《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.

418 PART IV The Immune System in Health and Disease Multiple immunizations with the polio vaccine are required to ensure that an adequate immune response is generated to each of the three strains of poliovirus that make up the Paralytic polio cases Recommendations for vaccination of adults deper 1952 the risk group. Vaccines for meningitis, pneumonia, and in fluenza are often given to groups living in close quarters(e.g Pertussis military recruits) or to individuals with reduced immunity 934 (e.g, the elderly). Depending on their destination, interna tional travelers are also routinely immunized against such endemic diseases as cholera, yellow fever, plague, typhoid, hepatitis, meningitis, typhus, and polio. Immunization against the deadly disease anthrax had been reserved fo Measles workers coming into close contact with infected animals or 1941 products from them. Recently, however, suspected use of anthrax spores by terrorists or in biological warfare has widened use of the vaccine to military personnel and civil- ians in areas at risk of attack with this deadly agent Vaccination is not 100% effective. With any vaccine, a ∮」ssmauperentageorepentwilrspondpolandthere problem if the majority of the population is immune to an Number of reported cases infectious agent. In this case, the chance of a susceptible ndividual contacting an infected individual is so low that FIGURE 18-1 Reported annual number of cases of rubella(Ger. the susceptible one is not likely to become infected. This man measles), polio, pertussis(whooping cough), mumps, measles, phenomenon is known as herd immunity. The appearance of and diphtheria in the United States in the peak year for which data are measles epidemics among college students and unvaccinated available (orange)compared with the number of cases of each dis- preschool-age children in the United States during the mid- ease in 1999(green). Currently, vaccines are available for each of these to late 1980s resulted partly from an overall decrease in vac- diseases, and vaccination is recommended for all children in the cinations, which had lowered the herd immunity of the pop United States. Data from Centers for Disease Control. l ulation(Figure 18-2). Among preschool-age children, 88% of those who developed measles were unvaccinated. Most of the college students who contracted measles had been vacci nated as children, but only once; the failure of the single dence of whooping cough, with 7405 cases in 1998. The re- of passively acquired maternal antibodies that reduced their cent development of an acellular pertussis vaccine that is as overall response to the vaccine. The increase in the incidence effective as the older vaccine, but with none of the side ef- of measles prompted the recommendation that children fects, is expected to reverse this trend receive two immunizations with the combined measles- As indicated in Table 18-3, children typically require mumps-rubella vaccine, one at 12-15 months of age and the nultiple boosters(repeated inoculations) at appropriately second at 4-6 years timed intervals to achieve effective immunity In the first The Centers for Disease Control( CDc) has called atten months of life the reason for this may be persistence of cir- tion to the decline in vaccination rates and herd immunity lating maternal antibodies in the young infant. For exam- among American children. For example, a 1995 publication ple, passively acquired maternal antibodies bind to epitopes reported that in California nearly one-third of all infants are on the DPt vaccine and block adequate activation of the im- unvaccinated and about half of all children under the age of mune system; therefore, this vaccine must be given several 2 are behind schedule on their vaccinations. Such a decrease times after the maternal antibody has been cleared from an in herd immunity portends serious consequences, as illus- infant's circulation in order to achieve adequate immunity. trated by recent events in the newly independent states of the Passively acquired maternal antibody also interferes with the former Soviet Union. By the mid-1990s, a diphtheria epi effectiveness of the measles vaccine; for this reason, the demic was raging in many regions of these new countries, MMR vaccine is not given before 12-15 months of age. In linked to a decrease in herd immunity resulting from de Third World countries, however, the measles vaccine is ad- creased vaccination rates after the breakup of the soviet are still present, because 30% hough maternal antibodies Union. This epidemic, which led to over 157,000 cases of ministered at 9 months 50% of young children in diptheria and 5000 deaths, is now controlled by mass immu these countries contract the disease before 15 months of age. nization programs

Multiple immunizations with the polio vaccine are required to ensure that an adequate immune response is generated to each of the three strains of poliovirus that make up the vaccine. Recommendations for vaccination of adults depend on the risk group. Vaccines for meningitis, pneumonia, and in￾fluenza are often given to groups living in close quarters (e.g., military recruits) or to individuals with reduced immunity (e.g., the elderly). Depending on their destination, interna￾tional travelers are also routinely immunized against such endemic diseases as cholera, yellow fever, plague, typhoid, hepatitis, meningitis, typhus, and polio. Immunization against the deadly disease anthrax had been reserved for workers coming into close contact with infected animals or products from them. Recently, however, suspected use of anthrax spores by terrorists or in biological warfare has widened use of the vaccine to military personnel and civil￾ians in areas at risk of attack with this deadly agent. Vaccination is not 100% effective. With any vaccine, a small percentage of recipients will respond poorly and there￾fore will not be adequately protected. This is not a serious problem if the majority of the population is immune to an infectious agent. In this case, the chance of a susceptible individual contacting an infected individual is so low that the susceptible one is not likely to become infected. This phenomenon is known as herd immunity. The appearance of measles epidemics among college students and unvaccinated preschool-age children in the United States during the mid￾to late 1980s resulted partly from an overall decrease in vac￾cinations, which had lowered the herd immunity of the pop￾ulation (Figure 18-2). Among preschool-age children, 88% of those who developed measles were unvaccinated. Most of the college students who contracted measles had been vacci￾nated as children, but only once; the failure of the single vac￾cination to protect them may have resulted from the presence of passively acquired maternal antibodies that reduced their overall response to the vaccine. The increase in the incidence of measles prompted the recommendation that children receive two immunizations with the combined measles￾mumps-rubella vaccine, one at 12–15 months of age and the second at 4–6 years. The Centers for Disease Control (CDC) has called atten￾tion to the decline in vaccination rates and herd immunity among American children. For example, a 1995 publication reported that in California nearly one-third of all infants are unvaccinated and about half of all children under the age of 2 are behind schedule on their vaccinations. Such a decrease in herd immunity portends serious consequences, as illus￾trated by recent events in the newly independent states of the former Soviet Union. By the mid-1990s, a diphtheria epi￾demic was raging in many regions of these new countries, linked to a decrease in herd immunity resulting from de￾creased vaccination rates after the breakup of the Soviet Union. This epidemic, which led to over 157,000 cases of diptheria and 5000 deaths, is now controlled by mass immu￾nization programs. 418 PART IV The Immune System in Health and Disease Paralytic polio 0 cases 1934 1952 Pertussis 1969 Rubella 1921 Diphtheria 1941 Measles Disease 1968 Mumps 1,000,000 100,000 10,000 1,000 Number of reported cases 100 10 0 FIGURE 18-1 Reported annual number of cases of rubella (Ger￾man measles), polio, pertussis (whooping cough), mumps, measles, and diphtheria in the United States in the peak year for which data are available (orange) compared with the number of cases of each dis￾ease in 1999 (green). Currently, vaccines are available for each of these diseases, and vaccination is recommended for all children in the United States. [Data from Centers for Disease Control.] dence of whooping cough, with 7405 cases in 1998. The re￾cent development of an acellular pertussis vaccine that is as effective as the older vaccine, but with none of the side ef￾fects, is expected to reverse this trend. As indicated in Table 18-3, children typically require multiple boosters (repeated inoculations) at appropriately timed intervals to achieve effective immunity. In the first months of life, the reason for this may be persistence of cir￾culating maternal antibodies in the young infant. For exam￾ple, passively acquired maternal antibodies bind to epitopes on the DPT vaccine and block adequate activation of the im￾mune system; therefore, this vaccine must be given several times after the maternal antibody has been cleared from an infant’s circulation in order to achieve adequate immunity. Passively acquired maternal antibody also interferes with the effectiveness of the measles vaccine; for this reason, the MMR vaccine is not given before 12–15 months of age. In Third World countries, however, the measles vaccine is ad￾ministered at 9 months, even though maternal antibodies are still present, because 30%–50% of young children in these countries contract the disease before 15 months of age

Vaccines chaPtEr 18 419 15 10 800 E700 Vaccine licensed 艺200 1 70727476788082848688 Year FIGURE 18-2 Introduction of the measles vaccine in 1962 led to a occurred mainly among unvaccinated young children and among dramatic decrease in the annual incidence of this disease in the college students; most of the latter had been vaccinated, but only United States. Occasional outbreaks of measles in the 1980s(inset) once, when they were young. Data from Centers for Disease Control. memory response continues to climb, reaching maximal lev Designing Vaccines for els at 6 months and persisting for years(Figure 18-3). If an Active Immunization immunized individual is later exposed to the poliovirus, these memory cells will respond by differentiating into Several factors must be kept in mind in developing a success- plasma cells that produce high levels of serum antibody. ful vaccine. First and foremost, the development of an im- which defend the individual from the infection. mune response does not necessarily mean that a state of In the remainder of this chapter, various approaches to protective immunity has been achieved. What is often critical the design of vaccines--both currently used vaccines and ex- is which branch of the immune system is activated, and perimental ones-are described, with an examination of therefore vaccine designers must recognize the important heir ability to induce humoral and cell-mediated immunity differences between activation of the humoral and the cell- and the production of memory cells mediated branches. A second factor is the development of immunologic memory. For example, a vaccine that induces a protective primary response may fail to induce the formation of memory cells, leaving the host unprotected after the pri- 2048 mary response to the vaccine subsides. Immunologic memory 喜 512 on the incubation period of the pathogen. in the case of 256 influenza virus, which has a very short incubation period (1 or 2 days), disease symptoms are already under way by the 2 32 time memory cells are activated. Effective protection against a 16 influenza therefore depends on maintaining high levels of neutralizing antibody by repeated immunizations; those erum antibod highest risk are immunized each year For pathogens with longer incubation period, maintaining detectable neutraliz- Vaccine ing antibody at the time of infection is not r sary. The poliovirus, for example, requires more than 3 days to begin to RE18-3 Immunization with a single dose of the Salk polio infect the central nervous system. An incubation period of vaccine induces a rapid increase in serum antibody levels, which this length gives the memory B cells time to respond by peak by 2 weeks and then decline. Induction of immunologic mem- producing high levels of serum antibody. Thus, the vaccine ory follows a slower time course, reaching maximal levels 6 months for polio is designed to induce high levels of immunologic after vaccination. The persistence of the memory response for years memory. After immunization with the Salk vaccine, serum after primary vaccination is responsible for immunity to polio antibody levels peak within 2 weeks and then decline, but the myelitis. From M. Zanetti et al., 1987, Immunol. Today 8: 18. 1

Designing Vaccines for Active Immunization Several factors must be kept in mind in developing a success￾ful vaccine. First and foremost, the development of an im￾mune response does not necessarily mean that a state of protective immunity has been achieved. What is often critical is which branch of the immune system is activated, and therefore vaccine designers must recognize the important differences between activation of the humoral and the cell￾mediated branches. A second factor is the development of immunologic memory. For example, a vaccine that induces a protective primary response may fail to induce the formation of memory cells, leaving the host unprotected after the pri￾mary response to the vaccine subsides. The role of memory cells in immunity depends, in part, on the incubation period of the pathogen. In the case of influenza virus, which has a very short incubation period (1 or 2 days), disease symptoms are already under way by the time memory cells are activated. Effective protection against influenza therefore depends on maintaining high levels of neutralizing antibody by repeated immunizations; those at highest risk are immunized each year. For pathogens with a longer incubation period, maintaining detectable neutraliz￾ing antibody at the time of infection is not necessary. The poliovirus, for example, requires more than 3 days to begin to infect the central nervous system. An incubation period of this length gives the memory B cells time to respond by producing high levels of serum antibody. Thus, the vaccine for polio is designed to induce high levels of immunologic memory. After immunization with the Salk vaccine, serum antibody levels peak within 2 weeks and then decline, but the memory response continues to climb, reaching maximal lev￾els at 6 months and persisting for years (Figure 18-3). If an immunized individual is later exposed to the poliovirus, these memory cells will respond by differentiating into plasma cells that produce high levels of serum antibody, which defend the individual from the infection. In the remainder of this chapter, various approaches to the design of vaccines—both currently used vaccines and ex￾perimental ones—are described, with an examination of their ability to induce humoral and cell-mediated immunity and the production of memory cells. Vaccines CHAPTER 18 419 FIGURE 18-2 Introduction of the measles vaccine in 1962 led to a dramatic decrease in the annual incidence of this disease in the United States. Occasional outbreaks of measles in the 1980s (inset) occurred mainly among unvaccinated young children and among college students; most of the latter had been vaccinated, but only once, when they were young. [Data from Centers for Disease Control.] 80 81 82 83 84 85 86 87 88 15 10 5 0 Number of cases, in thousands 1950 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 Number of cases, in thousands 1,000 900 800 700 600 500 400 300 200 100 0 Year Vaccine licensed Year 2048 1024 512 256 128 64 32 16 8 4 Mean antibody titer Immunologic memory Serum antibody 1 6 12 Vaccine Time, months FIGURE 18-3 Immunization with a single dose of the Salk polio vaccine induces a rapid increase in serum antibody levels, which peak by 2 weeks and then decline. Induction of immunologic mem￾ory follows a slower time course, reaching maximal levels 6 months after vaccination. The persistence of the memory response for years after primary vaccination is responsible for immunity to polio￾myelitis. [From M. Zanetti et al., 1987, Immunol. Today 8:18.]

420 PART IV The Immune System in Health and Disease Whole-Organism Vaccines TABLE 18.4 Classification of common vaccines for humans As Table 18-4 indicates, many of the common vaccines cur- rently in use consist of inactivated (killed) or live but attenu Disease or pathogen Type of vaccine ated(avirulent) bacterial cells or viral particles. The primary THOLE ORGANISMS characteristics of these two types of vaccines are compared in Table 18-5 to one another and to dna vaccines that are cur- Bacterial cells rently being tested for use in humans Anthrax Attenuated Viruses and Bacteria cause Pertussis. Inactivate Immunity Without Disease Inactivated In some cases, microorganisms can be attenuated so that they lose their ability to cause significant disease(pathogenicity) but retain their capacity for transient growth within an inoc- Typhoid Live attenuated ulated host Attenuation often can be achieved by growing a viral particles pathogenic bacterium or virus for prolonged periods under abnormal culture conditions. This procedure selects mutants Hepatitis A nactivated that are better suited to growth in the abnormal culture con- Influenza Inactivated ditions and are therefore less capable of growth in the natural Measles host. For example, an attenuated strain of Mycobacterium bo vis called Bacillus Calmette-Guerin(BCG) was developed ve attenuated by growing M. bovis on a medium containing increasing con- Polio(Sabin) Live attenuated centrations of bile. After 13 years, this strain had adapted to growth in strong bile and had become sufficiently attenuated Inactivated that it was suitable as a vaccine for tuberculosis. The sabin polio vaccine and the measles vaccine both consist of attenu ve attenuate ated viral strains. The poliovirus used in the Sabin vaccine was attenuated by growth in monkey kidney epithelial cells Rubella nactivated The measles vaccine contains a strain of rubella virus that Varicella zoster(chickenpox) Live attenuated was grown in duck embryo cells and later in human cell lines Yellow fever Live attenuated Attenuated vaccines have advantages and disadvantages ecause of their capacity for transient growth, such vaccines provide prolonged immune-system exposure to the individ PURIFIED MACROMOLECULES ual epitopes on the attenuated organisms, resulting genicity and production of memory cells. As Toxoids a consequence, these vaccines often require only a single im- Inactivated exotoxin munization, eliminating the need for repeated boosters. This Inactivated exotoxin property is a major advantage in Third World countries, where epidemiologic studies have shown that roughly 20% of individuals fail to return for each subsequent booster. The Haemophilus influenzae pility of many attenuated vaccines to replicate within host type cells makes them particularly suitable for inducing a cell Neissera meningitidis mediated response Streptococcus pneumoniae 23 distinct capsular The Sabin polio vaccine, consisting of three attenuated polysaccharides strains of poliovirus, is administered orally to children on a Surface antigen sugar cube or in sugar liquid. The attenuated viruses colonize Hepatitis B the intestine and induce protective immunity to all three antigen(HBsAg strains of virulent poliovirus. Sabin vaccine in the intestines induces production of secretory IgA, which serves as an im -"There is an now also an acellular pertussis vaccine consisting of toxoids and portant defense against naturally acquired poliovirus. The inactivated bacteria components. vaccine also induces IgM and igg classes of antibody. Unlike 'Bacillus Calmette-Guerin(BCG)is an avirulent strain of Mycobacterium most other attenuated vaccines, which require a single im- bovis. munizing dose, the Sabin polio vaccine requires boosters

Whole-Organism Vaccines As Table 18-4 indicates, many of the common vaccines cur￾rently in use consist of inactivated (killed) or live but attenu￾ated (avirulent) bacterial cells or viral particles. The primary characteristics of these two types of vaccines are compared in Table 18-5 to one another and to DNA vaccines that are cur￾rently being tested for use in humans. Attenuated Viruses and Bacteria Cause Immunity Without Disease In some cases, microorganisms can be attenuated so that they lose their ability to cause significant disease (pathogenicity) but retain their capacity for transient growth within an inoc￾ulated host. Attenuation often can be achieved by growing a pathogenic bacterium or virus for prolonged periods under abnormal culture conditions. This procedure selects mutants that are better suited to growth in the abnormal culture con￾ditions and are therefore less capable of growth in the natural host. For example, an attenuated strain of Mycobacterium bo￾vis called Bacillus Calmette-Guerin (BCG) was developed by growing M. bovis on a medium containing increasing con￾centrations of bile. After 13 years, this strain had adapted to growth in strong bile and had become sufficiently attenuated that it was suitable as a vaccine for tuberculosis. The Sabin polio vaccine and the measles vaccine both consist of attenu￾ated viral strains. The poliovirus used in the Sabin vaccine was attenuated by growth in monkey kidney epithelial cells. The measles vaccine contains a strain of rubella virus that was grown in duck embryo cells and later in human cell lines. Attenuated vaccines have advantages and disadvantages. Because of their capacity for transient growth, such vaccines provide prolonged immune-system exposure to the individ￾ual epitopes on the attenuated organisms, resulting in in￾creased immunogenicity and production of memory cells. As a consequence, these vaccines often require only a single im￾munization, eliminating the need for repeated boosters. This property is a major advantage in Third World countries, where epidemiologic studies have shown that roughly 20% of individuals fail to return for each subsequent booster. The ability of many attenuated vaccines to replicate within host cells makes them particularly suitable for inducing a cell￾mediated response. The Sabin polio vaccine, consisting of three attenuated strains of poliovirus, is administered orally to children on a sugar cube or in sugar liquid. The attenuated viruses colonize the intestine and induce protective immunity to all three strains of virulent poliovirus. Sabin vaccine in the intestines induces production of secretory IgA, which serves as an im￾portant defense against naturally acquired poliovirus. The vaccine also induces IgM and IgG classes of antibody. Unlike most other attenuated vaccines, which require a single im￾munizing dose, the Sabin polio vaccine requires boosters, 420 PART IV The Immune System in Health and Disease TABLE 18-4 Classification of common vaccines for humans Disease or pathogen Type of vaccine WHOLE ORGANISMS Bacterial cells Anthrax Inactivated Cholera Inactivated Pertussis* Inactivated Plague Inactivated Tuberculosis Live attenuated BCG† Typhoid Live attenuated Viral particles Hepatitis A Inactivated Influenza Inactivated Measles Live attenuated Mumps Live attenuated Polio (Sabin) Live attenuated Polio (Salk) Inactivated Rabies Inactivated Rotavirus Live attenuated Rubella Inactivated Varicella zoster (chickenpox) Live attenuated Yellow fever Live attenuated PURIFIED MACROMOLECULES Toxoids Diphtheria Inactivated exotoxin Tetanus Inactivated exotoxin Capsular polysaccharides Haemophilus influenzae Polysaccharide type b protein carrier Neissera meningitidis Polysaccharide Streptococcus pneumoniae 23 distinct capsular polysaccharides Surface antigen Hepatitis B Recombinant surface antigen (HBsAg) *There is an now also an acellular pertussis vaccine consisting of toxoids and inactivated bacteria components. † Bacillus Calmette-Guerin (BCG) is an avirulent strain of Mycobacterium bovis.

Vaccines chaPtEr 18 TABLE 18-5 Comparison of attenuated (live), inactivated (killed), and DNA vaccines Characteristic Attenuated vaccine Inactivated vaccine DNA vaccine Production Selection for avirulent Virulent pathogen is inactivated by Easily manufactured virulent pathogen chemicals or irradiation with y-rays and purified adverse culture co human pathogen different hosts Booster requirement Generally requires only a single Requires multiple boosters Single injection may suffice Relative stability Less stable More stable Highly stable Type of immunity induced Humoral and cell-mediated Humoral and cell-mediated Reversion tendency May revert to virulent form Cannot revert to virulent form Cannot revert because the three strains of attenuated poliovirus in the vac- cacy of the vaccine. a more convincing argument for vacci- cine interfere with each other's replication in the intestine. nation is the high death rate associated with measles infec With the first immunization, one strain will predominate in tion even in developed countries its growth, inducing immunity to that strain. With the sec Genetic engineering techniques provide a way to attenu ond immunization, the immunity generated by the previous ate a virus irreversibly by selectively removing genes that are immunization will limit the growth of the previously pre- necessary for virulence. This has been done with a her- dominant strain in the vaccine, enabling one of the two re- pesvirus vaccine for pigs, in which the thymidine kinase gene maining strains to predominate and induce immunity. was removed. Because thymidine kinase is required for the Finally, with the third immunization, immunity to all three virus to grow in certain types of cells(e.g, neurons), removal strains is achieved of this gene rendered the virus incapable of causing disease A major disadvantage of attenuated vaccines is the possi- It is possible that similar genetic engineering techniques bility that they will revert to a virulent form. The rate of could eliminate the risk of reversion of the attenuated polio reversion of the Sabin polio vaccine(OPV) leading to subse- vaccine. More recently, a vaccine against rotavirus, a major quent paralytic disease is about one case in 2. 4 million doses cause of infant diarrhea, was developed using genetic engi- of vaccine. This reversion implies that pathogenic forms of neering techniques to modify an animal rotavirus to contain the virus are being passed by a few immunized individuals antigens present on the human viruses and can find their way into the water supply, especially in ar- eas where sanitation standards are not rigorous or where Pathogenic Organisms Are Inactivated waste water must be recycled. This possibility has led to the by Heat or Chemical Treatment (see Table 18-3). The projected eradication of paralytic polio Another common approach in vaccine production is inacti- (Figure 18-4)will be impossible as long as OPV is used any- vation of the pathogen by heat or by chemical means so that where in the world. The alternative inactivated Salk vaccine it is no longer capable of replication in the host. It is critically should be substituted as the number of cases decrease, al- important to maintain the structure of epitopes on surface though there are problems in delivering this vaccine in devel- antigens during inactivation. Heat inactivation is generall oping countries. satisfactory because it causes extensive denaturation of Attenuated vaccines also may be associated with compli- proteins; thus, any epitopes that depend on higher orders of tions similar to those seen in the natural disease. A small protein structure are likely to be altered significantly. Chem percentage of recipients of the measles vaccine, for example, ical inactivation with formaldehyde or various alkylating develop post-vaccine encephalitis or other complications As agents has been successful. The Salk polio vaccine is pro- shown in Table 18-6(page 423), however, the risk of vaccine- duced by formaldehyde inactivation related complications is much lower than risks from infec Attenuated vaccines generally require only one dose to tion. An independent study showed that 75 million doses of induce long-lasting immunity. Killed vaccines, on the measles vaccine were given between 1970 and 1993, with an other hand, often require repeated boosters to maintain incidence of 48 cases of vaccine-related encephalopathy. The the immune status of the host. In addition, killed vaccines low in-cidence of this side effect compared with the rate of induce a predominantly humoral antibody response; they cephalopathy associated with infection argues for the effi- are less effective than attenuated vaccines in inducing

Vaccines CHAPTER 18 421 because the three strains of attenuated poliovirus in the vac￾cine interfere with each other’s replication in the intestine. With the first immunization, one strain will predominate in its growth, inducing immunity to that strain. With the sec￾ond immunization, the immunity generated by the previous immunization will limit the growth of the previously pre￾dominant strain in the vaccine, enabling one of the two re￾maining strains to predominate and induce immunity. Finally, with the third immunization, immunity to all three strains is achieved. A major disadvantage of attenuated vaccines is the possi￾bility that they will revert to a virulent form. The rate of reversion of the Sabin polio vaccine (OPV) leading to subse￾quent paralytic disease is about one case in 2.4 million doses of vaccine. This reversion implies that pathogenic forms of the virus are being passed by a few immunized individuals and can find their way into the water supply, especially in ar￾eas where sanitation standards are not rigorous or where waste water must be recycled. This possibility has led to the exclusive use of the inactivated polio vaccine in this country (see Table 18-3). The projected eradication of paralytic polio (Figure 18-4) will be impossible as long as OPV is used any￾where in the world. The alternative inactivated Salk vaccine should be substituted as the number of cases decrease, al￾though there are problems in delivering this vaccine in devel￾oping countries. Attenuated vaccines also may be associated with compli￾cations similar to those seen in the natural disease. A small percentage of recipients of the measles vaccine, for example, develop post-vaccine encephalitis or other complications. As shown in Table 18-6 (page 423), however, the risk of vaccine￾related complications is much lower than risks from infec￾tion. An independent study showed that 75 million doses of measles vaccine were given between 1970 and 1993, with an incidence of 48 cases of vaccine-related encephalopathy. The low in-cidence of this side effect compared with the rate of encephalopathy associated with infection argues for the effi￾cacy of the vaccine. A more convincing argument for vacci￾nation is the high death rate associated with measles infec￾tion even in developed countries. Genetic engineering techniques provide a way to attenu￾ate a virus irreversibly by selectively removing genes that are necessary for virulence. This has been done with a her￾pesvirus vaccine for pigs, in which the thymidine kinase gene was removed. Because thymidine kinase is required for the virus to grow in certain types of cells (e.g., neurons), removal of this gene rendered the virus incapable of causing disease. It is possible that similar genetic engineering techniques could eliminate the risk of reversion of the attenuated polio vaccine. More recently, a vaccine against rotavirus, a major cause of infant diarrhea, was developed using genetic engi￾neering techniques to modify an animal rotavirus to contain antigens present on the human viruses. Pathogenic Organisms Are Inactivated by Heat or Chemical Treatment Another common approach in vaccine production is inacti￾vation of the pathogen by heat or by chemical means so that it is no longer capable of replication in the host. It is critically important to maintain the structure of epitopes on surface antigens during inactivation. Heat inactivation is generally unsatisfactory because it causes extensive denaturation of proteins; thus, any epitopes that depend on higher orders of protein structure are likely to be altered significantly. Chem￾ical inactivation with formaldehyde or various alkylating agents has been successful. The Salk polio vaccine is pro￾duced by formaldehyde inactivation. Attenuated vaccines generally require only one dose to induce long-lasting immunity. Killed vaccines, on the other hand, often require repeated boosters to maintain the immune status of the host. In addition, killed vaccines induce a predominantly humoral antibody response; they are less effective than attenuated vaccines in inducing TABLE 18-5 Comparison of attenuated (live), inactivated (killed), and DNA vaccines Characteristic Attenuated vaccine Inactivated vaccine DNA vaccine Production Selection for avirulent organisms: Virulent pathogen is inactivated by Easily manufactured virulent pathogen is grown under chemicals or irradiation with -rays and purified adverse culture conditions or prolonged passage of a virulent human pathogen through different hosts Booster requirement Generally requires only a single Requires multiple boosters Single injection may suffice booster Relative stability Less stable More stable Highly stable Type of immunity induced Humoral and cell-mediated Mainly humoral Humoral and cell-mediated Reversion tendency May revert to virulent form Cannot revert to virulent form Cannot revert

422 ART IV The Immune System in Health and Disease d polio cases □0 cases □1-10 cases □ More than10 cases □ No repo 亟 □1-10 cases □ More than10 cases FIGURE 18-4 Progress toward the worldwide eradication of polio. cause reversion to pathogenic forms at a rate sufficiently high to pre- Comparison of infection numbers for 1988 with those for 1998 show vent total eradication of this once prevalent crippling disease / Data considerable progress in most parts of the world. Some experts from WHO./ question whether the use of live attenuated oral polio vaccine will cell-mediated immunity and in eliciting a secretory IgA risks. A serious complication with the first Salk vaccines arose when formaldehyde failed to kill all the virus in tw Even though they contain killed pathogens, inactivated vaccine lots, which caused paralytic polio in a high percent whole-organism vaccines are still associated with certain age of recipients

cell-mediated immunity and in eliciting a secretory IgA response. Even though they contain killed pathogens, inactivated whole-organism vaccines are still associated with certain risks. A serious complication with the first Salk vaccines arose when formaldehyde failed to kill all the virus in two vaccine lots, which caused paralytic polio in a high percent￾age of recipients. 422 PART IV The Immune System in Health and Disease FIGURE 18-4 Progress toward the worldwide eradication of polio. Comparison of infection numbers for 1988 with those for 1998 show considerable progress in most parts of the world. Some experts question whether the use of live attenuated oral polio vaccine will cause reversion to pathogenic forms at a rate sufficiently high to pre￾vent total eradication of this once prevalent crippling disease. [Data from WHO.] 0 cases Reported polio cases 1988 1–10 cases More than 10 cases No report 0 cases 1998 1–10 cases More than 10 cases No report