Jonas Salk in 1955 holds bottles of a culture used to grow polio vaccines.

A vaccine is a biological preparation that improves 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 foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.

Vaccines can be prophylactic (example: to prevent or ameliorate the effects of a future infection by any natural or "wild" pathogen), or therapeutic (e.g. vaccines against cancer are also being investigated; see cancer vaccine).

The term vaccine derives from Edward Jenner's 1796 use of cow pox (Latin variola vaccinia, adapted from the Latin vaccīn-us, from vacca, cow), to inoculate humans, providing them protection against smallpox.

Effectiveness[link]

Vaccines do not guarantee complete protection from a disease.^[1] Sometimes, this is because the host's immune system simply does not respond adequately or at all. This may be due to a lowered immunity in general (diabetes, steroid use, HIV infection, age) or because the host's immune system does not have a B cell capable of generating antibodies to that antigen.

Even if the host develops antibodies, the human immune system is not perfect and in any case the immune system might still not be able to defeat the infection immediately. In this case, the infection will be less severe and heal faster.

Adjuvants are typically used to boost immune response. Most often aluminium adjuvants are used, but adjuvants like squalene are also used in some vaccines and more vaccines with squalene and phosphate adjuvants are being tested. Larger doses are used in some cases for older people (50–75 years and up), whose immune response to a given vaccine is not as strong.^[2]

Maurice Hilleman's measles vaccine is estimated to prevent 1 million deaths every year.^[3]

The efficacy or performance of the vaccine is dependent on a number of factors:

• the disease itself (for some diseases vaccination performs better than for other diseases)
• the strain of vaccine (some vaccinations are for different strains of the disease)^[4]
• whether one kept to the timetable for the vaccinations (see Vaccination schedule)
• some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly
• other factors such as ethnicity, age, or genetic predisposition.

When a vaccinated individual does develop the disease vaccinated against, the disease is likely to be milder than without vaccination.^{[citation needed]}

The following are important considerations in the effectiveness of a vaccination program:^{[citation needed]}

1. careful modelling to anticipate the impact that an immunization campaign will have on the epidemiology of the disease in the medium to long term
2. ongoing surveillance for the relevant disease following introduction of a new vaccine and
3. maintaining high immunization rates, even when a disease has become rare.

In 1958 there were 763,094 cases of measles and 552 deaths in the United States.^[5][6] With the help of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56).^[6] In early 2008, there were 64 suspected cases of measles. 54 out of 64 infections were associated with importation from another country, although only 13% were actually acquired outside of the United States; 63 of these 64 individuals either had never been vaccinated against measles, or were uncertain whether they had been vaccinated.^[6]

Types[link]

Avian flu vaccine development by reverse genetics techniques.

Vaccines are dead or inactivated organisms or purified products derived from them.

There are several types of vaccines in use.^[7] These represent different strategies used to try to reduce risk of illness, while retaining the ability to induce a beneficial immune response.

Killed[link]

Some vaccines contain killed, but previously virulent, micro-organisms that have been destroyed with chemicals, heat, radioactivity or antibiotics. Examples are the influenza vaccine, cholera vaccine, bubonic plague vaccine, polio vaccine, hepatitis A vaccine, and rabies vaccine.

Attenuated[link]

Some vaccines contain live, attenuated microorganisms. Many of these are live viruses that have been cultivated under conditions that disable their virulent properties, or which use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. They typically provoke more durable immunological responses and are the preferred type for healthy adults. Examples include the viral diseases yellow fever, measles, rubella, and mumps and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain, but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. They have the capacity of transient growth so they give prolonged protection, and no booster dose is required. But they may get reverted to the virulent form and cause the disease.^[8]

Toxoid[link]

Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria. Toxoid vaccines are known for their efficacy. Not all toxoids are for micro-organisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.

Subunit[link]

Protein subunit – rather than introducing an inactivated or attenuated micro-organism to an immune system (which would constitute a "whole-agent" vaccine), a fragment of it can create an immune response. Examples include the subunit vaccine against Hepatitis B virus that is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients, but now produced by recombination of the viral genes into yeast), the virus-like particle (VLP) vaccine against human papillomavirus (HPV) that is composed of the viral major capsid protein, and the hemagglutinin and neuraminidase subunits of the influenza virus. Subunit vaccine is being used for plague immunization.

Conjugate[link]

Conjugate – certain bacteria have polysaccharide outer coats that are poorly immunogenic. By linking these outer coats to proteins (e.g. toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.

Experimental[link]

A number of innovative vaccines are also in development and in use:

• Dendritic cell vaccines combine dendritic cells with antigens in order to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors.^[9]
• Recombinant Vector – by combining the physiology of one micro-organism and the DNA of the other, immunity can be created against diseases that have complex infection processes
• DNA vaccination – in recent years^[when?] a new type of vaccine called DNA vaccination, created from an infectious agent's DNA, has been developed. It works by insertion (and expression, triggering immune system recognition) of viral or bacterial DNA into human or animal cells. Some cells of the immune system that recognize the proteins expressed will mount an attack against these proteins and cells expressing them. Because these cells live for a very long time, if the pathogen that normally expresses these proteins is encountered at a later time, they will be attacked instantly by the immune system. One advantage of DNA vaccines is that they are very easy to produce and store. As of 2006, DNA vaccination is still experimental.
• T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell mediated immunity.
• Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.^[10]

While most vaccines are created using inactivated or attenuated compounds from micro-organisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates or antigens.

Valence[link]

Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism.^[11] A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms.^[12] In certain cases a monovalent vaccine may be preferable for rapidly developing a strong immune response.^[13]

Developing immunity[link]

The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent comes along the body recognizes the protein coat on the virus, and thus is prepared to respond, by (1) neutralizing the target agent before it can enter cells, and (2) by recognizing and destroying infected cells before that agent can multiply to vast numbers.

When two or more vaccines are mixed together in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components. This phenomenon was first noted in the trivalent Sabin polio vaccine, where the amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine.^[14] This phenomenon has also been found to be a problem with the dengue vaccines currently being researched,^[when?] where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.^[15]

Vaccines have contributed to the eradication of smallpox, one of the most contagious and deadly diseases known to man. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only between humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of four countries (Afghanistan, India, Nigeria and Pakistan).[1] The difficulty of reaching all children as well as cultural misunderstandings, however, have caused the anticipated eradication date to be missed several times.

Schedule[link]

For country-specific information on vaccination policies and practices, see: Vaccination policy

In order to provide best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against: hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.^[16] The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. In order to combat declining compliance rates, various notification systems have been instituted and a number of combination injections are now marketed (e.g., Pneumococcal conjugate vaccine and MMRV vaccine), which provide protection against multiple diseases.

Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended at other ages or for repeated injections throughout life—most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011^[17]) and UK (as of 2009^[18]). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.

History[link]

Edward Jenner

Prior to vaccination, inoculation was practised, and brought to the West in 1721 by Lady Mary Wortley Montagu, who showed it to Hans Sloane, the King's physician.^{[citation needed]}

Sometime during the 1770s Edward Jenner heard a milkmaid boast that she would never have the often-fatal or disfiguring disease smallpox, because she had already had cowpox, which has a very mild effect in humans. In 1796, Jenner took pus from the hand of a milkmaid with cowpox, inoculated an 8-year-old boy with it, and six weeks later variolated the boy's arm with smallpox, afterwards observing that the boy did not catch smallpox.^[19][20] Further experimentation demonstrated the efficacy of the procedure on an infant.^[20] Since vaccination with cowpox was much safer than smallpox inoculation,^[21] the latter, though still widely practiced in England, was banned in 1840.^[22] Louis Pasteur generalized Jenner's idea by developing what he called a rabies vaccine, and in the nineteenth century vaccines were considered a matter of national prestige, and compulsory vaccination laws were passed.^[19]

The twentieth century saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including malaria and HIV.^[19]

Society and culture[link]

Opposition to vaccination[link]

The neutrality of this section is disputed. Please see the discussion on the talk page. Please do not remove this message until the dispute is resolved. (October 2011)

This article is missing information about Scientific rebuttal to the attacks. This concern has been noted on the talk page where whether or not to include such information may be discussed. (October 2011)

James Gillray, The Cow-Pock—or—the Wonderful Effects of the New Inoculation! (1802)

Opposition to vaccination, from a wide array of vaccine critics, has existed since the earliest vaccination campaigns.^[23] Although the benefits of preventing suffering and death from serious infectious diseases greatly outweigh the risks of rare adverse effects following immunization,^[24][25] disputes have arisen over the morality, ethics, effectiveness, and safety of vaccination. Some vaccination critics say that vaccines are ineffective against disease^[26] or that vaccine safety studies are inadequate.^[25][26] Some religious groups do not allow vaccination,^[27] and some political groups oppose mandatory vaccination on the grounds of individual liberty.^[23] 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 other children, perhaps too young for vaccines, who could contract infections from unvaccinated carriers (see herd immunity).^[28]

Economics of development[link]

One challenge in vaccine development is economic: many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases, because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.^[29]

Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations.^[30] Many vaccines have been highly cost effective and beneficial for public health.^[29] The number of vaccines actually administered has risen dramatically in recent decades.^[when?] This increase, particularly in the number of different vaccines administered to children before entry into schools^[31] may be due to government mandates and support, rather than economic incentive.^{[citation needed]}

Patents[link]

The filing of patents on vaccine development processes can also be viewed as an obstacle to the development of new vaccines. Because of the weak protection offered through a patent on the final product, the protection of the innovation regarding vaccines is often made through the patent of processes used on the development of new vaccines as well as the protection of secrecy.^[32]

Production[link]

Two workers make openings in chicken eggs in preparation for a measles vaccine.

Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza), or on continuous cell lines such as cultured human cells (e.g., for hepatitis A).^[33] Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Alternatively, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures. After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response of the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials.^[34] Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.^[35]

Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccine is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.^[35]

In 2010, India produced 60 percent of world's vaccine worth about $900 million.^[36]

Excipients[link]

Beside the active vaccine itself, the following excipients are commonly present in vaccine preparations:^[37]

• Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage.
• Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.
• Egg protein is present in influenza and yellow fever vaccines as they are prepared using chicken eggs. Other proteins may be present.
• Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to kill unwanted viruses and bacteria that might contaminate the vaccine during production.
• Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity.
• Thimerosal is a mercury-containing preservative that is added to vials of vaccine that contain more than one dose to prevent contamination and growth of potentially harmful bacteria.

Role of preservatives[link]

Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection that, in one 1928 incident, killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative.^[38] Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has better shelf life, and improves vaccine stability, potency, and safety, but in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its mercury content.^[39] Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims.^[40]

Delivery systems[link]

Woman receiving rubella vaccination, Brazil, 2008.

There are several new delivery systems in development^[when?] that will hopefully make vaccines more efficient to deliver. Possible methods include liposomes and ISCOM (immune stimulating complex).^[41]

The latest developments^[when?] in vaccine delivery technologies have resulted in oral vaccines. A polio vaccine was developed and tested by volunteer vaccinations with no formal training; the results were positive in that the ease of the vaccines increased. With an oral vaccine, there is no risk of blood contamination. Oral vaccines are likely to be solid which have proven to be more stable and less likely to freeze^{[citation needed]}; this stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines. A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".^[42]

A nanopatch is a needle free vaccine delivery system which is under development. A stamp-sized patch similar to an adhesive bandage contains about 20,000 microscopic projections per square inch.^[43] When worn on the skin, it will deliver vaccine directly to the skin, which has a higher concentration of immune cells than that in the muscles^{[citation needed]}, where needles and syringes deliver. It thus increases the effectiveness of the vaccination using a lower amount of vaccine used in traditional syringe delivery system^[44].

Plasmids[link]

The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.^[45]

Use in veterinary medicine[link]

Goat vaccination against sheep pox and pleural pneumonia

Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans.^[46] Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.

Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, bordatella, canine parainfluenza virus, and Lyme disease among others.

Trends[link]

Vaccine development has several trends:^[47]

• Until recently,^[when?] most vaccines were aimed at infants and children, but adolescents and adults are increasingly being targeted.^[47][48]
• Combinations of vaccines are becoming^[when?] more common; vaccines containing five or more components are used in many parts of the world.^[47]
• New methods of administering vaccines are being developed,^[when?] such as skin patches, aerosols via inhalation devices, and eating genetically engineered plants.^[47]
• Vaccines are being designed to stimulate innate immune responses, as well as adaptive.^[47]
• Attempts are being made to develop vaccines to help cure chronic infections, as opposed to preventing disease.^[47]
• Vaccines are being developed to defend against bioterrorist attacks such as anthrax, plague, and smallpox.^[47]
• Appreciation for sex and pregnancy differences in vaccine responses "might change the strategies used by public health officials".^[49]

Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders.^[50] For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure.^[51] Factors that have impact on the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.^[52]

See also[link]

References[link]

External links[link]

External videos
	Modern Vaccine and Adjuvant Production and Characterization, Genetic Engineering & Biotechnology News

• Vaccines and Antisera at the Open Directory Project
• The History of Vaccines, from the College of Physicians of Philadelphia
• University of Oxford Vaccinology Programme: a series of short courses in vaccinology

Andrew Jeremy Wakefield (born 1957) is a British former surgeon and medical researcher, known as an advocate for the discredited claim that there is a link between the measles, mumps and rubella (MMR) vaccine, autism and bowel disease, and for his fraudulent 1998 research paper in support of that claim.^[1]

Four years after the publication of the paper, other researchers' results had still failed to reproduce Wakefield's findings or confirm his hypothesis of a relation between childhood gastrointestinal disorders and autism.^[2] A 2004 investigation by Sunday Times reporter Brian Deer identified undisclosed financial conflicts of interest on Wakefield's part,^[3] and most of his coauthors then withdrew their support for the study's interpretations.^[4] The British General Medical Council (GMC) conducted an inquiry into allegations of misconduct against Wakefield and two former colleagues.^[5] The investigation centred on Deer's numerous findings, including one that autistic children were subjected to unnecessary invasive medical procedures,^[6] such as colonoscopy and lumbar puncture, and that Wakefield acted without the required ethical approval from an institutional review board.

On 28 January 2010, a five-member statutory tribunal of the GMC found three dozen charges proved, including four counts of dishonesty and 12 counts involving the abuse of developmentally challenged children.^[7] The panel ruled that Wakefield had "failed in his duties as a responsible consultant", acted both against the interests of his patients, and "dishonestly and irresponsibly" in his published research.^[8][9][10] The Lancet immediately and fully retracted his 1998 publication on the basis of the GMC’s findings, noting that elements of the manuscript had been falsified.^[11] Wakefield was struck off the Medical Register in May 2010, with a statement identifying dishonest falsification in the Lancet research,^[12] and is barred from practising medicine in the UK.^[13]

In January 2011, an editorial accompanying an article by Brian Deer in BMJ identified Wakefield's work as an "elaborate fraud".^[1][14][15] In a follow-up article,^[16] Deer said that Wakefield had planned to launch a venture on the back of an MMR vaccination scare that would profit from new medical tests and "litigation driven testing".^[17] Wakefield's study and public recommendations against the use of the combined MMR vaccine were linked to a steep decline in vaccination rates in the United Kingdom and a corresponding rise in measles cases, resulting in serious illness and fatalities.^[18][19][20] Wakefield has continued to defend his research and conclusions, saying there was no fraud, hoax or profit motive.^[21][22]

Personal life and career[link]

Wakefield was born in 1957;^[23][24] his father was a neurologist and his mother was a general practitioner.^[25] After leaving the independent King Edward's School, Bath,^[26] Wakefield studied medicine at St Mary's Hospital Medical School^[25] (now Imperial College School of Medicine), fully qualifying in 1981. He became a fellow of the Royal College of Surgeons in 1985.^[24] At the University of Toronto (U of T) from 1986 to 1989, he was part of a team that studied tissue rejection problems with small intestine transplantation, using animal models.^[27][28] He continued his studies of small intestine transplantation under a Wellcome Trust traveling fellowship at U of T in Canada.^[24]

Back in the UK, he worked on the liver transplant programme at the Royal Free Hospital in London.^[24] In 1995, while conducting research into Crohn's disease, he was approached by Rosemary Kessick, the parent of an autistic child, who was seeking help with her son's bowel problems and autism; Kessick ran a group called Allergy Induced Autism.^[29] In 1996, Wakefield turned his attention to researching the connection between the MMR vaccine and autism.^[24] At the time of his MMR research study, Wakefield was senior lecturer and honorary consultant in experimental gastroenterology at the Royal Free Hospital School of Medicine (from 2008 UCL Medical School). He resigned in 2001,^[30] by "mutual agreement and was made a fellow of the Royal College of Pathologists",^[31] and moved to the US in 2001^[32] or 2004,^[31] both dates according to 'The Times'. One report noted he was asked to leave Royal Free Hospital in 2004 after he did not fulfill a request to duplicate the findings in his controversial Lancet paper.^[33]

Wakefield subsequently helped establish and served as the executive director of Thoughtful House Center for Children, a center for the study of autism in Austin, Texas where, according to The Times he "continued to promote the theory of a link between the MMR vaccine and autism, despite admitting it was 'not proved'."^[31] He resigned from Thoughtful House in February 2010, after the British General Medical Council found that he had been "dishonest and irresponsible" in conducting his earlier autism research in England.^[27][34] The Times reported in May 2010 that he was a medical advisor for Visceral, a UK charity that "researches bowel disease and developmental disorders".^[31]

Wakefield is no longer licensed in the UK as a physician,^[13] and is not licensed in the US.^[35] As of January 2011, he lives in the US where he has a following including celebrities like Jenny McCarthy^[36] who wrote the foreword for Wakefield's autobiography, Callous Disregard, and believes her son's autism is due to vaccines.^[20] According to Deer, as of 2011, he lives near Austin with his wife, Carmel, and four children.^[27]

In 2011, Wakefield was at the top of the list of the worst doctors of 2011 in Medscape's list of "Physicians of the Year: Best and Worst".^[37] In January 2012, TIME Magazine named Wakefield in a list of "Great Science Frauds".^[38]

MMR controversy[link]

On 28 February 1998, a paper written by Wakefield and twelve other authors about twelve autistic children was published in The Lancet.^[39] In it, the authors claimed to have identified a new syndrome which they called autistic enterocolitis, raising the possibility of a link between a novel form of bowel disease, autism, and the MMR vaccine. In the study's "findings", the authors noted that the parents of eight of the twelve children linked what were described as "behavioural symptoms" with MMR, and in its "results" reported that the onset of these symptoms began within two weeks of MMR vaccination.^[39] In the published Lancet summary, known as the "interpretation", the authors wrote:

"We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers."^[39]

These possible triggers were reported to be MMR in eight cases, and measles infection in one. The paper was instantly controversial, leading to widespread publicity in the UK and the convening of a special panel of the UK's Medical Research Council the following month.^[40] One study done based in Japan found that there was no causal relationship between the MMR vaccine and autism in groups of children given the triple MMR vaccine and children who received individual measles, mumps and rubella vaccinations. The MMR was replaced with individual vaccinations in 1993.^[41]

Although the paper said that no causal connection had been proven, and before it was published, Wakefield made statements at a press conference and in a video news release issued by the hospital, calling for suspension of the triple MMR vaccine until more research could be done.^[42] The press conference was later criticized as 'science by press conference'.^[43] According to BBC News, it was this press conference, rather than the Lancet paper, that fueled the MMR vaccination scare.^[44] According to the BBC, "He told journalists it was a 'moral issue' and he could no longer support the continued use of the three-in-one jab for measles, mumps and rubella. 'Urgent further research is needed to determine whether MMR may give rise to this complication in a small number of people,' Dr Wakefield said at the time."^[44] He said, "If you give three viruses together, three live viruses, then you potentially increase the risk of an adverse event occurring, particularly when one of those viruses influences the immune system in the way that measles does."^[42] He suggested parents should opt for single jabs against measles, mumps and rubella, separated by gaps of one year.

In December 2001, Wakefield resigned from the Royal Free Hospital, saying, "I have been asked to go because my research results are unpopular."^[30] The medical school said that he had left "by mutual agreement." In February 2002, Wakefield stated, "What precipitated this crisis was the removal of the single vaccine, the removal of choice, and that is what has caused the furore – because the doctors, the gurus, are treating the public as though they are some kind of moronic mass who cannot make an informed decision for themselves."^[45]

Aftermath of initial controversy[link]

Wakefield continued conducting clinical research in the US after leaving the Royal Free Hospital in December 2001. He joined a controversial American researcher, Jeffrey Bradstreet, at the International Child Development Resource Center, to conduct further studies on the possible relationship between the MMR vaccine and autism.^[46]

In 2004, Wakefield started work at the Thoughtful House research center in Austin, Texas.^[47] Wakefield served as Executive Director of Thoughtful House until February 2010, when he resigned in the wake of findings against him by the British General Medical Council.^[34][48]

In February 2004, controversy resurfaced when Wakefield was accused of a conflict of interest. The Sunday Times reported that some of the parents of the 12 children in the Lancet study were recruited via a UK lawyer preparing a lawsuit against MMR manufacturers, and that the Royal Free Hospital had received £55,000 from the UK's Legal Aid Board (now the Legal Services Commission) to pay for the research.^[49] Previously, in October 2003, the board had cut off public funding for the litigation against MMR manufacturers.^[50] Following an investigation of The Sunday Times allegations by the UK General Medical Council, Wakefield was charged with serious professional misconduct, including dishonesty.^[51] In December 2006, the Sunday Times further reported that in addition to the money they gave the Royal Free Hospital, the lawyers responsible for the MMR lawsuit had paid Wakefield personally more than £400,000, which he had not previously disclosed.^[52]

Twenty-four hours before the 2004 Sunday Times report, The Lancet responded to the investigation in a public statement, describing Wakefield's research as "fatally flawed". The Lancet's editor said he believed the paper would have been rejected as biased if the peer reviewers had been aware of Wakefield's conflict of interest.^[53] Ten of Wakefield's twelve co-authors of the Lancet paper later published a retraction of an interpretation:^[54] The section of the paper retracted read as follows:

"Interpretation. We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers."

The retraction stated:^[54]

"We wish to make it clear that in this paper no causal link was established between (the) vaccine and autism, as the data were insufficient. However the possibility of such a link was raised, and consequent events have had major implications for public health. In view of this, we consider now is the appropriate time that we should together formally retract the interpretation placed upon these findings in the paper, according to precedent."^[55]

Wakefield v Channel 4 and others[link]

In November 2004, Channel 4 broadcast a one-hour Dispatches investigation by reporter Brian Deer; the Toronto Star said Deer had "produced documentary evidence that Wakefield applied for a patent on a single-jab measles vaccine before his campaign against the MMR vaccine, raising questions about his motives".^[27][56]

In addition to Wakefield's unpublished initial patent submission,^[56] Deer released a copy of the published patent application.^[57] At page 1, the first paragraph of this stated:

"The present invention relates to a new vaccine/immunisation for the prevention and/or prophylaxis against measles virus infection and to a pharmaceutical or therapeutic composition for the treatment of IBD (Inflammatory Bowel Disease); particularly Crohn's Disease and Ulcerative Colitis and regressive behavioural disease (RBD) (also referred to as "Pervasive Developmental Disorder)."

Before describing the research in Wakefield's 1998 Lancet paper, at the same page this patent explicitly states that the MMR vaccine causes autism:

"It has now also been shown that use of the MMR vaccine (which is taken to include live attentuated measles vaccine virus, measles virus, mumps vaccine virus and rubella vaccine virus, and wild strains of the aforementioned viruses) results in ileal lymphoid nodular hyperplasia, chronic colitis and pervasive developmental disorder including autism (RBD), in some infants."

According to Deer, a letter from Wakefield's lawyers to him dated 31 Jan 2005 said: "Dr Wakefield did not plan a rival vaccine."^[56]

In the Dispatches programme, Deer also revealed that Nicholas Chadwick, a researcher working under Wakefield's supervision in the Royal Free medical school, had failed to find measles virus in the children reported on in The Lancet.^[58]

In January 2005, Wakefield initiated libel proceedings against Channel 4, the independent production company Twenty Twenty and Brian Deer. At the same time, Wakefield issued libel proceedings against The Sunday Times, and against Deer personally over his website briandeer.com.^[59] Within weeks of issuing his claims, however, Wakefield sought to have the action frozen until after the conclusion of General Medical Council proceedings against him. Fighting back, Channel 4 and Deer obtained a High Court order compelling Wakefield to continue with his action, or discontinue it. After a hearing in court on 27 and 28 October 2005, Mr Justice David Eady ruled against a Stay of proceedings, stating:

"It thus appears that the Claimant wishes to use the existence of the libel proceedings for public relations purposes, and to deter other critics, while at the same time isolating himself from the “downside” of such litigation, in having to answer a substantial defence of justification."

He also said in his judgment:

"I am quite satisfied, therefore, that the Claimant wished to extract whatever advantage he could from the existence of the proceedings while not wishing to progress them or to give the Defendants an opportunity of meeting the claims."^[60]

The judgment identified Channel 4's "very lengthy extracts" regarding Wakefield, where Deer's allegations are that he had:^[60]

i) Spread fear that the MMR vaccine might lead to autism, even though he knew that his own laboratory had carried out tests whose results dramatically contradicted his claims in that the measles virus had not been found in a single one of the children concerned in his study and he knew or ought to have known that there was absolutely no basis at all for his belief that the MMR should be broken up into single vaccines.

(ii) In spreading such fear, acted dishonestly and for mercenary motives in that, although he improperly failed to disclose the fact, he planned a rival vaccine and products (such as a diagnostic kit based on his theory) that could have made his fortune.

(iii) Gravely abused the children under his care by unethically carrying out extensive invasive procedures (on occasions requiring three people to hold a child down), thereby driving nurses to leave and causing his medical colleagues serious concern and unhappiness.

(iv) Improperly and/or dishonestly failed to disclose to his colleagues and to the public at large that his research on autistic children had begun with a contract with solicitors which were trying to sue the manufacturers of the MMR vaccine.

(v) Improperly and/or dishonestly lent his reputation to the International Child Development Resource Centre which promoted to very vulnerable parents expensive products for whose efficacy (as he knew or should have known) there was no scientific evidence.

In addition the Justice Eady's ruling states that "...the views or conclusions of the GMC disciplinary body would not, so far as I can tell, be relevant or admissible...", that Channel 4's allegations "...go to undermine fundamentally the Claimant's professional integrity and honesty..." and that "It cannot seriously be suggested that priority should be given to GMC proceedings for the resolution of issues...".

Other proceedings continued for two years, but in December 2006, Deer reported figures obtained from the Legal Services Commission showing that it had paid £435,643 in undisclosed fees to Wakefield for him to build a case against the MMR vaccine,^[61] payments which The Sunday Times reported had begun two years before the Lancet paper.^[52]

Within days of Deer's report, Wakefield dropped all his libel actions^[62] and was required to pay all the defendants' legal costs.^[63][64]

Other concerns[link]

Other concerns regarding Wakefield were that an extension of his project caused life-threatening complications in one child, who received substantial compensation in an out-of-court settlement.^[65] Wakefield's data were also questioned;^[19] a former graduate student, who appeared in Deer's programme, later testified that Wakefield ignored laboratory data which conflicted with his hypothesis. An independent investigation of a collaborating laboratory questioned the accuracy of the data underpinning Wakefield's claims.^[66]

In June 2005, the BBC programme Horizon reported on an unnamed and unpublished study of blood samples from a group of 100 autistic children and 200 children without autism. They reported finding 99% of the samples contained no trace of the measles virus, and the samples that did contain the virus were just as likely to be from non-autistic children, i.e. only three samples contained the measles virus, one from an autistic child and two from a neuro-typical child. The study's authors found no evidence of any link between MMR and autism.^[67]

The Institute of Medicine (IOM) of the United States National Academy of Sciences,^[68] along with the CDC^[69] and the UK National Health Service,^[70] have found no link between vaccines and autism. Reviews in the medical literature have also found no link between the MMR vaccine and autism or with bowel disease, which Wakefield called "autistic enterocolitis."^[71][72][73]