antibodies produced in vitro by cell culture are used instead if available.

Economics of Immunizations

If individuals make the decision to immunize based on the Private Marginal Benefit we see a quantity of Q1 at the price P1 while the socially optimal point is at quantity Q* and price P*. The distance between the private and marginal benefit lines is the cost of the marginal benefit to society. Immunization Externality.png
If individuals make the decision to immunize based on the Private Marginal Benefit we see a quantity of Q1 at the price P1 while the socially optimal point is at quantity Q* and price P*. The distance between the private and marginal benefit lines is the cost of the marginal benefit to society.
Immunization A does not have a social marginal benefit large enough to shift Q1 to Q(e), instead it lands at Q* Non Eradicated Shift.png
Immunization A does not have a social marginal benefit large enough to shift Q1 to Q(e), instead it lands at Q*

Positive Externality

Immunizations impose what is known as a positive consumer externality on society. In addition to providing the individual with protection against certain antigens it adds greater protection to all other individuals in society through herd immunity. Because this extra protection is not accounted for in the market transactions for immunizations we see an undervaluing of the marginal benefit of each immunization. This market failure is caused by individuals making decisions based on their private marginal benefit instead of the social marginal benefit. Society’s undervaluing of immunizations means that through normal market transactions we end up at a quantity that is lower than what is socially optimal. [6]

For example, if individual A values their own immunity to an antigen at $100 but the immunization costs $150, individual A will decide against receiving immunization. However, if the added benefit of herd immunity means person B values person A’s immunity at $70 then the total social marginal benefit of their immunization is $170. Individual A’s private marginal benefit being lower than the social marginal benefit leads to an under-consumption of immunizations.

Socially Optimal Outcome

Having private marginal benefits lower than social marginal benefits will always lead to an under-consumption of any good. The size of the disparity is determined by the value that society places on each different immunization. Many times, immunizations do not reach a socially optimum quantity high enough to eradicate the antigen. Instead, they reach a social quantity that allows for an optimal amount of sick individuals. Most of the commonly immunized diseases in the United States still see a small presence with occasional larger outbreaks. Measles is a good example of a disease whose social optimum leaves enough room for outbreaks in the United States that often lead to the deaths of a handful of individuals. [7]

Immunization B has a social marginal benefit large enough to bring Q1 to Q(e), the quantity at which eradication occurs Eradicated Immunization Shift.png
Immunization B has a social marginal benefit large enough to bring Q1 to Q(e), the quantity at which eradication occurs

There are also examples of illnesses so dangerous that the social optimum ended with the eradication of the virus, such as smallpox. In these cases, the social marginal benefit is so large that society is willing to pay the cost to reach a level of immunization that makes the spread and survival of the disease impossible.

Despite the severity of certain illnesses, the cost of immunization versus the social marginal benefit means that total eradication is not always the end goal of immunization. Though it is hard to tell exactly where the socially optimal outcome is, we know that it is not the eradication of all disease for which an immunization exists.

Internalizing the Externality

In order to internalize the positive externality imposed by immunizations payments equal to the marginal benefit must be made. In countries like the United States these payment usually come in the form of subsidies from the government. Before 1962 immunization programs in the United States were run on the local and state level of governments. The inconsistency in subsidies lead to some regions of the United States reaching the socially optimal quantity while other regions were left without subsidies and remained at the private marginal benefit level of immunizations. Since 1962 and the Vaccination Assistance Act, the United States as a whole has been moving towards the socially optimal outcome on a larger scale. [8] Despite government subsidies it is difficult to tell when social optimum has been achieved. In addition to hardships determining the true social marginal benefit of immunizations we see cultural movements shifting private marginal benefit curves. Vaccine controversies have changed the way some private citizens view the marginal benefit of being immunized. If Individual A believes that there is a large health risk, possibly larger than the antigen itself, associated with immunization they will not be willing to pay for or receive immunization. With fewer willing participants and a widening marginal benefit reaching a social optimum becomes more difficult for governments to achieve through subsidies.

Outside of government intervention through subsidies, non profit organizations can also move a society towards the socially optimal outcome by providing free immunizations to developing regions. Without the ability to afford the immunizations to begin with, developing societies will not be able to reach a quantity determined by private marginal benefits. By running immunization programs organizations are able to move privately under-immunized communities towards the social optimum.

See also

Related Research Articles

Vaccine biological preparatory medicine that improves immunity to a particular disease

A vaccine is a biological preparation that provides active acquired immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. Vaccines can be prophylactic, or therapeutic.

DNA vaccination vaccine containing DNA

DNA vaccination is a technique for protecting against disease by injection with genetically engineered DNA so cells directly produce an antigen, producing a protective immunological response. DNA vaccines have potential advantages over conventional vaccines, including the ability to induce a wider range of immune response types.

Cowpox Human disease

Cowpox is an infectious disease caused by the cowpox virus. The virus, part of the genus Orthopoxvirus, is closely related to the vaccinia virus. The virus is zoonotic, meaning that it is transferable between species, such as from animal to human. The transferral of the disease was first observed in dairymaids who touched the udders of infected cows and consequently developed the signature pustules on their hands. Cowpox is more commonly found in animals other than bovines, such as rodents. Cowpox is similar to, but much milder than, the highly contagious and often deadly smallpox disease. Its close resemblance to the mild form of smallpox and the observation that dairy farmers were immune from smallpox inspired the first smallpox vaccine, created and administered by English physician Edward Jenner.

Herd immunity

Herd immunity is a form of indirect protection from infectious disease that occurs when a large percentage of a population has become immune to an infection, thereby providing a measure of protection for individuals who are not immune. In a population in which a large number of individuals are immune, chains of infection are likely to be disrupted, which stops or slows the spread of disease. The greater the proportion of individuals in a community who are immune, the smaller the probability that those who are not immune will come into contact with an infectious individual.

In biology, immunity is the balanced state of multicellular organisms having adequate biological defenses to fight infection, disease, or other unwanted biological invasion, while having adequate tolerance to avoid allergy, and autoimmune diseases.

Polyclonal antibodies (pAbs) are antibodies that are secreted by different B cell lineages within the body. They are a collection of immunoglobulin molecules that react against a specific antigen, each identifying a different epitope.

Vaccine hesitancy Unsubstantiated scares regarding immunisation

Vaccine hesitancy is a reluctance or refusal to be vaccinated or to have one's children vaccinated. Identified by the World Health Organization as one of the top ten global health threats of 2019, it contradicts overwhelming scientific consensus about the safety and efficacy of vaccines.

Immunocompetence is the ability of the body to produce a normal immune response following exposure to an antigen. Immunocompetence is the opposite of immunodeficiency or immuno-incompetent or immuno-compromised. Examples include:

Vaccination and religion have interrelations of varying kinds. Almost no religions object to vaccination, and some parents either fake religious adherence or invent fake religions to provide exemption.

Contact immunity

Contact immunity is the property of some vaccines, where a vaccinated individual can confer immunity upon unimmunized individuals through contact with bodily fluids or excrement. In other words, if Amelia has been vaccinated for virus X and Roberto has not, Roberto can receive immunity to virus X just by coming into contact with Amelia. The term was coined by Romanian physician Ion Cantacuzino.

Artificial induction of immunity is the artificial induction of immunity to specific diseases – making people immune to disease by means other than waiting for them to catch the disease. The purpose is to reduce the risk of death and suffering.

Timeline of immunology:

In medical terms, a booster dose is an extra administration of a vaccine after an earlier (prime) dose. After initial immunization, a booster injection or booster dose is a re-exposure to the immunizing antigen. It is intended to increase immunity against that antigen back to protective levels, after memory against that antigen has declined through time. For example, tetanus shot boosters are often recommended every 10 years, after which memory cells specific against tetanus have lost their function or undergone apoptosis.

Passive immunity is the transfer of active humoral immunity of ready-made antibodies. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and it can also be induced artificially, when high levels of antibodies specific to a pathogen or toxin are transferred to non-immune persons through blood products that contain antibodies, such as in immunoglobulin therapy or antiserum therapy. Passive immunization is used when there is a high risk of infection and insufficient time for the body to develop its own immune response, or to reduce the symptoms of ongoing or immunosuppressive diseases. Passive immunization can be provided when people cannot synthesize antibodies, and when they have been exposed to a disease that they do not have immunity against.

Active immunization is the induction of immunity after exposure to an antigen. Antibodies are created by the recipient and may be stored permanently.

Malaria vaccine

Malaria vaccine is a vaccine that is used to prevent malaria. The only approved vaccine as of 2015 is RTS,S. It requires four injections, and has a relatively low efficacy. Due to this low efficacy, WHO does not recommend the use of RTS,S vaccine in babies between 6 and 12 weeks of age.

An attenuated vaccine is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable. Attenuation takes an infectious agent and alters it so that it becomes harmless or less virulent. These vaccines contrast to those produced by "killing" the virus.

Active immunotherapy is a type of immunotherapy that aims to stimulate the host's immune system or a specific immune response to a disease or pathogen and is most commonly used in cancer treatments. Active immunotherapy is also used for treatment of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, prion disease, and multiple sclerosis. Active immunotherapies induce an immune response through direct immune system stimulation, while immunotherapies that administer antibodies directly to the system are classified as passive immunotherapies. Active immunotherapies can elicit generic and specific immune responses depending on the goal of the treatment. The categories of active immunotherapy divide into:

Vaccinia immune globulin (VIG) is made from the pooled blood of individuals who have been inoculated with the smallpox vaccine. The antibodies these individuals developed in response to the smallpox vaccine are removed and purified. This results in VIG. It can be administered intravenously. It is used to treat individuals who have developed progressive vaccinia after smallpox vaccination. It was also used along with cidofovirinfor the 2003 Midwest monkeypox outbreak as concomitant therapy to reduce the serious side effects of smallpox vaccine.

References

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  2. Needham J (1999). "Part 6, Medicine". Science and Civilization in China: Volume 6, Biology and Biological Technology. Cambridge: Cambridge University Press. p. 134.
  3. Silverstein, Arthur M. (2009). A History of Immunology (2nd ed.). Academic Press. p. 293. ISBN   9780080919461..
  4. Voltaire (1742). "Letter XI". Letters on the English.
  5. "Ten Great Public Health Achievements in the 20th Century". CDC
  6. Hinman, A. R.; Orenstein, W. A.; Rodewald, L. (2004-05-15). "Financing Immunizations in the United States". Clinical Infectious Diseases. 38 (10): 1440–1446. doi:10.1086/420748. ISSN   1058-4838.
  7. Cook, Joseph; Jeuland, Marc; Maskery, Brian; Lauria, Donald; Sur, Dipika; Clemens, John; Whittington, Dale (2009). "Using private demand studies to calculate socially optimal vaccine subsidies in developing countries". Journal of Policy Analysis and Management. 28 (1): 6–28. doi:10.1002/pam.20401. ISSN   0276-8739. PMID   19090047.
  8. "Vaccine-Preventable Diseases, Immunizations, and MMWR --- 1961--2011". www.cdc.gov. Retrieved 2018-03-07.