spb/wp30_uqo

1{2  "document_id": "lb_hotpotqa_76096cce081ab5b9ef72be19076ee0a79d9e9239474e8b73",3  "family": "public_hotpotqa",4  "split": "dev",5  "text": "Passage 1:\nVaccine\nA vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. 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.\nVaccines can be prophylactic (to prevent or ameliorate the effects of a future infection by a natural or \"wild\" pathogen), or therapeutic (to fight a disease that has already occurred, such as cancer). Some vaccines offer full sterilizing immunity, in which infection is prevented completely.The administration of vaccines is called vaccination. 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 restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports that licensed vaccines are currently available for twenty-five different preventable infections.The first recorded use of Inoculation to prevent smallpox occurred in the 16th century in China, with the earliest hints of the practice in China coming during the 10th century . It was also the first disease for which a vaccine was produced.The folk practice of inoculation against smallpox was brought from Turkey to Britain in 1721 by Lady Mary Wortley Montagu.\nThe terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner (who both developed the concept of vaccines and created the first vaccine) to denote cowpox. He used the phrase in 1798 for the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. In 1881, to honor Jenner, Louis Pasteur proposed that the terms should be extended to cover the new protective inoculations then being developed. The science of vaccine development and production is termed vaccinology.\n\nEffects\nThere is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The immune system recognizes vaccine agents as foreign, destroys them, and \"remembers\" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the agent, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status. One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system. A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction. \nIn some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact. They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.The efficacy or performance of the vaccine is dependent on several factors:\n\nthe disease itself (for some diseases vaccination performs better than for others)\nthe strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)\nwhether the vaccination schedule has been properly observed.\nidiosyncratic response to vaccination; some individuals are \"non-responders\" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.\nassorted factors such as ethnicity, age, or genetic predisposition.If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less virulent than in unvaccinated cases.Important considerations in an effective vaccination program:\ncareful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term\nongoing surveillance for the relevant disease following introduction of a new vaccine\nmaintenance of high immunization rates, even when a disease has become rareIn 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. 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 among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.The measles vaccine is estimated to prevent a million deaths every year.\n\nAdverse effects\nVaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine. MMR vaccine is rarely associated with febrile seizures.Host-(\"vaccinee\")-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.Severe side effects are extremely rare. Varicella vaccine is rarely associated with complications in immunodeficient individuals, and rotavirus vaccines are moderately associated with intussusception.At least 19 countries have no-fault compensation programs to provide compensation for those with severe adverse effects of vaccination. The United States' program is known as the National Childhood Vaccine Injury Act, and the United Kingdom employs the Vaccine Damage Payment.\n\nTypes\nVaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.\n\nAttenuated\nSome vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, mumps, and rubella, 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. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. But they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.\n\nInactivated\nSome vaccines contain inactivated, but previously virulent, micro-organisms that have been destroyed with chemicals, heat, or radiation – \"ghosts\", with intact but empty bacterial cell envelopes. They are considered an intermediate phase between the inactivated and attenuated vaccines. Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.\n\nToxoid\nToxoid vaccines are made from inactivated toxic compounds that cause illness rather than the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for micro-organisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.\n\nSubunit\nRather than introducing an inactivated or attenuated micro-organism to an immune system (which would constitute a \"whole-agent\" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitis B, which 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). Another example is edible algae vaccines, such as the virus-like particle (VLP) vaccine against human papillomavirus (HPV), which is composed of the viral major capsid protein. Another example is the hemagglutinin and neuraminidase subunits of the influenza virus. A subunit vaccine is being used for plague immunization.\n\nConjugate\nCertain bacteria have a polysaccharide outer coat that is 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.\n\nOuter membrane vesicle\nOuter membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.\n\nHeterotypic\nHeterologous vaccines also known as \"Jennerian vaccines\", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against tuberculosis.\n\nGenetic vaccine\nThe subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.\n\nViral vector\nViral vector vaccines use a safe virus to insert pathogen genes in the body to produce specific antigens, such as surface proteins, to stimulate an immune response.\n\nRNA\nAn mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the COVID-19 vaccines are a number of RNA vaccines to combat the COVID-19 pandemic and some have been approved or have received emergency use authorization in some countries. For example, the Pfizer-BioNTech vaccine and Moderna mRNA vaccine are approved for use in adults and children in the US.\n\nDNA\nDNA vaccination – The proposed mechanism is the insertion and expression of viral or bacterial DNA in human or animal cells (enhanced by the use of electroporation), triggering immune system recognition. 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 potential advantage of DNA vaccines is that they are very easy to produce and store.\nIn August 2021, Indian authorities gave emergency approval to ZyCoV-D. Developed by Cadila Healthcare, it is the first DNA vaccine approved for humans.\n\nExperimental\nMany innovative vaccines are also in development and use.\n\nDendritic cell vaccines combine dendritic cells with antigens 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 and are also tested in malignant melanoma.\nRecombinant vector – by combining the physiology of one micro-organism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.\nT-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.\nTargeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.\nThe 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.\nBacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.\nAntigen-presenting cellWhile 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.\n\nValence\nVaccines 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. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.\n\nInteractions\nWhen two or more vaccines are mixed 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.\nThis 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. It was also noted in a 2001 study to be a problem with dengue vaccines, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.\n\nOther contents\nAdjuvants\nVaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster.In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.\n\nPreservatives\nVaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal (a.k.a. Thimerosal in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a 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. Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims. Furthermore, a 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.\n\nExcipients\nBeside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations:\nAluminum 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.\nAntibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.\nEgg protein is present in the influenza vaccine and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present.\nFormaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production.\nMonosodium 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.\nThiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.\n\nNomenclature\nVarious fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that \"The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP.\"Some examples are \"DTaP\" for diphtheria and tetanus toxoids and acellular pertussis vaccine, \"DT\" for diphtheria and tetanus toxoids, and \"Td\" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that \"Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case \"d\" and \"p\" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism.\"Another list of established vaccine abbreviations is at the CDC's page called \"Vaccine Acronyms and Abbreviations\", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for \"OPV\" is \"poliovirus vaccine live oral\" rather than \"oral poliovirus vaccine\".\n\nLicensing\nA vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.\n\nWorld Health Organization\nVaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.\n\nEuropean Union\nIn the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the member states comply (\"centralized\"), are licensed for only some member states (\"decentralized\"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.\n\nUnited States\nUnder the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.\n\nIndia\nDrugs Controller General of India is the head of department of the Central Drugs Standard Control Organization of the Government of India responsible for approval of licences of specified categories of drugs such as vaccines AND others like blood and blood products, IV fluids, and sera in India.\n\nPostmarketing surveillance\nUntil a vaccine is in use for the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.\n\nScheduling\nIn order to provide the 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. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. 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.The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.\nBesides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for 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) and UK (as of 2009). 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.Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when it supply is limited, e.g. in the setting of a pandemic.\n\nEconomics of development\nOne 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.Most vaccine development to date has relied on \"push\" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools may be due to government mandates and support, rather than economic incentive.\n\nPatents\nAccording to the World Health Organization, the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier.When increased production of vaccines was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on COVID-19 vaccines, which would \"eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products\".\n\nProduction\nVaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.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). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, 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 to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.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 vaccines 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.\n\nVaccine manufacturers\nThe companies with the highest market share in vaccine production are Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013).: 42  Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43  Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.: 47  The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs.: 48  China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China.: 48  Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49\n\nDelivery systems\nOne of the most common methods of delivering vaccines into the human body is injection.\nThe development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such 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.\nA microneedle approach, which is still in stages of development, uses \"pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin\".An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.\n\nIn veterinary medicine\nVaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. 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.\nWhere 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, Bordetella, canine parainfluenza virus, and Lyme disease, among others.\nCases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years. In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.\n\nDIVA vaccines\nDIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not.The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus 1 infections have been developed.The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus 1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, Actinobacillus pleuropneumonia and Salmonella infections in pigs.\n\nHistory\nPrior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. The earliest hints of the practice of variolation for smallpox in China come during the tenth century. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of \"nasal insufflation\" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.: 60  Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers.\nMary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died. In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840.\nFollowing on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.Vaccinology flourished in the twentieth century, which 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 herpes simplex, malaria, gonorrhea, and HIV.\n\nGenerations of vaccines\nFirst generation vaccines are whole-organism vaccines – either live and weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (TC or CTL) responses, helper T-cell (TH) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T cell responses and may not work at all for some diseases.Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.RNA vaccines and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.\n\nTrends\nSince at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.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. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.\n\nPlants as bioreactors for vaccine production\nThe idea of vaccine production via transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes inserted that cause them to produce vaccines usable for humans. In 2005, bananas were developed that produce a human vaccine against hepatitis B.\n\nVaccine hesitancy\nVaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore characterized vaccine hesitancy as one of the top ten global health threats in 2019.\n\nSee also\nPassage 2:\nMarco Marcola\nMarco Marcola (1740–1793) was an Italian painter, born and mainly active in Verona. He was initially apprenticed to his father Giovanni Battista Marcola. Among his pupils were Antonio Pachera, Bellino Bellini, and Domenico Zanconti. He is also known as Marco Marcuola. His sister Angela Marcola was also a painter.\n\nSources\nZannandreis, Diego (1891).  Giuseppe Biadego (ed.). Le vite dei pittori, scultori e architetti veronesi. Verona: Stabilimento Tipo-Litografico G. Franchini. p. 478.\nPassage 3:\nRue Lhomond\nRue Lhomond is a street in the 5th arrondissement of Paris, France. It is located in the quartier du Val-de-Grâce and has existed since the 15th century. It was once known as rue des Poteries after its Gallo-Roman pottery workshops (re-discovered in the 18th century), then from around 1600 as rue des Pots and finally rue des Postes. It was given its present name in 1867 after the priest, grammarian and scholar Charles François Lhomond (1727-1794).\n\nHistory\nThe street has housed several Catholic seminaries and convents, along with a British seminary established at number 22 by permission of Louis XIV of France in 1684 and active until 1790.Rue Lhomond features in the Georges Simenon novel ′Maigret Takes a Room′. In the novel Maigret takes a room in a boarding house to discover who shot his subordinate Janvier.\n\nBuildings\nPassage 4:\nVatos Locos\nVatos Locos is a Chicano slang term that means \"crazy Dudes\". It is also used as the name of multiple small gangs around the USA, Canada and Mexico. Many \"Vatos Locos\" use the colors red, black, green or brown.The film Blood In Blood Out (1993) which was written by poet Jimmy Santiago Baca, is based on the experiences of gang members of a fictional gang called Vatos Locos.The video game Call of Juarez: The Cartel features a fictional Vatos Locos gang.\n\nSee also\nList of gangs in Mexico\nPassage 5:\nGiuseppe Appiani\nGiuseppe Appiani (1740 or 1754–1812) was an Italian painter of the Neoclassic periods. He was born in Vaprio d'Adda, near Milan, where he was mainly active. His parents moved to Monza, where his first mentor was the painter Giovanni Maria Gariboldi. At age 21, he moved to Milan, where he worked in the studios of Giorgi, and later Giuliano Traballesi. He was active in restoration of paintings. Another painter, Giuseppe Appiani (Porto, c. 1700-Triefenstein, c. 1785), was active in Germany.\nPassage 6:\nMassimiliano Soldani Benzi\nMassimiliano Soldani or Massimiliano Soldani Benzi (15 July 1656 – 23 February 1740) was an Italian baroque sculptor and medallist, mainly active in Florence. Born at Montevarchi, the son of a Tuscan cavalry captain, Soldani was employed by the Medici for his entire career.\n\nName\nHe first went under the name Soldani but, claiming descent from the family of bishop Soldani of Fiesole and from the aristocratic Benzi family of Figline, he applied for and received, in 1693, an official letter acknowledging his nobility based on this ancestry. From this date forward, he called himself, and is referred to in many documents as, Soldani Benzi.\n\nLife\nSoldani began training in the Medici drawing school in Florence. He attracted the attention of Grand Duke Cosimo III de' Medici who sent Soldani to his grand-ducal academy in Rome to study under Ciro Ferri and Ercole Ferrata, and to train in coining. During his years in Rome (1678–81), he showed much promise and was asked by Queen Christina of Sweden to create several medals. He started this enterprise but left it unfinished as Cosimo transferred the artist to Paris to work with the famous medallist Joseph Roettiers.While there in 1682, Soldani came into contact with Charles Le Brun and minister Jean-Baptiste Colbert. Learning that the artist was working on a medal portrait of Louis XIV, a courtier Soldani refers to the courtier as \"Mons.r Duca d'Homone\"  (possibly Louis, duc d'Aumont who was very interested in the art of medals) introduced the young man to the king. The model for this medal of Louis XIV is now in the Art Gallery of Ontario in Toronto.Grand Duke Cosimo in the meantime decided that it was time for Soldani to return to Florence and take charge of the Grand-ducal Mint, the job he was meant to occupy from the very start. Upon the death of the current director, Soldani was officially made Maestro dei Coni e Custode della Zecca in 1688. As such he had his workshop and living quarters in the Uffizi.When he finally gave up work at the age of about 80, Soldani Benzi retired to his Villa Petrolo near Bucine where he died in 1740.\n\nWork\nSoldani developed into one of the finest bronze casters of his time in Europe. Though first specialising as a medallist, Soldani also produced bronze reliefs, bronze vases and free-standing figures and busts.\nFor Joseph Johann Adam, Prince of Liechtenstein, he produced a series of bronze copies of works of the Medici collection, mainly antique busts and figures but also after works by Michelangelo and Gianlorenzo Bernini.Klaus Lankheit recognized in a small bronze Pietà attributed to Soldani at the Walters Art Museum a \"balanced triangular composition\" that is \"almost a relief in form\" and suggested that it had been composed first as a relief; A more elaborate version, with additional figures, in the Kress collection at the Seattle Art Museum, was identified as by Soldani by Ulrich Middeldorf. A second table bronze, Venus and the Wounded Adonis, on a richly-mounted ebony base raised on bronze paw feet, is also at the Walters Art Museum.At rare intervals he exhibited terra cotta bozzetti at the irregularly staged exhibitions of the Accademia del Disegno, Florence: in 1715 a Pietà in terracotta by \"Sig. M.S.\" A highly finished terracotta relief, Agony in the Garden of Gethsemane, doubtless intended as a modello to be cast in bronze as a private devotional work, is in the Metropolitan Museum of Art.A major document of his career is his autobiography, dated 1718, correspondence, and the inventory taken after his death.A collection of his drawings is in the Uffizi in Florence.\n\nDoccia\nAfter his death, his heirs sold some of his wax models to marchese Carlo Ginori, who had them adapted by his chief modeller, Gaspero Bruschi, and reproduced in porcelain at his Doccia porcelain manufactory near Florence. Thus Soldani's Apollo in His Chariot, Venus Plucking the Wings of Cupid and Virtue Overpowering Vice all exist as Doccia porcelain groups.\n\nNotes\nFurther reading\nKlaus Lankheit, Soldani (Benzi), Massimiliano, Oxford Art Online\n\nExternal links\n(Fitzwilliam Museum) Leda and the Swan, bronze\nBiografia em portugues\nEuropean sculpture and metalwork, a collection catalog from The Metropolitan Museum of Art Libraries (fully available online as PDF), which contains material on Benzi (see index)\nPassage 7:\nFrancesco Corneliani\nFrancesco Corneliani (1740-1815) was an Italian painter, mainly active in a Neoclassic style in his native Milan.\n\nHe was born to Carlo Corneliani (or Corneliano), and was intended to become a jeweller. He  trained under Sangiorgi at the Accademia Ambrosiana. In 1760, influenced by the paintings of Anton Rafael Mengs, he left for Parma and worked under Carlo Calani. He returned to Milan where he painted lunette frescoes in the Casa Candiani.\nHe also painted the lunettes over the altars to the side of the chorus in the church of San Sebastiano. He made portraits of the family in the walls of the house of Castiglioni. He painted the four evangelists for the church of San Gervasio in Bergamo.He was a close friend of Andrea Appiani and is described as a man alien to intrigue and vanity, pious without ostentation, he lived retired but always ready to work on works of art and piety He died in Milan.\n\n\n== Sources ==\nPassage 8:\nFrançois Beaucourt\nFrançois Beaucourt (1740–1794) is said to be the first native-born Canadian painter who studied in France with a professional reputation. He was active mainly in the Province of Quebec.\n\nCareer\nFrançois Malepart Beaucourt was born in Laprairie, Quebec. Paul Beaucourt, his father, was an amateur painter and military engineer. After he died, the family seems to have returned to France. In 1773, Beaucourt married the daughter of his painting master, Joseph Camagne, in Bordeaux, afterwards painting in France and Russia. He was accepted into the local academy in Bordeaux in 1784. In Canada, after 1786, he painted a wide variety of subjects, mostly portraits, including a self-portrait in the National Gallery of Canada. In 1792, he worked in Philadelphia but returned to Montreal that year. In 1794, he died in Montreal. One critic speaks of his \"decorative and light provincial rococo\" manner.\nPassage 9:\nNorman Newell\nNorman Newell  (25 January 1919 – 1 December 2004) was an English record producer, who was mainly active in the 1950s and 1960s. He was also the co-writer of many notable songs. As an A&R manager for EMI, he worked with musicians such as Shirley Bassey, Dalida, Claude François, Vera Lynn, Russ Conway, Bette Midler, Judy Garland, Petula Clark, Jake Thackray, Malcolm Roberts, Bobby Crush and Peter and Gordon.\nNewell was particularly known for his recorded productions of West End musicals. His songs have been covered by Judy Garland, Frank Sinatra, Celine Dion and Aretha Franklin. In 1999, Newell's song, \"Portrait of My Love\", originally recorded by Matt Monro in 1960, was honoured at the BMI Awards in London for having two million radio plays.\n\nEarly life\nNewell was born in Plaistow, Essex (now part of Greater London) to a poor family. He aspired to be an actor, but expected to work for London Transport. During the Second World War, Newell befriended the variety performer Bill Waddington, and wrote lyrics to his music. Following the end of the war, Waddington found Newell a job selling sheet music at the Cinephonic Music Company on Charing Cross Road. He began his career as a songwriter for the London-based publisher.\n\nMusic producer\nNewell joined EMI's Columbia label as a staff producer in 1949, and was head of the label for its most successful years. During this period, he produced records by Petula Clark, the French male voice choir Les Compagnons de la Chanson, Josef Locke, Ronnie Ronalde, The Beverley Sisters, Dorothy Squires and the bandleader Victor Silvester. He also discovered the singer Steve Conway, who recorded Newell's \"My Thanks To You\" (with music by Noel Gay).In 1953, Newell moved to the new Philips record label, and produced their first release by a British artist, Johnny Brandon. Newell asked Geoff Love to arrange the song, and this marked the start of their professional relationship, in which Love's albums as Manuel and his Music of the Mountains would be produced by Newell. Following six months working at MGM in America, Newell came back to EMI in 1954, whereupon he recorded the comedians Norman Wisdom and Joyce Grenfell. Although Newell \"did not understand\" rock 'n' roll, he produced albums of the television shows Drumbeat and 6.5 Special. He used Trevor Stanford as a rehearsal pianist, and began recording with him in 1957, under the name Russ Conway, the surname being a tribute to Steve Conway, who had died in 1952.Newell went freelance in 1965, and was then put under contract with EMI, where he produced the top selling single of 1965, \"Tears\", by comedian Ken Dodd.\n\nLyricist\nNewell was also a much sought-after lyricist, sometimes writing under the pen-name David West, and responsible for co-writing songs that included \"Portrait of My Love\" (music by Cyril Ornadel), a UK Singles Chart hit for Matt Monro. In addition, he provided the English lyrics for \"More\" (the theme from the film Mondo Cane). Newell also wrote the English lyrics of Shirley Bassey's 1961 No. 1 hit \"Reach for the Stars\", (composed by Nini Oliviero and Riz Ortolani) and Bassey's \"This Is My Life\" (\"La vita\", written by Antonio Amurri and Bruno Canfora). Commenting on the latter, Bassey said that \"Norman knows more about me than I do.\"Further compositions by Newell were \"The Importance of Your Love\" (\"Important C'est La Rose\", by Gilbert Bécaud); \"Born to Sing\" (\"Mourir Sur scène\", by Dalida); \"Monday Morning Again\" (\"Le Lundi au Soleil\", by Claude François) and \"Never, Never, Never\" (\"Grande grande grande\"), which was a hit for Bassey in 1973. With the composer Philip Green, he co-wrote the United Kingdom's 1963 Eurovision Song Contest entry, \"Say Wonderful Things\", recorded by Ronnie Carroll. The song was later recorded in the United States by Patti Page.He wrote the English lyrics to the German song \"Sailor\", a number one UK hit for Petula Clark and a top ten hit for Anne Shelton in 1961. In 1964, Newell produced Peter and Gordon's number one UK hit \"A World Without Love\", which also topped the charts in the United States and several other countries. The song \"Forget Domani\", from the film The Yellow Rolls-Royce (1964), with lyrics by Newell to music by Riz Ortolani, won a Golden Globe Award for Best Original Song.\nNewell wrote English-language lyrics to \"The White Rose of Athens\" for Nana Mouskouri, and Vicky Leandros's 1972 Eurovision Song Contest winning entry, \"Après toi\" (\"Come What May\"). \"Come What May\" reached No.2 on the UK and Republic of Ireland singles charts in 1972.\nIn his later years, Newell penned lyrics to Pietro Mascagni's \"Intermezzo\" from Cavalleria rusticana. The song, entitled \"Pray For Love\", was recorded by Vince Hill.\nHis numerous contacts in the music publishing industry in the United Kingdom assisted EMI in securing the rights for British recordings of cast albums for many American shows opening in London. Newell also wrote the lyrics for the West End musical Mister Venus (with music by Russ Conway), but the show was not a success. Despite starring Frankie Howerd, the show ran for just 16 performances at the Prince of Wales Theatre in 1958.\n\nLater career\nNewell continued working as a producer into the 1980s, including on Shirley Bassey's Gold selling album I Am What I Am, recorded with the London Symphony Orchestra. \nHe also wrote the English lyrics for the 1983 Julio Iglesias recording of \"Hey\", which featured in the Platinum selling album Julio.He also produced several cast recordings of West End musicals for First Night Records: Seven Brides For Seven Brothers – Original London Cast (1986), Annie Get Your Gun – 1986 London Cast (starring Suzi Quatro and Eric Flynn), Kiss Me, Kate – 1987 Royal Shakespeare Company Cast (starring Paul Jones, Nichola McAuliffe and Fiona Hendley), and South Pacific – 1988 London Cast (starring Gemma Craven and Emile Belcourt). George Martin said of Newell that he \"always wanted to be a Stephen Sondheim,\" but noted that \"his main strength came from his ability to handle big showbiz entertainers.\"Newell retired in 1990. However, he continued to write lyrics, and his final works were with Les Reed.\n\nHonours\nDuring his career, Norman Newell won a Grammy, an Emmy and three Ivor Novello Awards for his contribution to the entertainment industry, as well as six British Music Industry Awards. He was awarded an OBE in 2003.\n\nPersonal life and death\nNewell, who was gay, lived in Rustington, West Sussex. After a series of debilitating strokes, he was moved to a local nursing home. He died on 1 December 2004, aged 85.\nPassage 10:\nProvince of Quebec (1763–1791)\nThe Province of Quebec (French: Province de Québec) was a colony in British North America which comprised the former French colony of Canada. It was established by the Kingdom of Great Britain in 1763, following the conquest of New France by British forces during the Seven Years' War. As part of the Treaty of Paris, France gave up its claim to the colony; it instead negotiated to keep the small profitable island of Guadeloupe.Following the Royal Proclamation of 1763, Canada was renamed the Province of Quebec, and from 1774 extended from the coast of Labrador on the Atlantic Ocean, southwest through the Saint Lawrence River Valley to the Great Lakes and beyond to the confluence of the Ohio and Mississippi Rivers. Portions of its southwest, those areas south of the Great Lakes, were later ceded to the newly established United States in the Treaty of Paris (1783) at the conclusion of the American Revolution; although the British maintained a military presence there until 1796. In 1791, the territory north of the Great Lakes was reorganised and divided into Lower Canada and Upper Canada.\n\nHistory\nUnder the Proclamation, Quebec included the cities of Quebec and Montreal, as well as a zone surrounding them, but did not extend as far west as the Great Lakes or as far north as Rupert's Land.In 1774, the Parliament of Great Britain, Frederick North, Lord North, Prime Minister, passed the Quebec Act that allowed Quebec to restore the use of French customary law (Coutume de Paris) in private matters alongside the English common law system, and allowing the Catholic Church to collect tithes. The act also enlarged the boundaries of Quebec to include the Ohio Country and part of the Illinois Country, from the Appalachian Mountains on the east, south to the Ohio River, west to the Mississippi River and north to the southern boundary of lands owned by the Hudson's Bay Company, or Rupert's Land.\nPrince Edward  Duke of Kent lived in Quebec City \n(Known as the Prince of Quebec)from 1791-1793 this was when Michigan territory was a part of Quebec and a member of Parliament. \nDetroit was transferred to Quebec under the Quebec Act of 1774 . \nIt was then the third-largest city in the Province of Quebec, after Montreal and Quebec. 1792 Detroit, including settlements on both sides of the river, holds its first election, sending\nthree representatives to the Parliament of Upper Canada.\nThe Act Against Slavery, 1793, an anti-slavery act passed in Upper Canada. The Act was created partially in response to Loyalist refugees who brought slaves with them.\nMichigan Territory was a part of Upper Canada from 1790-1796  British control of Detroit and Michigan after the American Revolution. When Quebec split into Lower and Upper Canada in 1791, Michigan was part of Kent County, Upper Canada. It held its first democratic elections in August 1792 to send delegates to the new provincial parliament at Newark (now  Niagara-on-the-Lake). \nWestern District was one of four districts of the Province of Quebec created in 1788 in the western reaches of the Montreal District which were later detached in 1791 to create the new colony of Upper Canada. Known as Hesse District (named after Hesse in Germany) until 1792.\nThrough Quebec, the British Crown retained access to the Ohio and Illinois Countries after the Treaty of Paris (1783) ceded control of this land to the United States. By well-established trade and military routes across the Great Lakes, the British continued to supply not only their own troops but a wide alliance of Native American nations through Detroit, Fort Niagara, Fort Michilimackinac, and so on, until these posts were turned over to the United States following the Jay Treaty (1794).\nQuebec retained its seigneurial system after the conquest. Owing to an influx of Loyalist refugees from the American Revolutionary War, the demographics of Quebec came to shift and now included a substantial English-speaking Protestant element from the former Thirteen Colonies. These United Empire Loyalists settled mainly in the Eastern Townships, Montreal, and what was known then as the pays d'en haut west of the Ottawa River. The Constitutional Act of 1791 divided the colony in two at the Ottawa River, so that the western part (Upper Canada) could be under the English legal system, with English speakers in the majority. The eastern part was named Lower Canada.\n\nGovernors\nIn 1760, following the capitulation of Montreal, the colony was placed under military government, with civil government only instituted beginning in 1764. The following were the governors:\n\nJames Murray 1760–1766\nGuy Carleton, 1st Baron Dorchester 1766–1778\nSir Frederick Haldimand 1778–1786\nGuy Carleton, 1st Baron Dorchester 1786–1796There were also \"lieutenant governors\", but these were merely the deputies of the governors, and should not be confused with the subsequent to 1791 Lieutenant-Governor of Quebec.\n\nGuy Carleton (lieutenant governor to James Murray)\t1766–1768\nHector Theophilus de Cramahé (lieutenant governor to Guy Carleton)\t1771–1782\nHenry Hamilton (lieutenant governor to Frederick Haldimand)\t1782–1785\nHenry Hope (lieutenant governor to the Lord Dorchester)\t1785–1788\nAlured Clarke (lieutenant governor to the Lord Dorchester)\t1790\n\nCounsellors to the governor\nThe Province of Quebec did not have an elected legislature and was ruled directly by the governor with advice from counsellors. A council responsible to advise the governor (then James Murray) on all affairs of state was created in 1764. In 1774, the Quebec Act created a Council for the Affairs of the Province of Quebec to advise the governor on legislative affairs. The Legislative Council served as an advisory council to the governor until a legislative assembly was established after 1791.\nThe individuals James Murray called into the council from 1764 to 1766:\n\nList of councillors under Carleton from 1766 to 1774:\n\nGeography\nAround 1763 to 1764, the province was divided into two judicial districts:\n\nMontreal District – covering the western parts of Quebec along the St. Lawrence River including Montreal and much of Ontario (Eastern and Southern Ontario)\nQuebec District – covering the eastern parts of Quebec along the St. Lawrence and LabradorIn 1790, the Trois-Rivières District was formed out of part of Quebec District.\nThe Trois-Rivières and Quebec districts continued after 1791 when Lower Canada came into existence, while Montreal District west of the Ottawa River became Upper Canada and east of the Ottawa River was partitioned into many electoral districts.\n\nSee also\nFormer colonies and territories in Canada\nTerritorial evolution of Canada after 1867",6  "char_len": 72535,7  "document_hash": "c04e46c81e6abcde3e92df10f208e2edcce47a3ca93bbf12775d52b5ccf4fb80",8  "questions": [9    {10      "question_id": "q00",11      "qtype": "hotpotqa",12      "question": "When did the place in Canada where François Beaucourt (1740-1794) was mainly active acquired its present name?"13    }14  ]15}