《免疫学》（英文版） Chapter 18 Vaccines

chapter 18 caines HE DISCIPLINE OF IMMUNOLOGY HAS ITS ROOTS IN the early vaccination trials of Edward Jenner and Louis Pasteur. Since those pioneering efforts, vac cines have been developed for many diseases that were once major afflictions of mankind. The incidence of diseases such rubella(german measles), poliomyelitis, and tetanus has de clined dramatically as vaccination has become more com- mon. Clearly, vaccination is a cost-effective weapon for Vaccination with DNA disease prevention. Perhaps in no other case have the bene fits of vaccination been as dramatically evident as in the Active and Passive Immunization eradication of smallpox, one of mankind's long-standing and most terrible scourges. Since October 1977, not a single Designing Vaccines for Active Immunization naturally acquired smallpox case has been reported any- n Whole-Organism Vaccines where in the world. Equally encouraging is the predicted eradication of polio. The last recorded case of naturally ac- Purified Macromolecules as vaccines g Recombinant- Vector Vaccines 1991, and the World Health Organization(WHO) predicts that paralytic polio will be eradicated throughout the world DNA Vaccines within the next few years. A new addition to the weapons Multivalent Subunit vaccines gainst childhood disease is a vaccine against bacterial pneu- monia, a major cause of infant death a crying need remains for vaccines against other diseases Every year, millions throughout the world die from malaria, tuberculosis, and AIDS, diseases for which there are no effec- common usage. Experience has shown that not every vaccine tive vaccines. It is estimated by the World Health Organiza- candidate that was successful in laboratory and animal stud tion that 16,000 individuals a day, or 5.8 million a year, ies prevents disease in humans. Some potential vaccines become infected with HIv-1, the virus that causes AIDS. An cause unacceptable side effects, and some may even worsen effective vaccine could have an immense impact on the con- the disease they were meant to prevent. Live virus vaccines trol of this tragic spread of death and disaster. In addition to pose a special threat to those with primary or acquired im or thew enges presented by diseases for which no vaccines ex- munodeficiency(see Chapter 19). Stringent testing is an ist, there remains the need to improve the safety and efficacy solute necessity, because vaccines will be given to large of present vaccines and to find ways to lower their cost and numbers of well persons. Adverse side effects, even those that deliver them efficiently to all who need them, especially in de- occur at very low frequency, must be balanced against the po- loping countries of the world. The Who estimates that tential benefit of protection by the vaccine millions of infant deaths in the world are due to diseases that Vaccine development begins with basic research. Recent could be prevented by existing vaccines(see Clinical Focus). advances in immunology and molecular biology have led to The road to successful development of a vaccine that can effective new vaccines and to promising strategies for finding be approved for human use, manufactured at reasonable new vaccine candidates. Knowledge of the differences in epi cost, and efficiently delivered to at-risk populations is costly, topes recognized by t cells and B cells has enabled immuno ng, and tedious. Procedures for manufacture of materials ogists to begin to design vaccine candidates to maximize that can be tested in humans and the ways they are tested in activation of both arms of the immune system. As differences clinical trials are regulated closely. Even those candidate in antigen-processing pathways became evident, scientists cines that survive initial scrutiny and are approved for use in began to design vaccines and to use adjuvants that maximize human trials are not guaranteed to find their way into antigen presentation with class I or class II MHC molecules

common usage. Experience has shown that not every vaccine candidate that was successful in laboratory and animal stud￾ies prevents disease in humans. Some potential vaccines cause unacceptable side effects, and some may even worsen the disease they were meant to prevent. Live virus vaccines pose a special threat to those with primary or acquired im￾munodeficiency (see Chapter 19). Stringent testing is an ab￾solute necessity, because vaccines will be given to large numbers of well persons. Adverse side effects, even those that occur at very low frequency, must be balanced against the po￾tential benefit of protection by the vaccine. Vaccine development begins with basic research. Recent advances in immunology and molecular biology have led to effective new vaccines and to promising strategies for finding new vaccine candidates. Knowledge of the differences in epi￾topes recognized by T cells and B cells has enabled immunol￾ogists to begin to design vaccine candidates to maximize activation of both arms of the immune system. As differences in antigen-processing pathways became evident, scientists began to design vaccines and to use adjuvants that maximize antigen presentation with class I or class II MHC molecules. chapter 18 ■ Active and Passive Immunization ■ Designing Vaccines for Active Immunization ■ Whole-Organism Vaccines ■ Purified Macromolecules as Vaccines ■ Recombinant-Vector Vaccines ■ DNA Vaccines ■ Multivalent Subunit Vaccines Vaccines T        the early vaccination trials of Edward Jenner and Louis Pasteur. Since those pioneering efforts, vac￾cines have been developed for many diseases that were once major afflictions of mankind. The incidence of diseases such as diphtheria, measles, mumps, pertussis (whooping cough), rubella (German measles), poliomyelitis, and tetanus has de￾clined dramatically as vaccination has become more com￾mon. Clearly, vaccination is a cost-effective weapon for disease prevention. Perhaps in no other case have the bene￾fits of vaccination been as dramatically evident as in the eradication of smallpox, one of mankind’s long-standing and most terrible scourges. Since October 1977, not a single naturally acquired smallpox case has been reported any￾where in the world. Equally encouraging is the predicted eradication of polio. The last recorded case of naturally ac￾quired polio in the Western Hemisphere occurred in Peru in 1991, and the World Health Organization (WHO) predicts that paralytic polio will be eradicated throughout the world within the next few years. A new addition to the weapons against childhood disease is a vaccine against bacterial pneu￾monia, a major cause of infant death. A crying need remains for vaccines against other diseases. Every year, millions throughout the world die from malaria, tuberculosis, and AIDS, diseases for which there are no effec￾tive vaccines. It is estimated by the World Health Organiza￾tion that 16,000 individuals a day, or 5.8 million a year, become infected with HIV-1, the virus that causes AIDS. An effective vaccine could have an immense impact on the con￾trol of this tragic spread of death and disaster. In addition to the challenges presented by diseases for which no vaccines ex￾ist, there remains the need to improve the safety and efficacy of present vaccines and to find ways to lower their cost and deliver them efficiently to all who need them, especially in de￾veloping countries of the world. The WHO estimates that millions of infant deaths in the world are due to diseases that could be prevented by existing vaccines (see Clinical Focus). The road to successful development of a vaccine that can be approved for human use, manufactured at reasonable cost, and efficiently delivered to at-risk populations is costly, long, and tedious. Procedures for manufacture of materials that can be tested in humans and the ways they are tested in clinical trials are regulated closely. Even those candidate vac￾cines that survive initial scrutiny and are approved for use in human trials are not guaranteed to find their way into Vaccination with DNA

aRT Iv The Immune System in Health and Disease CLINICAL FOCUS Vaccination Challenges in the such as the contention that vaccines U.S. and Developing Countries countered by correct information from trusted sources to retreat from our progress in immunization by noncom- recently of a causal relationship between pliance will return us to the age when eviously common vaccination and autism, a condition of measles, mumps, whooping cough, and childhood diseases are seldom seen in unknown etiology. Most such reports polio were part of the risk of growing up the United States, a testament to the ef- are based solely on the coincidental tim- Children in the developing world suf- fectiveness of vaccination. A major bar- ing of vaccination and onset of disease, fer from a problem different from those rier to similar success in the rest of the or on limited sampling and poor statisti- in the United States. Examination of in- world is the difficulty of delivering vac. cal analyses. So far, no alleged asso- fant deaths worldwide shows that exist- cines to all children. However, even at ciations have withstood scrutiny that ing vaccines could save the lives of home the U.S. is becoming a victim of included large population samples and millions of children. As seen in the table, its own success. Some parents who acceptable statistical methods. there are safe, effective vaccines for five have never encountered diseases now While children in this country are pro- of the top ten killers of children. Al nearly vanquished in the U.S. do not tected against a variety of once-deadly though the list of diseases in the table in consider it important to have their in- diseases, this protection depends on cludes HIV, TB, and malaria, for which fants vaccinated or they may be lax in continuation of our immunization pro- no vaccines are available, administration adhering to recommended schedules of grams. Dependency on herd immunity is of the vaccines that are recommended immunization. Others hold the unin. dangerous for both the individual and for infants in the United States could cut formed belief that the risks associated society. Adverse reactions to vaccines child mortality in the world by approxi- with vaccination outweigh the risk of in- must be examined thoroughly, of course, mately half fection. This flawed reasoning is fueled and if a vaccine causes unacceptable What barriers exist to the achievement by periodic allegations of linkage be- side reactions, the vaccination program of worldwide vaccination and complete tween vaccination and various disor- must be reconsidered. At the same time, eradication of many childhood diseases? ders, such as the report circulating anecdotal reports of disease brought on The inability to achieve higher levels of Genetic engineering techniques can be used to develop vac- do not cause disease or with antigenic components from the cines to ze the immune response to selected epitopes pathogens. This section describes current usage of passive and to delivery of the vaccines. This chapter de- and active immunization techniques scribes the vaccines now in use and describes vaccine strate- gies, including experimental designs that may lead to the Passive Immunization Involves transfer vaccines of the future of Preformed Antibodies Jenner and Pasteur are recognized as the pioneers of vaccina tion, or induction of active immunity, but similar recogni- Active and Passive Immunization tion is due to Emil von Behring and Hidesaburo Kitasato for their contributions to passive immunity. These investigators Immunity to infectious microorganisms can be achieved by were the first to show that immunity elicited in one animal active or passive immunization In each case, immunity can can be transferred to another by injecting it with serum from be acquired either by natural pr from mother to fetus or by previous infection by the organ Passive immunization, in which preformed antibodies are ism)or by artificial means such as injection of antibodies or transferred to a recipient, occurs naturally by transfer of ma- vaccines(Table 18-1, on page 416). The agents used for in- ternal antibodies across the placenta to the developing fetus ducing passive immunity include antibodies from humans or Maternal antibodies to diphtheria, tetanus, streptococci, animals, whereas active immunization is achieved by inocu- rubeola, rubella, mumps, and poliovirus all afford pa lation with microbial pathogens that induce immunity but sively acquired protection to the developing fetus. Maternal

414 PART IV The Immune System in Health and Disease recently of a causal relationship between vaccination and autism, a condition of unknown etiology. Most such reports are based solely on the coincidental tim￾ing of vaccination and onset of disease, or on limited sampling and poor statisti￾cal analyses. So far, no alleged asso￾ciations have withstood scrutiny that included large population samples and acceptable statistical methods. While children in this country are pro￾tected against a variety of once-deadly diseases, this protection depends on continuation of our immunization pro￾grams. Dependency on herd immunity is dangerous for both the individual and society. Adverse reactions to vaccines must be examined thoroughly, of course, and if a vaccine causes unacceptable side reactions, the vaccination program must be reconsidered. At the same time, anecdotal reports of disease brought on by vaccines, and unsupported beliefs, such as the contention that vaccines weaken the immune system, must be countered by correct information from trusted sources. To retreat from our progress in immunization by noncom￾pliance will return us to the age when measles, mumps, whooping cough, and polio were part of the risk of growing up. Children in the developing world suf￾fer from a problem different from those in the United States. Examination of in￾fant deaths worldwide shows that exist￾ing vaccines could save the lives of millions of children. As seen in the table, there are safe, effective vaccines for five of the top ten killers of children. Al￾though the list of diseases in the table in￾cludes HIV, TB, and malaria, for which no vaccines are available, administration of the vaccines that are recommended for infants in the United States could cut child mortality in the world by approxi￾mately half. What barriers exist to the achievement of worldwide vaccination and complete eradication of many childhood diseases? The inability to achieve higher levels of Many previously common childhood diseases are seldom seen in the United States, a testament to the ef￾fectiveness of vaccination. A major bar￾rier to similar success in the rest of the world is the difficulty of delivering vac￾cines to all children. However, even at home the U.S. is becoming a victim of its own success. Some parents who have never encountered diseases now nearly vanquished in the U.S. do not consider it important to have their in￾fants vaccinated or they may be lax in adhering to recommended schedules of immunization. Others hold the unin￾formed belief that the risks associated with vaccination outweigh the risk of in￾fection. This flawed reasoning is fueled by periodic allegations of linkage be￾tween vaccination and various disor￾ders, such as the report circulating CLINICAL FOCUS Vaccination: Challenges in the U.S. and Developing Countries Genetic engineering techniques can be used to develop vac￾cines to maximize the immune response to selected epitopes and to simplify delivery of the vaccines. This chapter de￾scribes the vaccines now in use and describes vaccine strate￾gies, including experimental designs that may lead to the vaccines of the future. Active and Passive Immunization Immunity to infectious microorganisms can be achieved by active or passive immunization. In each case, immunity can be acquired either by natural processes (usually by transfer from mother to fetus or by previous infection by the organ￾ism) or by artificial means such as injection of antibodies or vaccines (Table 18-1, on page 416). The agents used for in￾ducing passive immunity include antibodies from humans or animals, whereas active immunization is achieved by inocu￾lation with microbial pathogens that induce immunity but do not cause disease or with antigenic components from the pathogens. This section describes current usage of passive and active immunization techniques. Passive Immunization Involves Transfer of Preformed Antibodies Jenner and Pasteur are recognized as the pioneers of vaccina￾tion, or induction of active immunity, but similar recogni￾tion is due to Emil von Behring and Hidesaburo Kitasato for their contributions to passive immunity. These investigators were the first to show that immunity elicited in one animal can be transferred to another by injecting it with serum from the first (see Clinical Focus, Chapter 4). Passive immunization, in which preformed antibodies are transferred to a recipient, occurs naturally by transfer of ma￾ternal antibodies across the placenta to the developing fetus. Maternal antibodies to diphtheria, tetanus, streptococci, rubeola, rubella, mumps, and poliovirus all afford pas￾sively acquired protection to the developing fetus. Maternal

Vaccines CHAPTER 18 415 vaccination even in the United States is an one that does not will require further de- able. The challenge to the biomedical re- indication of the difficulty of the task. Even velopment before it reaches the popula- search community is to develop bette if we assume that suitable vaccines have tions most at risk safer, cheaper, easier-to-administer forms been developed and that compliance is Immunization saves millions of lives, of these vaccines so that worldwide im- universal, the ability to produce and deliver and viable vaccines are increasingly avail- munization becomes a reality. the vaccines everywhere is a profound challenge. The World Health Organization WHO)has stated that the ideal vaccine Estimated annual deaths worldwide of children under 5 years of would have the following properties: age, by pathogen Affordable worldwide Pathogen Deaths( millions) g Heat stable a Effective after a single dose Pneumococcus Applicable to a number of diseases Measles Administered by a mucosal route Hemophilus(a-f, nst) 0.9 Suitable for administration early in life Rotavirus" Few, if any, vaccines in common use to alaria 0. day conform to all of these properties However, the WHO goals can guide us in RSV the pursuit of vaccines useful for world- wide application. They further aid us in Pertussis setting priorities, especially for develop. Tetanus ment of the vaccines needed most in de. Tuberculos 0.1 veloping countries. For example, an "Pathogens shown in bold are those for which an effective vaccine exists HIV/AIDS vaccine that meets the who criteria could have an immediate effect" a licensed vaccine is being tested for possible side-effects on the world AIDS epidemic, whereas SOURCE: Adapted from Shann and Steinhoff, 1999, Lancet 354(Suppl l): 7-11 antibodies present in colostrum and milk also provide pas- Infection by pathogens whose effects may be ameliorated sive immunity to the infant by antibody. For example, if individuals who have not Passive immunization can also be achieved by injecting a received up-to-date active immunization against tetanus recipient with preformed antibodies In the past, before vac- suffer a puncture wound, they are given an injection of cines and antibiotics became available, passive immunization horse antiserum to tetanus toxin. The preformed horse provided a major defense against various infectious diseases. antibody neutralizes any tetanus toxin produced by Despite the risks(see Chapter 16)incurred by injecting ani- Clostridium tetani in the wound mal sera, usually horse serum, this was the only effective ther apy for otherwise fatal diseases. Currently, there are several Passive immunization is routinely administered to indi- viduals exposed to botulism, tetanus, diphtheria, hepatitis, conditions that warrant the use of passive immunization. measles, and rabies(Table 18-2). Passively administered anti These include serum is also used to provide protection from poisonous Deficiency in synthesis of antibody as a result of snake and insect bites. Passive immunization can provide im congenital or acquired B-cell defects, alone or together mediate protection to travelers or health-care workers who ith other immunodeficiencies will soon be exposed to an infectious organism and lack ac tive immunity to it. Because passive immunization does not Exposure or likely exposure to a disease that will ca activate the immune system, it generates no memory re- complications (e.g, a child with leukemia exposed to sponse and the protection provided is transient. varicella or measles), or when time does not permit For certain diseases such as the acute respiratory failure in adequate protection by active immunization children caused by respiratory syncytial virus(Rsv), passive

antibodies present in colostrum and milk also provide pas￾sive immunity to the infant. Passive immunization can also be achieved by injecting a recipient with preformed antibodies. In the past, before vac￾cines and antibiotics became available, passive immunization provided a major defense against various infectious diseases. Despite the risks (see Chapter 16) incurred by injecting ani￾mal sera, usually horse serum, this was the only effective ther￾apy for otherwise fatal diseases. Currently, there are several conditions that warrant the use of passive immunization. These include: ■ Deficiency in synthesis of antibody as a result of congenital or acquired B-cell defects, alone or together with other immunodeficiencies. ■ Exposure or likely exposure to a disease that will cause complications (e.g., a child with leukemia exposed to varicella or measles), or when time does not permit adequate protection by active immunization. Vaccines CHAPTER 18 415 ■ Infection by pathogens whose effects may be ameliorated by antibody. For example, if individuals who have not received up-to-date active immunization against tetanus suffer a puncture wound, they are given an injection of horse antiserum to tetanus toxin. The preformed horse antibody neutralizes any tetanus toxin produced by Clostridium tetani in the wound. Passive immunization is routinely administered to indi￾viduals exposed to botulism, tetanus, diphtheria, hepatitis, measles, and rabies (Table 18-2). Passively administered anti￾serum is also used to provide protection from poisonous snake and insect bites. Passive immunization can provide im￾mediate protection to travelers or health-care workers who will soon be exposed to an infectious organism and lack ac￾tive immunity to it. Because passive immunization does not activate the immune system, it generates no memory re￾sponse and the protection provided is transient. For certain diseases such as the acute respiratory failure in children caused by respiratory syncytial virus (RSV), passive Estimated annual deaths worldwide of children under 5 years of age, by pathogen Pathogen Deaths (millions) Pneumococcus* 1.2 Measles 1.1 Hemophilus (a–f, nst) 0.9 Rotavirus** 0.8 Malaria 0.7 HIV 0.5 RSV 0.5 Pertussis 0.4 Tetanus 0.4 Tuberculosis 0.1 *Pathogens shown in bold are those for which an effective vaccine exists. ** A licensed vaccine is being tested for possible side-effects. SOURCE: Adapted from Shann and Steinhoff, 1999, Lancet 354 (Suppl II):7–11. vaccination even in the United States is an indication of the difficulty of the task. Even if we assume that suitable vaccines have been developed and that compliance is universal, the ability to produce and deliver the vaccines everywhere is a profound challenge. The World Health Organization (WHO) has stated that the ideal vaccine would have the following properties: ■ Affordable worldwide ■ Heat stable ■ Effective after a single dose ■ Applicable to a number of diseases ■ Administered by a mucosal route ■ Suitable for administration early in life Few, if any, vaccines in common use to￾day conform to all of these properties. However, the WHO goals can guide us in the pursuit of vaccines useful for world￾wide application. They further aid us in setting priorities, especially for develop￾ment of the vaccines needed most in de￾veloping countries. For example, an HIV/AIDS vaccine that meets the WHO criteria could have an immediate effect on the world AIDS epidemic, whereas one that does not will require further de￾velopment before it reaches the popula￾tions most at risk. Immunization saves millions of lives, and viable vaccines are increasingly avail￾able. The challenge to the biomedical re￾search community is to develop better, safer, cheaper, easier-to-administer forms of these vaccines so that worldwide im￾munization becomes a reality

416 aRT Iv The Immune System in Health and Disease TABLE 18-1 Acquisition of passive and active TABLE 18-2 Common agents used for passive immunity munization lype Acquired through Disease Agent Passive immunity Natural maternal antibody Black widow spider bite Horse antivenin mmune globulin Botulism Humanized monoclonal antib Horse antitoxin Hepatitis A and b Pooled human immune gamma Active immunity Natural infection Measles Pooled human immune gamma Attenuated organisms Rabies Pooled human immune gamma Inactivated organisms Purified microbial macromolecules Respiratory disease monoclonal anti-RSv. Cloned microbial antigens Snake bite Horse antivenin Expressed as recombinant protein d human immune gamma As cloned dna alone or in virus ulin or horse antitoxin Respiratory syncytial virus Multivalent complexes aining solution derived from human blood, obtained b ld ethanol fractionation of large pools of plasma; available in intramuscu- specific for determinants on the injected antibody Immune complexes of this ige bound to the passively administered 'An antibody derived from the serum of animals that have been stimulated antibody can mediate systemic mast cell degranulation, leading to systemic anaphylaxis. Other individuals produce 'A suspension of attenuated live or killed microorganisms, or antigenic por. IgG or IgM antibodies specific for the foreign antibody, ons of them, presented to a potential host to induce immunity and prevent which form complement-activating immune complexes. The deposition of these complexes in the tissues can lead to acterial toxin that has been modified to be nontoxic but retains the type Ill hypersensitive reactions. Even when human gamma ty to stimulate the formation of antitoxin. globulin is administered passively, the recipient can gener ate an anti-allotype response to the human immunoglobu lin, although its intensity is usually much less than that of an anti-isotype response immunization is the best preventative currently available Active Immunization elicits monoclonal antibody or a combination of two monoclonal Long-Term Protection antibodies may be administered to children at risk for RSV disease. these monoclonal antibodies are red in mice Whereas the aim of passive immunization is transient pro but have been"humanized" by splicing the constant regions tection or alleviation of an existing condition, the goal of ac of human Igg to the mouse variable regions(see Chapter 5). tive immunization is to elicit protective immunity and This modification prevents many of the complications that immunologic memory. When active immunization is suc- may follow a second injection of the complete mouse anti- cessful, a subsequent exposure to the pathogenic agent elicits body, which is a highly immunogenic foreign protein a heightened immune response that successfully eliminates Although passive immunization may be an effective the pathogen or prevents disease mediated by its products treatment, it should be used with caution because certain Active immunization can be achieved by natural infection risks are associated with the injection of preformed with a microorganism, or it can be acquired artificially by ad antibody. If the antibody was produced in another species, ministration of a vaccine(see Table 18-1). In active immu such as a horse, the recipient can mount a strong response nization, as the name implies, the immune system plays an to the isotypic determinants of the foreign antibody. This active role-proliferation of antigen-reactive T and b cells anti-isotype response can serious complications. results in the formation of memory cells. Active immuniza Some individuals, for example, produce IgE antibody tion with various types of vaccines has played an important

immunization is the best preventative currently available. A monoclonal antibody or a combination of two monoclonal antibodies may be administered to children at risk for RSV disease. These monoclonal antibodies are prepared in mice but have been “humanized” by splicing the constant regions of human IgG to the mouse variable regions (see Chapter 5). This modification prevents many of the complications that may follow a second injection of the complete mouse anti￾body, which is a highly immunogenic foreign protein. Although passive immunization may be an effective treatment, it should be used with caution because certain risks are associated with the injection of preformed antibody. If the antibody was produced in another species, such as a horse, the recipient can mount a strong response to the isotypic determinants of the foreign antibody. This anti-isotype response can cause serious complications. Some individuals, for example, produce IgE antibody specific for determinants on the injected antibody. Immune complexes of this IgE bound to the passively administered antibody can mediate systemic mast cell degranulation, leading to systemic anaphylaxis. Other individuals produce IgG or IgM antibodies specific for the foreign antibody, which form complement-activating immune complexes. The deposition of these complexes in the tissues can lead to type III hypersensitive reactions. Even when human gamma globulin is administered passively, the recipient can gener￾ate an anti-allotype response to the human immunoglobu￾lin, although its intensity is usually much less than that of an anti-isotype response. Active Immunization Elicits Long-Term Protection Whereas the aim of passive immunization is transient pro￾tection or alleviation of an existing condition, the goal of ac￾tive immunization is to elicit protective immunity and immunologic memory. When active immunization is suc￾cessful, a subsequent exposure to the pathogenic agent elicits a heightened immune response that successfully eliminates the pathogen or prevents disease mediated by its products. Active immunization can be achieved by natural infection with a microorganism, or it can be acquired artificially by ad￾ministration of a vaccine (see Table 18-1). In active immu￾nization, as the name implies, the immune system plays an active role—proliferation of antigen-reactive T and B cells results in the formation of memory cells. Active immuniza￾tion with various types of vaccines has played an important 416 PART IV The Immune System in Health and Disease TABLE 18-1 Acquisition of passive and active immunity Type Acquired through Passive immunity Natural maternal antibody Immune globulin* Humanized monoclonal antibody Antitoxin† Active immunity Natural infection Vaccines‡ Attenuated organisms Inactivated organisms Purified microbial macromolecules Cloned microbial antigens Expressed as recombinant protein As cloned DNA alone or in virus vectors Multivalent complexes Toxoid§ *An antibody-containing solution derived from human blood, obtained by cold ethanol fractionation of large pools of plasma; available in intramuscu￾lar and intravenous preparations. † An antibody derived from the serum of animals that have been stimulated with specific antigens. ‡ A suspension of attenuated live or killed microorganisms, or antigenic por￾tions of them, presented to a potential host to induce immunity and prevent disease. § A bacterial toxin that has been modified to be nontoxic but retains the capacity to stimulate the formation of antitoxin. TABLE 18-2 Common agents used for passive immunization Disease Agent Black widow spider bite Horse antivenin Botulism Horse antitoxin Diphtheria Horse antitoxin Hepatitis A and B Pooled human immune gamma globulin Measles Pooled human immune gamma globulin Rabies Pooled human immune gamma globulin Respiratory disease Monoclonal anti-RSV* Snake bite Horse antivenin Tetanus Pooled human immune gamma globulin or horse antitoxin *Respiratory syncytial virus

Vaccines chaPtEr 18 417 role in the reduction of deaths from infectious diseases, espe- Pneumococcal conjugate vaccine(PCV): a new addition cially among children to the list Vaccination of children is begun at about 2 months of age. In addition, hepatitis a vaccine at 18 months and influenza this country, updated in 2002 by the American Academy of vaccines alter 6 months are recommended for infants in Pediatrics, is outlined in Table 18-3. The program includes high-risk populaR\ss ad ion ading use of various vaccines the following vaccines for childhood immunization has led to a dramatic decrease Hepatitis B vaccine in the incidence of common childhood diseases in the united States(Figure 18-1). The comparisons of disease incidence in Diphtheria-pertussis(acellular)-tetanus(DPaT ombined vac 1999 to that reported in the peak years show dramatic drops caine and, in one case, complete elimination of the disease in the Inactivated(Salk) polio vaccine(IPV); the oral(Sabin) United States. As long as widespread, effective immunization vaccine is no longer recommended for use in the United programs are maintained, the incidence of these childhood diseases should remain low However the occurrence of side reactions to a vaccine may cause a drop in its use, which can Measles-mumps-rubella(MMr) combined vaccine re-emt mergence of that disease. For example, the side ef- s Haemophilus influenzae(Hib)vaccine fects from the pertussis attenuated bacterial vaccine included seizures, encephalitis, brain damage, and even death. De- Varicella zoster(Var)vaccine for chickenpox reased usage of the vaccine led to an increase in the inci TABLE 18-3 Recommended childhood immunization schedule in the United States, 2002 AGE Birth 1m 2 mo 4 mos 6 mos 12 mos 15 mos 18 mos 4-6 yr Hepatitis BT phtheria, tetanus pertussis H influenzae, type b Inactivated polios Measles, mumps, rubella This schedule indicates the recommended ages for routine administration of currently licensed childhood vaccines. Bars indicate ranges of recommended ages. Any dose not given at the recommended age should be given as a"" immunization at any subsequent visit when indicated and feasible. Different schedules exist depending upon the HBsAg status of the mother. A first vaccination after the first month is recommended only if the mother is HBsAg negative. 'DTaP (diphtheria and tetanus toxoids and acellular pertussis vaccine) is the preferred vaccine for all doses in the immunization series. Td(tetanus and diphtheria toxoids) is recommended at 11-12 years of age if at least 5 years have 知ony us(IPV) vaccine is now recommended vaccine of choice for mass immunization campaigns to control outbreaks due to wild poliovirus. =Varicella (Var) vaccine is recommended at any visit on or after the first birthday for susceptible children, i.e., those who lack a reliable history of chickenpox (as judged by a health-care provider) and who have not been immunized Susceptible persons 13 years of age or older should receive 2 doses, given at least 4 weeks apart. SOURCE: Adapted from the ECBT Web site(see references); approved by the American Academy of Pediatrics

role in the reduction of deaths from infectious diseases, espe￾cially among children. Vaccination of children is begun at about 2 months of age. The recommended program of childhood immunizations in this country, updated in 2002 by the American Academy of Pediatrics, is outlined in Table 18-3. The program includes the following vaccines: ■ Hepatitis B vaccine ■ Diphtheria-pertussis (acellular)-tetanus (DPaT) combined vaccine ■ Inactivated (Salk) polio vaccine (IPV); the oral (Sabin) vaccine is no longer recommended for use in the United States ■ Measles-mumps-rubella (MMR) combined vaccine ■ Haemophilus influenzae (Hib) vaccine ■ Varicella zoster (Var) vaccine for chickenpox ■ Pneumococcal conjugate vaccine (PCV); a new addition to the list. In addition, hepatitis A vaccine at 18 months and influenza vaccines after 6 months are recommended for infants in high-risk populations. The introduction and spreading use of various vaccines for childhood immunization has led to a dramatic decrease in the incidence of common childhood diseases in the United States (Figure 18-1). The comparisons of disease incidence in 1999 to that reported in the peak years show dramatic drops and, in one case, complete elimination of the disease in the United States. As long as widespread, effective immunization programs are maintained, the incidence of these childhood diseases should remain low. However, the occurrence of side reactions to a vaccine may cause a drop in its use, which can lead to re-emergence of that disease. For example, the side ef￾fects from the pertussis attenuated bacterial vaccine included seizures, encephalitis, brain damage, and even death. De￾creased usage of the vaccine led to an increase in the inci￾Vaccines CHAPTER 18 417 TABLE 18-3 Recommended childhood immunization schedule in the United States, 2002 AGE Vaccine* Birth 1 mo 2 mos 4 mos 6 mos 12 mos 15 mos 18 mos 4–6 yrs Hepatitis B† Diphtheria, tetanus, pertussis‡ H. influenzae, type b Inactivated polio§ Pneumococcal conjugate Measles, mumps, rubella Varicella# *This schedule indicates the recommended ages for routine administration of currently licensed childhood vaccines. Bars indicate ranges of recommended ages. Any dose not given at the recommended age should be given as a “catch-up” immunization at any subsequent visit when indicated and feasible. † Different schedules exist depending upon the HBsAg status of the mother. A first vaccination after the first month is recommended only if the mother is HBsAg negative. ‡ DTaP (diphtheria and tetanus toxoids and acellular pertussis vaccine) is the preferred vaccine for all doses in the immunization series. Td (tetanus and diphtheria toxoids) is recommended at 11–12 years of age if at least 5 years have elapsed since the last dose. § Only inactivated poliovirus (IPV) vaccine is now recommended for use in the United States. However, OPV remains the vaccine of choice for mass immunization campaigns to control outbreaks due to wild poliovirus. # Varicella (Var) vaccine is recommended at any visit on or after the first birthday for susceptible children, i.e., those who lack a reliable history of chickenpox (as judged by a health-care provider) and who have not been immunized. Susceptible persons 13 years of age or older should receive 2 doses, given at least 4 weeks apart. SOURCE: Adapted from the ECBT Web site (see references); approved by the American Academy of Pediatrics.