Vaccination is the administration of a vaccine to help the immune system develop protection from a disease. Vaccines contain a microorganism or virus 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 and tetanus from much of the world.
Child receiving an oral polio vaccine
Smallpox was most likely the first disease people tried to prevent by inoculation and was the first disease for which a vaccine was produced. The smallpox vaccine was invented in 1796 by English physician Edward Jenner and, although at least six people had used the same principles years earlier, he was the first to publish evidence that it was effective and to provide advice on its production. Louis Pasteur furthered the concept through his work in microbiology. The immunization was called vaccination because it was derived from a virus affecting cows (Latin: vacca 'cow'). Smallpox was a contagious and deadly disease, causing the deaths of 20–60% of infected adults and over 80% of infected children. When smallpox was finally eradicated in 1979, it had already killed an estimated 300–500 million people in the 20th century.
Vaccination and immunization have a similar meaning in everyday language. This is distinct from inoculation, which uses unweakened live pathogens. Vaccination efforts have been met with some controversy on scientific, ethical, political, medical safety, and religious grounds, although no major religions oppose vaccination, and some consider it an obligation due to the potential to save lives. In the United States, people may receive compensation for those injuries under the National Vaccine Injury Compensation Program. Early success brought widespread acceptance, and mass vaccination campaigns have greatly reduced the incidence of many diseases in numerous geographic regions
Mechanism of functionEdit
Vaccines are a way of artificially activating the immune system to protect against infectious disease. The activation occurs through priming the immune system with an immunogen. Stimulating immune responses with an infectious agent is known as immunization. Vaccination includes various ways of administering immunogens.
Most vaccines are administered before a patient has contracted a disease to help increase future protection. However, some vaccines are administered after the patient already has contracted a disease. Vaccines given after exposure to smallpox are reported to offer some protection from disease or may reduce the severity of disease. The first rabies immunization was given by Louis Pasteur to a child after he was bitten by a rabid dog. Since its discovery, the rabies vaccine have been proven effective in preventing rabies in humans when administered several times over 14 days along with rabies immune globulin and wound care. Other examples include experimental AIDS, cancer and Alzheimer's disease vaccines. Such immunizations aim to trigger an immune response more rapidly and with less harm than natural infection.
Most vaccines are given by injection as they are not absorbed reliably through the intestines. Live attenuated polio, rotavirus, some typhoid, and some cholera vaccines are given orally to produce immunity in the bowel. While vaccination provides a lasting effect, it usually takes several weeks to develop. This differs from passive immunity (the transfer of antibodies, such as in breastfeeding) has immediate effect.
A vaccine failure is when an organism contracts a disease in spite of being vaccinated against it. Primary vaccine failure occurs when an organism's immune system does not produce antibodies when first vaccinated. Vaccines can fail when several series are given and fail to produce an immune response. The term "vaccine failure" does not necessarily imply that the vaccine is defective. Most vaccine failures are simply from individual variations in immune response.
Vaccination versus inoculationEdit
The term inoculation is often used interchangeably with vaccination. However, some argue that the terms are not synonymous. Dr Byron Plant explains: "Vaccination is the more commonly used term, which actually consists of a 'safe' injection of a sample taken from a cow suffering from cowpox... Inoculation, a practice probably as old as the disease itself, is the injection of the variola virus taken from a pustule or scab of a smallpox sufferer into the superficial layers of the skin, commonly on the upper arm of the subject. Often inoculation was done 'arm-to-arm' or, less effectively, 'scab-to-arm'..." Inoculation oftentimes caused the patient to become infected with smallpox, and in some cases the infection turned into a severe case.
Vaccine development and approvalEdit
Just like any medication or procedure, no vaccine can be 100% safe or effective for everyone because each person's body can react differently. While minor side effects, such as soreness or low grade fever, are relatively common, serious side effects are very rare and occur in about 1 out of every 100,000 vaccinations and typically involve allergic reactions that can cause hives or difficulty breathing. However, vaccines are the safest they ever have been in history and each vaccine undergoes rigorous clinical trials to ensure their safety and efficacy before FDA approval. Prior to human testing, vaccines are run through computer algorithms to model how they will interact with the immune system and are tested on cells in a culture. During the next round of testing, researchers study vaccines in animal, including mice, rabbits, guinea pigs, and monkeys. Vaccines that pass each of these stages of testing are then approved by the FDA to start a three-phase series of human testing, advancing to higher phases only if they are deemed safe and effective at the previous phase. The people in these trials participate voluntarily and are required to prove they understand the purpose of the study and the potential risks. During phase I trials, a vaccine is tested in a group of about 20 people with the primary goal of assessing the vaccine's safety. Phase II trials expand the testing to include 50 to several hundred people. During this stage, the vaccine's safety continues to be evaluated and researchers also gather data on the effectiveness and the ideal dose of the vaccine. Vaccines determined to be safe and efficacious then advance to phase III trials, which focuses on the efficacy of the vaccine in hundreds to thousands of volunteers. This phase can take several years to complete and researchers use this opportunity to compare the vaccinated volunteers to those who have not been vaccinated to highlight any true reactions to the vaccine that occur. If a vaccine passes all of the phases of testing, the manufacturer can then apply for licensure of the vaccine through the FDA. Before the FDA approves use in the general public, they extensively review the results to the clinical trials, safety tests, purity tests, and manufacturing methods and establish that the manufacturer itself is up to government standards in many other areas. However, safety testing of the vaccines never ends even after FDA approval. The FDA continues to monitor the manufacturing protocols, batch purity, and the manufacturing facility itself. Additionally, most vaccines also undergo phase IV trials, which monitors the safe and efficacy of vaccines in tens of thousands of people, or more, across many years. This allows for delayed or very rare reactions to be detected and evaluated.
|CDC Immunization Safety Office initiatives||Government organizations||Non-government organizations|
|Vaccine Adverse Event Reporting System (VAERS)||Food and Drug Administration (FDA) Center for Biologics Evaluation and Research (CBER)||Immunization Action Coalition (IAC)|
|Vaccine Safety Datalink (VSD)||Health Resources and Service Administration (HRSA)||Institute for Safe Medication Practices (ISMP)|
|Clinical Immunization Safety Assessment (CISA) Project||National Institutes of Health (NIH)|
|Emergency preparedness for vaccine safety||National Vaccine Program Office (NVPO)|
The administration protocols, efficacy, and adverse events of vaccines are very strictly monitored. Organizations of the federal government, including the CDC and FDA, as well as organizations independent of the government are constantly re-evaluating our vaccine practices. As with all medications, vaccine use is driven by validated data and both the formulations and administration protocols of vaccines are subject to evolve as data continues to be gathered.
The Centers for Disease Control and Prevention (CDC) has compiled a list of vaccines and their possible side effects. The risk of side effects varies from one vaccine to the next, but below are examples of side effects and their approximate rate of occurrence with the diphtheria, tetanus, and acellular pertussis (DTaP) vaccine, a common childhood vaccine.
Mild side effects (common)
- Mild fever (1 in 4)
- Redness, soreness, swelling at the injection site (1 in 4)
- Fatigue, poor appetite (1 in 10)
- Vomiting (1 in 50)
Moderate side effects (uncommon)
- Seizure (1 in 14,000)
- High fever (over 105 °F) (1 in 16,000)
Severe side effects (rare)
- Serious allergic reaction (1 in 1,000,000)
- Other severe problems including long-term seizure, coma, brain damage have been reported, but are so rare that it is not possible to tell if they are from the vaccine or not
Ingredients commonly of concernEdit
The ingredients of vaccines can vary greatly from one to the next and no two vaccines are the same. The CDC has compiled a list of vaccines and their ingredients that is readily accessible on their website.
Aluminium is an adjuvant ingredient in some vaccines. An adjuvant is a certain type of ingredient that is used to help the body's immune system create a stronger immune response after receiving the vaccination. Aluminium is in a salt form and is used in the following compounds: aluminium hydroxide, aluminium phosphate, and aluminium potassium sulfate. In chemistry, a salt is the ionic version of an element; another example is table salt: Na+
(sodium) and Cl−
(chloride). For a given element, the ion form has different properties from the elemental form. Although it is possible to have aluminium toxicity, aluminium salts have been used effectively and safely since the 1930s when they were first used with the diphtheria and tetanus vaccines. Although there is a small increase in the chance of having a local reaction to a vaccine with an aluminium salt (redness, soreness, swelling), there is no increased risk of any serious reactions.
Certain vaccines contain a compound called thimerosal, which is an organic compound that contains mercury. Mercury is commonly found in two forms that differ by the number of carbon groups in its chemical structure. Methylmercury (one carbon group) is found in fish and is the form that people usually ingest, while ethylmercury (two carbon groups) is the form that is in thimerosal. Although the two have similar chemical compounds, they do not have the same chemical properties and interact with the human body differently. Ethylmercury is cleared from the body faster than methylmercury and is less likely to cause toxic effects.
Thimerosal is used to prevent the growth of bacteria and fungi in vials that contain more than one dose of a vaccine. This helps reduce the risk of potential infections and or serious illness that could occur from contamination of a vaccine vial. Although there is a small increase in risk of injection site redness and swelling with vaccines containing thimerosal, there is no increased risk of serious harm, including autism. Even though evidence supports the safety and efficacy of thimerosal in vaccines, thimerosal was removed from childhood vaccines in the United States in 2001 as a precaution.
It is known that the process of inoculation was used by Chinese physicians in the 10th century. Scholar Ole Lund comments: "The earliest documented examples of vaccination are from India and China in the 17th century, where vaccination with powdered scabs from people infected with smallpox was used to protect against the disease. Smallpox used to be a common disease throughout the world and 20 to 30% of infected persons died from the disease. Smallpox was responsible for 8 to 20% of all deaths in several European countries in the 18th century. The tradition of vaccination may have originated in India in AD 1000." The mention of inoculation in the Sact'eya Grantham, an Ayurvedic text, was noted by the French scholar Henri Marie Husson in the journal Dictionaire des sciences médicales. However, the idea that inoculation originated in India has been challenged, as few of the ancient Sanskrit medical texts described the process of inoculation. Accounts of inoculation against smallpox in China can be found as early as the late 10th century and was reportedly widely practised in China in the reign of the Longqing Emperor (r. 1567–72) during the Ming Dynasty (1368–1644). 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. According to Voltaire (1742), the Turks derived their use of inoculation to 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". The Greek physicians Emmanuel Timonis (1669–1720) from the island of Chios and Jacob Pylarinos (1659–1718) from Cephalonia practised smallpox inoculation at Constantinople in the beginning of 18th century and published their work in Philosophical Transactions of the Royal Society in 1714. This kind of inoculation and other forms of variolation were introduced into England by Lady Montagu, a famous English letter-writer and wife of the English ambassador at Istanbul between 1716 and 1718, who almost died from smallpox as a young adult and was physically scarred from it. Inoculation was adopted both in England and in America nearly half a century before Jenner's famous smallpox vaccine of 1796 but the death rate of about 2% from this method meant that it was mainly used during dangerous outbreaks of the disease and remained controversial. It was noticed during the 18th century that people who had suffered from the less virulent cowpox were immune to smallpox, and the first recorded use of this idea was by a farmer Benjamin Jesty at Yetminster in Dorset, who had suffered the disease and transmitted it to his own family in 1774, his sons subsequently not getting the mild version of smallpox when later inoculated in 1789.
It was Edward Jenner, a doctor in Berkeley in Gloucestershire, who established the procedure by introducing material from a cowpox vesicle on Sarah Nelmes, a milkmaid, into the arm of a boy named James Phipps. Two months later he inoculated the boy with smallpox and the disease did not develop. In 1798 Jenner published An Inquiry into the Causes and Effects of the Variolae Vacciniae, which coined the term vaccination and created widespread interest. He distinguished 'true' and 'spurious' cowpox (which did not give the desired effect) and developed an "arm-to-arm" method of propagating the vaccine from the vaccinated individual's pustule. Early attempts at confirmation were confounded by contamination with smallpox, but despite controversy within the medical profession and religious opposition to the use of animal material, by 1801 his report was translated into six languages and over 100,000 people were vaccinated.
Since then vaccination campaigns have spread throughout the globe, sometimes prescribed by law or regulations (See Vaccination Acts). Vaccines are now used against a wide variety of diseases. Louis Pasteur further developed the technique during the 19th century, extending its use to killed agents protecting against anthrax and rabies. The method Pasteur used entailed treating the agents for those diseases so they lost the ability to infect, whereas inoculation was the hopeful selection of a less virulent form of the disease, and Jenner's vaccination entailed the substitution of a different and less dangerous disease. Pasteur adopted the name vaccine as a generic term in honour of Jenner's discovery.
In modern times, the first vaccine-preventable disease targeted for eradication was smallpox. The World Health Organization (WHO) coordinated this global eradication effort. The last naturally occurring case of smallpox occurred in Somalia in 1977. In 1988, the governing body of WHO targeted polio for eradication by 2000. Although the target was missed, cases have been reduced by 99.99%.
In 2000, the Global Alliance for Vaccines and Immunization was established to strengthen routine vaccinations and introduce new and under-used vaccines in countries with a per capita GDP of under US $1000.
Society and cultureEdit
To eliminate the risk of outbreaks of some diseases, at various times governments and other institutions have employed policies requiring vaccination for all people. For example, an 1853 law required universal vaccination against smallpox in England and Wales, with fines levied on people who did not comply. Common contemporary U.S. vaccination policies require that children receive recommended vaccinations before entering public school.
Beginning with early vaccination in the nineteenth century, these policies were resisted by a variety of groups, collectively called antivaccinationists, who object on scientific, ethical, political, medical safety, religious, and other grounds. Common objections are that vaccinations do not work, that compulsory vaccination constitutes excessive government intervention in personal matters, or that the proposed vaccinations are not sufficiently safe. Many modern vaccination policies allow exemptions for people who have compromised immune systems, allergies to the components used in vaccinations or strongly held objections.
In countries with limited financial resources, limited vaccination coverage results in greater morbidity and mortality due to infectious disease. More affluent countries are able to subsidize vaccinations for at-risk groups, resulting in more comprehensive and effective coverage. In Australia, for example, the Government subsidizes vaccinations for seniors and indigenous Australians.
Public Health Law Research, an independent US based organization, reported in 2009 that there is insufficient evidence to assess the effectiveness of requiring vaccinations as a condition for specified jobs as a means of reducing incidence of specific diseases among particularly vulnerable populations; that there is sufficient evidence supporting the effectiveness of requiring vaccinations as a condition for attending child care facilities and schools; and that there is strong evidence supporting the effectiveness of standing orders, which allow healthcare workers without prescription authority to administer vaccine as a public health intervention.
La vaccine or Le préjugé vaincu by Louis-Léopold Boilly, 1807
A doctor vaccinating a small girl, other girls with loosened blouses wait their turn apprehensively by Lance Calkin
German caricature showing von Behring extracting the serum with a tap.
Allegations of vaccine injuries in recent decades have appeared in litigation in the U.S. Some families have won substantial awards from sympathetic juries, even though most public health officials have said that the claims of injuries were unfounded. In response, several vaccine makers stopped production, which the US government believed could be a threat to public health, so laws were passed to shield manufacturers from liabilities stemming from vaccine injury claims. The safety and side effects of multiple vaccines have been tested in order to uphold the viability of vaccines as a barrier against disease. The influenza vaccine was tested in controlled trials and proven to have negligible side effects equal to that of a placebo. Some concerns from families might have arisen from social beliefs and norms that cause them to mistrust or refuse vaccinations, contributing to this discrepancy in side effects that were unfounded.
Opposition to vaccinationEdit
Opposition to vaccination, from a wide array of vaccine critics, has existed since the earliest vaccination campaigns. Although the benefits of preventing serious illness and death from infectious diseases greatly outweigh the risks of rare serious adverse effects following immunization, disputes have arisen over the morality, ethics, effectiveness, and safety of vaccination. Some vaccination critics say that vaccines are ineffective against disease or that vaccine safety studies are inadequate. Some religious groups do not allow vaccination, and some political groups oppose mandatory vaccination on the grounds of individual liberty. In response, concern has been raised that spreading unfounded information about the medical risks of vaccines increases rates of life-threatening infections, not only in the children whose parents refused vaccinations, but also in those who cannot be vaccinated due to age or immunodeficiency, who could contract infections from unvaccinated carriers (see herd immunity). Some parents believe vaccinations cause autism, although there is no scientific evidence to support this idea. In 2011, Andrew Wakefield, a leading proponent of the theory that MMR vaccine causes autism, was found to have been financially motivated to falsify research data and was subsequently stripped of his medical license. In the United States people who refuse vaccines for non-medical reasons have made up a large percentage of the cases of measles, and subsequent cases of permanent hearing loss and death caused by the disease.
Many parents do not vaccinate their children because they feel that diseases are no longer present due to vaccination. This is a false assumption, since diseases held in check by immunization programs can and do still return if immunization is dropped. These pathogens could possibly infect vaccinated people, due to the pathogen's ability to mutate when it is able to live in unvaccinated hosts. In 2010, California had the worst whooping cough outbreak in 50 years. A possible contributing factor was parents choosing not to vaccinate their children. There was also a case in Texas in 2012 where 21 members of a church contracted measles because they chose not to immunize.
Vaccination and autismEdit
The notion of a connection between vaccines and autism originated in a 1998 paper published in the The Lancet whose lead author was a physician named Andrew Wakefield. His study concluded that eight of the 12 patients (ages 3–10) developed behavioral symptoms consistent with autism following the MMR vaccine (an immunization against measles, mumps, and rubella). The article was widely criticized for lack of scientific rigor and it was proven that Wakefield falsified data in the article. In 2004, 10 of the original 12 co-authors (not including Wakefield) published a retraction of the article and stated the following: "We wish to make it clear that in this paper no causal link was established between MMR vaccine and autism as the data were insufficient." In 2010, The Lancet officially retracted the article stating that several elements of the article were incorrect, including falsified data and protocols. This Lancet article has sparked a much greater anti-vaccination movement, particularly in the United States. Even though the article was fraudulent and was retracted, 1 in 4 parents still believe vaccines can cause autism.
To date, all validated and definitive studies have shown that there is no correlation between vaccines and autism. One of the studies published in 2015 confirms there is no link between autism and the MMR vaccine. Infants were given a health plan, that included an MMR vaccine, and were continuously studied until they reached 5 years old. There was no link between the vaccine and children who had a normally developed sibling or a sibling that had autism making them a higher risk for developing autism themselves.
The memory of humans can be difficult in trying to correct wrong information that was originally seen. Even though there is evidence to go against the Wakefield study and with some of the co-authors going back to change the evidence first presented, people still believe and go off of this evidence. They still decide not to vaccinate. It can be difficult to retract information even with new evidence that proves the opposite of the original due to information lingering in the memory. Studies and research are being done to see what an effective way of correcting misinformation in the memory may be. Since the Wakefield study was released over 20 years ago, it could be easier for the generations now to be educated on vaccinations and be given current research. This way we may be able to eliminate having to try to correct the memory. A very small percentage of people have reactions to vaccines, and if there is a reaction it is often mild. These reactions do not include autism.
Routes of administrationEdit
A vaccine administration may be oral, by injection (intramuscular, intradermal, subcutaneous), by puncture, transdermal or intranasal. Several recent clinical trials have aimed to deliver the vaccines via mucosal surfaces to be up-taken by the common mucosal immunity system, thus avoiding the need for injections.
Global trends in vaccinationEdit
The World Health Organization (WHO) estimate that vaccination averts 2–3 million deaths per year (in all age groups), and up to 1.5 million children die each year due to diseases that could have been prevented by vaccination. They estimate that 29% of deaths of children under five years old in 2013 were vaccine preventable. In other developing parts of the world, they are faced with the challenge of having a decreased availability of resources and vaccinations. Countries such as those in Sub-Saharan Africa cannot afford to provide the full range of childhood vaccinations.
Vaccines have led to major decreases in the prevalence of infectious diseases in the United States. In 2007, studies regarding the effectiveness of vaccines on mortality or morbidity rates of those exposed to various diseases have shown almost 100% decreases in death rates, and about a 90% decrease in exposure rates. This has allowed specific organizations and states to adopt standards for recommended early childhood vaccinations. Lower income families who are unable to otherwise afford vaccinations are supported by these organizations and specific government laws. The Vaccine for Children Program and the Social Security Act are two major players in supporting lower socioeconomic groups.
In 2000, the CDC declared that measles had been eliminated in the US (defined as no disease transmission for 12 continuous months). However, with the growing anti-vaccine movement, the US has seen a resurgence of certain vaccine-preventable diseases. The measles virus has now lost its elimination status in the US as the number of measles cases continues to rise in recent years with a total of 17 outbreaks in 2018 and 465 outbreaks in 2019 (as of April 4th, 2019).
Economics of vaccinationEdit
Health is often used as one of the metrics for determining the economic prosperity of a country. This is because healthier individuals are generally better suited to contributing to the economic development of a country than the sick. There are many reasons for this. A person who is vaccinated for influenza, not only protects himself from the risk of influenza, but, simultaneously, prevents himself from infecting those around him. This leads to a healthier society, which allows individuals to be more economically productive. Children are consequently able to attend school more often and have been shown to do better academically. Similarly, adults are able to work more often, more efficiently, and more effectively.
Costs and benefitsEdit
On the whole, vaccinations induce a net benefit to society. Vaccines are often noted for their high return on investment (ROI) values, especially when considering the long-term effects. Some vaccines have much higher ROI values than others. Studies have shown that the ratios of vaccination benefits to costs can differ substantially—from 27:1 for diphtheria/pertussis, to 13.5:1 for measles, 4.76:1 for varicella, and 0.68–1.1 : 1 for pneumococcal conjugate. Some governments choose to subsidize the costs of vaccines, due to some of the high ROI values attributed to vaccinations.The United States subsidizes over half of all vaccines for children, which costs between $400 and $600 each. Although most children do get vaccinated, the adult population of the USA is still below the recommended immunization levels. Many factors can be attributed to this issue. Many adults who have other health conditions are unable to be safely immunized, whereas others opt not to be immunized for the sake of private financial benefits. Many Americans are underinsured, and, as such, are required to pay for vaccines out-of-pocket. Others are responsible for paying high deductibles and co-pays. Although vaccinations usually induce long-term economic benefits, many governments struggle to pay the high short-term costs associated with labor and production. Consequently, many countries neglect to provide such services.
The Coalition for Epidemic Preparedness Innovations published a study in The Lancet in 2018 which estimated the costs of developing vaccines for diseases that could escalate into global humanitarian crises. They focused on 11 diseases which cause relatively few deaths at present and primarily strike the poor which have been highlighted as pandemic risks:
- Crimean Congo hemorrhagic fever
- Lassa fever
- Marburg virus disease
- Middle East respiratory syndrome coronavirus
- Nipah virus infection
- Rift Valley fever
- Severe acute respiratory syndrome
- Severe fever with thrombocytopenia syndrome
They estimated that it would cost between $2.8 billion and $3.7 billion to develop at least one vaccine for each of them. This should be set against the potential cost of an outbreak. The 2003 SARS outbreak in East Asia cost $54 billion.
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|Wikimedia Commons has media related to Vaccinations.|
- U.S. government Vaccine Research Center: Information regarding preventive vaccine research studies
- The Vaccine Page links to resources in many countries.
- Immunisation schedule for the UK. Published by the UK Department of Health. (PDF)
- CDC.gov - 'National Immunization Program: leading the way to healthy lives', US Centers for Disease Control (CDC information on vaccinations)
- CDC.gov - 'Mercury and Vaccines (Thimerosal)', US Centers for Disease Control
- CDC.gov - Vaccines timeline
- Immunize.org - Immunization Action Coalition' (nonprofit working to increase immunization rates)
- WHO.int - 'Immunizations, vaccines and biologicals: Towards a World free of Vaccine Preventable Diseases', World Health Organization (WHO's global vaccination campaign website)
- Health-EU Portal Vaccinations in the EU
- History of Vaccines Medical education site from the College of Physicians of Philadelphia, the oldest medical professional society in the US
- Images of vaccine-preventable diseases
- Immunisation, BBC Radio 4 discussion with Nadja Durbach, Chris Dye & Sanjoy Bhattacharya (In Our Time, Apr. 20, 2006)