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Vaccination or immunization “is a means of providing specific protection against many common and damaging pathogens by stimulating an organism’s immune system to either produce humoral antibodies against the pathogen (or toxins produced by the pathogen) or T cells that can provide cell-mediated immunity” (Ghaffar and Haqqi, 2010). Though ancient scientists did mention about prevention of infectious diseases through immunisation, it was Edward Jenner who developed the first vaccine. The vaccine was developed against small pox in the year 1796. The next vaccine came up almost a century later by Louis Pasteur. The vaccine was anti-rabies vaccine and was first used in 1885. The development of anti-rabies vaccine kindled hope for prevention of other infectious diseases, leading to immense research and development of several other vaccines (Shah, Nitin and Kukrej, 2007).
The term ‘vaccination’ was coined by Edward Jenner. Vaccination is the method of causing immunity to a disease by administration of an antigenic material into the body. The term vaccination is used interchangeably with immunity, which is derived from the Greek word “immune” which means “to be protected.” Several vaccines have been developed which either prevent or ameliorate several infectious diseases. The first disease for which vaccine was developed is small pox. Infact, even before Edward Jenner developed a proper vaccine against small pox, people in India and China inoculated fluids taken from small pox vesicles of patients suffering from mild course of disease.
Despite the marked usefulness of vaccination in the prevention of infectious diseases, vaccination is still a much debated topic and has several medical safety, ethical, political and religious implications. In this essay, vaccination, types of vaccines, implications of vaccination and novel vaccines will be discussed with reference to recent literature.
Mechanism of action of vaccines
Vaccines act by developing immunity to the particular disease by inducing the development of antibodies. There are basically 2 types of immunity, innate immunity and acquired immunity. Innate immunity develops after actual exposure to the disease organism. Acquired immunity develops after exposure to vaccination. Acquired immunity may be active or passive immunity. Active immunity is that immunity that develops following exposure to antigenic stimulus, while passive immunity develops after direct injection of antibodies in the form of either sera or immunoglobulins, inside the body. The type of immunity rendered by vaccination is active immunity. Passive immunity confers temporary protection. The antibodies are taken from individuals or animals who are already infected with the disease. Active immunity renders long term protection (Ghaffar and Haqqi, 2010).
A pathogenic infectious agent induces disease and at the same time triggers the immune system of the host to develop antibodies against the disease. These antibodies help in the recovery of the host from the disease and continue to offer protection to subsequent infections from the same pathogen. This principle has been used for vaccination. Through vaccination, antigens which mimic the original pathogen of the respective disease are introduced into the body. The antigens only trigger the immune response, but do not cause the disease. The immune response may be cell-mediated or humoral, or even both, depending on which series of T helper lymphocytes are stimulated. Stimulation of Th1 series leads to lymphocytic response, while stimulation of Th2 series leads to humoral response.
The timing of vaccine is based on several factors, the most important of which is the susceptibility of the disease, reactogenecity and presence of maternal antibodies. Thus, BCG and OPV vaccines are given at birth, because the child can get exposed to tuberculosis and polio at birth due to absence of maternal immunity and risk of susceptibility at this age. Similarly, vaccines against diphtheria, tetanus, pertussis, hemophilus influenza are given in early childhood for maximum reactogenecity and protection against the diseases (Shah, 2007).
Many vaccines are given together and this makes sense because concurrent administration of more than one vaccine does not interfere with the “take” of one another. It is important to give atleast 4 weeks time before the administration of second dose of the same vaccine (Shah, 2007).
Types of vaccines
The antigens in vaccines may be either live organisms, modified exotoxins, subunits of organisms or whole inactivated organisms. There are basically two types of vaccine: live vaccines and inactivated vaccines. In live vaccines, the pathogen, either virus or bacteria is weakened or attenuated. They act by causing non-clinical and self-limiting disease, thus triggering the immune system and inducing immunity. On administration, the pathogens multiply in the host and trigger immune response. The pathogens do not cause any disease because they are attenuated. However, in immunocompromised patients, live vaccines can cause disease. One major advantage with live vaccines is that a single dose is sufficient to confer long-term immunity. Examples of live vaccines are oral polio vaccine, measles vaccine, mumps vaccine and yellow fever vaccine (Ghaffar and Haqqi, 2010).
Inactivated vaccines consist of either killed pathogens, subunits of pathogens or toxins released by pathogens. The killed vaccines are made up of pathogens which are grown in suitable culture, subsequent to which the pathogens, either bacteria or virus are killed either thermally or chemically with formaldehyde. More often than not, the polysaccharide immunogenic antigen is binded chemically with a protein molecule, to enhance the immunogenecity of the vaccine. Inactivated vaccines have to be given in multiple doses. The immunity is for a short period. Hence boosters doses are essential. Examples of inactivated virus vaccines are, hepatitis A vaccine, inactivated polio vaccine and rabies vaccine. Inactivated bacterial vaccines are whole cell killed typhoid vaccine and pertussis vaccine. Viral subunit vaccine is HBsAg vaccine. Toxoid vaccines are tetanus and diphtheria vaccines. Capsular polysaccharide vaccines are hemophilus influenza, typhoid Vi, pneumococcal and meningococcal vaccines. In these vaccines, though the pathogens are destroyed and are not able to undergo replications, the capsid proteins, which are antigens are recognized by the immune system of the vaccinees, causing an immune response (Ghaffar and Haqqi, 2010). Bacterial subunit vaccine is acellular pertussis vaccine. Sub-unit vaccines are those which use purified components of the cell wall to initiate immune response in the vaccinee. Some of the examples of such vaccines are meningococcus, pertussis, hemophilus and pneumococcus vaccines. An interesting vaccine worth discussing at this juncture is the hepatitis-B vaccine which is developed by purification of the antigenic proteins that are manufactured subsequent to expression from a gene that is cloned into a vector like yeast (Ghaffar and Haqqi, 2010). Polysaccharide vaccines are basically weak antigens that are T-independent and hence cause IgM responses without development of immunologic memory that is critical for stable and long-term immunity. In such vaccines, the immunogenecity is enhanced by conjugating the antigens with other proteins like meningococcus, hemophilus and pneumococcus that are T-dependent and induce immulogic memory (Ghaffar and Haqqi, 2010).
The type of vaccination needed for a specific disease depends on the pathogenesis of the disease. For example, pathogens like diphtheria and tetanus cause the disease by releasing certain toxins called exotoxins. In these cases, antibodies which neutralise and prevent the binding of the exotoxin to respective receptors on the target cells prevent the disease. Thus vaccines against diphtheria and tetanus are toxoids. On the other hand, other pathogens have other pathogeneses, and consequently, antibodies which either react directly with the pathogen or eliminate the pathogen through either intracellular killing, complement mediated lysis or phagocytosis are essential. Pathogens like protozoa, viruses and intracellular bacteria which harbor inside the cells cannot be accessed by the antibodies and in such diseases, cells harboring the pathogens need to be destroyed (Ghaffar and Haqqi, 2010).
Immunity conferred by a particular vaccine may be either lifelong or may last for few months. Examples of former type of vaccines are mumps, rubella, measles, tuberculosis, small pox and yellow fever. Cholera vaccine confers immunity only for few months and hence may be used only during outbreaks. Vaccines like diphtheria, tetanus, pertussis, polio and hemophilus influenza are part of primary immunization and must be given between 2-3 months of age. Mumps, measles and rubella vaccines must be given between 13- 15 months (Shah et al, 2007).
Adjuvants are those chemicals which are added in the vaccine to enhance the immunogenecity of the vaccines. The most widely used adjuvants are aluminum salts, which are used in DPT. Other adjuvants which are in experimental stage include Freud’s complete and incomplete adjuvants, certain oligonucleotides and some synthetic polymers. Certain bacteria also act as adjuvants and examples are Nocardia and BCG. Adjuvants increase immunogenecity by recognizing TOLL-like receptors, leading to activation of mononuclear phagocytes and induction of certain cytokines which enhance Th1 and Th2 responses (Ghaffar and Haqqi, 2010).
Prophylactic and therapeutic immunisation
Most of the vaccines are given as a prophylactic measures against their respective diseases, in the sense, the vaccines are given prior to exposure to the disease pathogen. In case of rabies and tetanus, the vaccination is given after exposure to the pathogen and this is known as post-exposure immunization. In some situations like tetanus, which has very short incubation period, both active and passive immunisation may be necessary post-exposure (Shah, 2007).
Only particular strains are used for the development of any vaccine. Danish 1331 and Copenhagen are the commonly used strains in the BCG vaccine. Both are strains of mycobacterium bovis. In each 0.1ml, 0.1- 0.4 million live viable bacilli are present. Each vial of OPV vaccine contains more than one million inactivated viruses 1,2 and 3. Measles vaccine is derived from live attenuated Edmonston Zagreb strain that is grown in the human diploid cell culture. MMR vaccine vaccine contains 1000 TCID50 of measles, 5000 TCID50 of mumps and 1000 TCID50 of rubella virus . There are several strains from which measles vaccine is developed and they are Edmonston Zagreb, Schwarz, Moraten and Edmonston B strains. The strains are grown in human diploid cell culture and live attenuated viruses are used to prepare the vaccine. Of these, Edmonston Zagreb strain is the most commonly used strain. The mumps strains used are Urabe AM9, Leningrad-Zagreb, RIT 4385 or Jerryl Lynn. The efficacy between various strains is similar. The strains are grown in chick embryo or human diploid cell cultures. For preparing the rubella vaccine, the strain used is RA 27/3 vaccine strain. The virus is grown in human diploid or chick embryo cell cultures. Live attenuated form of the virus is used for preparation of the vaccine (Shah, 2007).
BCG vaccines are available in multi-dose dark colored ampoules. Single dose vaccine is not available. The vials are available as 10-dose vial and 20 dose vial. The 10 dose vial has to be reconstituted with 0.5 ml of normal saline and the 20 dose vial has to be reconstituted with 1ml sodium chloride solution (Shah, 2007).
Storage again, depends on the type of vaccine. Constituents of BCG vaccine are freeze-dried and can be stored at temperatures between 2-80 degree centigrade for one year. The preparation is vacuum sealed. Hence the ampoule must be opened carefully after gradual filing to avoid sudden entry of air and spillage of the contents. Reconstitution is done using normal saline. The vaccine has no preservative and thus the chances of bacterial contamination are high. Hence after reconstitution, the vaccine must be used within 4 hours and the left over vaccine must be discarded. Until those 4 hours, the vaccine has to be stored between 2- 8 degree centigrade. Oral polio vaccine contains stabilising agent magnesium sulphate and hence is stable after refrigeration. At state and district levels, the polio vaccine stocks must be stored at -200 degree centigrade. In clinics, it must be stored in the freezer. While transferring the vaccine to an outreach facility, the vaccine must be carried in proper vaccine carriers loaded with ice packs to maintain temperature between 2- 80 degree centigrade. DPT vaccine has to be stored between 2-8 degree centigrade. The vaccine should never be frozen and any vial accidentally frozen must be discarded. Measles vaccine can either be frozen or stored in refrigerator compartment (Shah, 2007).
Shelf life varies from vaccine to vaccine. While some vaccines can be stored for several years, some others can be stored only for few months. For BCG, when stored under recommended temperatures in dark place, the shelf life is 24 months. Measles vaccine is supplied as freeze-dried and the shelf-life is 1-2 years or even more (Shah, 2007).
While some vaccines like DPT and typhoid are ready-to-use vaccines, others like BCG, measles and hemophilus influenza vaccines are freeze dried need to be reconstituted with appropriate solutions. BCG vaccine has to be reconstituted with sodium chloride solution provided by the manufacturers. measles vaccine must be reconstituted with sterile water. The vaccine does not have any preservative and hence strict asepsis must be maintained while diluting and aspirating contents. Reconstituted vaccine must not be stored (Shah, 2007).
Site and mode of administration depends on the vaccine. For BCG, the vaccine can be given anywhere. However, the recommended site is the convex aspect of the left shoulder for the purpose of easy visualization of the scar. The most preferred site of injection is the site at which the deltoid inserts into the humerus. Injection at sites higher than this level on the arm are likely to develop keloid (CDC, 2009).
Oral polio vaccine is administered orally. The principle behind oral vaccination is that high gut immunity levels prevent transmission of the wild or pathogenic polio viruses. DPT, Hemophilus influenza, inactivated polio , hepatitis A, hepatitis B, typhoid, and other such vaccine shave to be given intramuscularly and measles, mumps, rubella and varicella vaccines need to be given subcutaneously.
The seroconversion rates of the oral polio vaccine are variable. For polio viruses type- 1, 2 and 3, the seroconversion rates after one dose of vaccine are 73%, 90% and 70%. Hence multiple doses are recommended to achive seroconversion of 90- 95 percent for all the 3 types of vaccine (Shah, 2007).
Advantages of vaccination
The advantages of vaccines are innumerous and hence all countries in the world have adopted vaccination in their public health policy. infact, vaccination is the best means of prevention of certain infectious disease, especially in new borns, infants and childrens who are vulnerable to certain diseases. In many cases, even if the vaccinee develops the disease for which he or she is vaccinated, the course of the disease is usally mild and recovery is fast. Attenuated vaccines trigger all phases of immune system and confer more stable immunity. Most live attenuated vaccines need no boosters. they are cheap and immunity develops quickly. The drugs are easy to transport. Some live vaccines like oral polio vaccine are easy to administer, can be given orally (Shah, 2007).
Vaccines are useful not only to prevent disease, but also to eradicate the disease from the globe. Small pox, a deadly poxy disease was eradicated from the world only through vaccination. Currently, polio is on the verge of eradication because of oral polio vaccines and inactivated polio vaccine. However, there is ongoing debate about the continuing use of these vaccines with respect to community protection, as against individual protection. This debate arises in the wake of rising cases of paralytic poliomyelitis and vaccine derived polioviruses with oral polio vaccine (Thacker and Shendurnikar, 2003). Researchers are under the opinion that once poliovirus is eradicated, vaccine derived poliomyelitis will surge if oral polio vaccine administration is continued. To gaurd the development of this problem, inactivated polio vaccine which is administered in the form of injection is being introduced even in developing and underdeveloped countries (Shah, 2007).
Bacillus Calmette Guerin vaccine or BCG vaccine is a vaccine against tuberculosis that was first developed in 1921 by Albert Calmette, a French microbiologist and Camille Guerin, a veterinary surgeon. Currently, BCG is the only vaccine against tuberculosis. The mechanism of immunity induced by this vaccine is cell-mediated immunity. The protective effect of this vaccine is not very good, especially for pulmonary tuberculosis (<50%). However, it is recommended to give this vaccine to all children at birth for whatever little protection it offers in view of the high rates of incidence and prevalence of tuberculosis in the country. The vaccine is more efficacious is preventing miliary and meningeal tuberculosis, both of which are associated with high morbidity and mortality (50%- 80%) (National Tuberculosis Advisory Committee, 2006).
Vaccines are a of immense economic value in the health care system and this is evident from the cost-benefit ratios (1:10) of poliomyelitis and measles (Mason et al, 2002). However, in developing and underdeveloped countries many people do not have the access to many vaccines due to lack of infrastructure, coordinated health policies and cost factor.
Disadvantages of vaccination
Vaccination is associated with many side effects. However the benefits of vaccination outweigh the disadvantages of vaccination. The safety of vaccines is always a disputed aspect, expecially by critics. However, vaccines are selected basically based on the “necessity, safety and efficacy” and they licensed only after undergoing 3 phases of trials. The first phase is on human volunteers for safety and tolerance aspects. The second trial tests immune response and safety in human volunteers and the third trial checks for field efficacy nd safety. After these trials, potency, purity and sterility tests are performed by both the manufacturer and the Drug controller of the country and only when these are satisfactory is the vaccine released into market.
The efficacy of certain vaccines like BCG is doubted. While many studies have shown this vaccine to be efficacious, promoting its ised in Asian and African countries, the vaccine is not recommended for routine use in the United States because of the doubts casted on the benefits of the vaccine through some studies (CDC, 2009).
Improper manufacturing of inactivated vaccines can result in infections due to intact pathogens. Booster doses are essential for inactivated vaccines because the antigens cannot reproduce and thus periodic reinforcement of immune response is mandatory (Ghaffar and Haqqi, 2010).
Some previous studies published a causal relationship betwen measles-mumps-rubella vaccine and autism. However, the Institute of Medicine nd Immunisation Safety Review Committee (2004) investigated the relationship and rejected the causal relationship.
Though vaccination against varicella is highly efficacious, many experts do not recommend the vaccine because naturally acquired immunity offers protection life long and prevents adult chicken more which is more severe than childhood chicken pox. Infact, some studies have shown that iniversant infant vaccination of chicken pox will cause a surge in chicken pox in adulthoos and during pregnancy. Based on these studies, experts are of the opinion that though chicken pox vaccination prevents economic loss due to loss of work time, health care costs may arise (Ferson, 1995). Some experts are of the opinion that the shift of surge in cases towards adulthood and oldage can be minimised by administering the vaccine in 2-3 doses, instead of single dose (Senterre, 2004). In some countries, a new combination vaccine consisting of vaccines against measles, mumps, rubella and varicella has been developed. While the argument as to whether universal vaccination against varicella continues, this combination vaccine is viewed from a critical point because of increased risk of febrile seizures. (Klein et al, 2010).
Vaccine against Japanese Encephalitis, a zoonotic viral disease is widely used in countries in Asia. The vaccine is an inactivated vaccine developed from infected brain tissue of mouse. This vaccine is expensive and needs to be administered in 2-3 doses. Even booster dose is required for this vaccine. However the vaccine is associated with adverse reactions in significant number of people. In China and other regions like Korea, a cheap vaccine is used with strain SA 14- 14- 2. This vaccine is not associted with significant allergic reactions. Though the vaccine has been deemed effective, there are not many trials to support the safe and efficient use of this vaccine (Plesner, 2003).
Some vaccines are very costly. For example, the vaccines against HPV virus, for the prevention of cervical cancer are around 100US dollars. The efficacy of the vaccine is 70 percent and hence screening for cervical cancer needs to be done even despite vaccination. The vaccine has to be given in 3 doses and many people cannot afford the price (Madrid-Madrina, 2009).
Live attenuated vaccines are difficult to transport and have a risk of undergoing secondary mutation which can cause virulence. Also, these vaccines can cause disease in immunosuppressed persons, which makes them useless in those with immunocompromise. It is for these reasons that live oral polio virus vaccine, also known as the Sabin vaccine is being gradually replaced by inactivated polio vaccine or Salk vaccine.
Almost all vaccines have some adverse effects. The most common adverse effect is soreness and redness at the site of injection. other adverse effects include fever, malaise, disconfort, allergic reaction or even neurological problems. The type of side effect depends on the vaccine. In BCG, adverse reaction in the form of papule and ulcer formation is an indication of successful vaccine administration. Soon after the vaccine is administered a wheal of atleast 5 mm develops which is an indication that the vaccine was administered in the most appropriate manner. After about 2-3 weeks, a small papule develops at the site of injection which gradually increases in size to about 4- 8mm by the end of 5-6 weeks. After about 6 weeks, the papule ruptures and an ulcer develops. This ulcer heals slowly and develops a scar after 6- 12 weeks. Other undesirable adverse reactions can occur in 1-10 percent cases. They are delayed healing of ulcer, lymphangitis, enlargement of ipsilateral cervical and axillary lymph nodes, abscess formation, osteomyelitis and rarely disseminated BCG vaccination. After DPT administration, side effects in noted in more than 40 percent of vaccinees. The most common adverse effect noted is pain and redness at the site of injection. The pain may be so severe that the child may not be able to move the limb and walk. Induration and swelling may also be present. Fever is also very common. It may last for 24- 72 hours and responds well to paracetamol. All children who have been administered this vaccine must receive paracetamol whether there is fever or not, for control of pain. Other systemic side effects include vomiting, anorexia, irritability, lassitude and excessive crying.The side effects are due to pertussis vaccine. Rarely, seizures can occur after administration of the vaccine. For vaccines like measles and varicella, rash and fever many occur (Shah, 2007).
Some adverse effects can be nasty. For example, Swine flu vaccine is associated with Guillian barre syndrome, anaphylactic shock, vasculitis, paralysis and even death and this aspect is preventing many individuals from taking the vaccine.(Menzies et al, 2008). Pneumococcal vaccine can rarely can anaphylactic shock or even convulsions (Haber et al, 2009).
Thus vaccination is associated with several risks and prior to administration of vaccines, the risks and benefits must be ascertained.
2 ore more vaccines can be either given together at the same time. Currently, two or more vaccines are administered through the same injection. The combination depends on the vaccine and the manufacturer’s criteria. For several years, diphtheria, tetanus and pertussis were given as combination vaccine, known as DPT. Similarly measles, mumps and rubella are also available as combination vaccines. other recent combination vaccines include hepatitis A and B vaccines, DPT with hemophilus influenza and inactivated polio vaccine, etc. Combination vaccines are safe and reduce the number of injections that need to be given to the child. They do not decrease the efficacy of vaccination. They increase the compliance to vaccination (Shah, 2007).
Some novel vaccines have been developed and are under trial in the wake of debate between advantages and disadvantages of current vaccines available. Some of the important ones are DNA vaccines, immunodominant peptides and anti-idiotype molecules. of recent interest in the field of vaccination are plant-vaccines, which are erived from plants and can be administered orally or through oral mucosa (WHO, 2010). The vaccines derived thus are expected to be cheap with minimal side effects. research in plant vaccines is a result of revolution in proteomics and genomics, and greater understanding of the molecular basis of infectious diseases and advances in modern biotechnology. Edible plant vaccines employ a new strategy of combining plant biology with medical science. Research has shown that some variants of tobacco express hepatitis B surface antigen and streptomutans surface protein and infact the torch of research in plant-derived vaccines is taken from here. Novel vaccines have only ‘sub-units’ of the pathogen and hence do not cause any virulence even in immunosuppressed patients. other than tobacco, other plants which are potential sources of vaccines are tomato, banana, alfalfa, legumes and certain cereals (Refer figure and tables below). Some research has pointed to the role of oral transgenic plant-derived vaccines in the prevention of diarrhoeal diseases by some pathogens like norovirus, enterotoxigenic Escherichia coli and cholera (Tacket, 2004). Plant-derived vaccines have several advantages. Besides lower cost of vaccination, another major advantages of the vaccines are that they are administered orally and hence the need for injection equipment is not needed. This decreases the risks associated with injections like unsafe injection, poor sterilization, misuse and reuse. The vaccines will need less rigorous formulations for manufacture and supply unlike injections. Another major advantage of plant-derived vaccines is heat stability which avoids the maintenance of expensive cold-chains, and allows easy portability of the vaccine. Since most of the plant-derived vaccines are effective mucosally, it is an advantage because most infections are acquired through mucosa and mucosal immunity prevents entry of the pathogens into the host. Plant-derived vaccines can be given as combination vaccines. Plant derived vaccines can be given even for diseases not covered under regular vaccination like sexually transmitted diseases, dengue hookworm and HIV. The development of plant-derived vaccines is yet in cocoon stage due to return of investment doubts, uncertain licentures, limited human trials and lack of expertise (Arzten, 2002).
Fig.1. Plant derived vaccine development strategy (Das, 2009).
Table 1. Antigens produced in transgenic plants (Das, 2009)
Hepatitis B surface antigen
Rabies virus glycoprotein
Norwalk virus capsid protein
E.coliheat-labile enterotoxin B subunit
Cholera toxin B subunit
Mouse glutamate decarboxylase
VP1 protein of foot and mouth disease virus
Glycoprotein swine-transmissible gastroenteritis
Table-2. Transient production of antigens in plants after infection with plant viruses expressing a recombinant gene (Das, 2009)
Protein Plant Carrier
Influenza antigen Tobacco TMV
Murine zona pellucida antigen Tobacco TMV
Rabies antigen Spinach AFMV
HIV-1 antigen Tobacco AFMV
Mink enteritis virus antigen Black eyed bean CPMV
Colon cancer antigen Tobacco TMV
Table-3 Antibodies and antibody fragments produced in transgenic plants (Das, 2009)
Antibody Antigen Plant
IgG (k) Transition stage analog Tobacco
IgM (Î») NP(4-hydroxy-3-nitrophenyl) Tobacco
Single domain (dAb) Substance P Tobacco
Single chain Fv Phytochrome Tobacco
Single chain Fv Artichoke mottled virus Tobacco
Fab; IgG (k) Human creatin kinase Arabidopsis
IgG (k) Fungal cutinase Tobacco
IgG (k) and SIgG/A S. mutagens adhesin Tobacco
Single chain Fv Abscisic acid Tobacco
Single chain Fv Nematode antigen Tobacco
Single chain Fv Î²-glucuronidase Tobacco
Single chain Atrazin, Paraquat Tobacco
IgG Glycoprotein B of Soybean
Herpes simplex virus
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