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 influenza 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, international 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 civilians 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 therefore 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 midto late 1980s resulted partly from an overall decrease in vaccinations, which had lowered the herd immunity of the population (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 vaccinated as children, but only once; the failure of the single vaccination 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 measlesmumps-rubella vaccine, one at 12–15 months of age and the second at 4–6 years. The Centers for Disease Control (CDC) has called attention 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 illustrated by recent events in the newly independent states of the former Soviet Union. By the mid-1990s, a diphtheria epidemic was raging in many regions of these new countries, linked to a decrease in herd immunity resulting from decreased 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 immunization 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 (German 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 disease 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 recent development of an acellular pertussis vaccine that is as effective as the older vaccine, but with none of the side effects, 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 circulating maternal antibodies in the young infant. For example, passively acquired maternal antibodies bind to epitopes on the DPT vaccine and block adequate activation of the immune 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 administered 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 successful vaccine. First and foremost, the development of an immune 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 cellmediated 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 primary 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 neutralizing 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 levels 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 experimental 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 memory 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 poliomyelitis. [From M. Zanetti et al., 1987, Immunol. Today 8:18.]