affiliate_link

gkHub

​Vaccines play a special role in the health and security of nations. The World Health Organization (WHO) cites immunization and the provision of clean water as the two public health interventions that have had the greatest impact on the world’s health, and the World Bank notes that vaccines are among the most cost-effective health interventions available.Over the past century, the integration of immunization into routine health care services in many countries has provided caregivers with some degree of control over disease-related morbidity and mortality, especially among infants and children. Despite these extraordinary successes, vaccines and their constituents (e.g., the mercury compound thimerosal, formerly used as a preservative) have come under attack in some countries as causes of neurodevelopmental disorders such as autism and attention-deficit hyperactivity disorder, diabetes, and a variety of allergic and autoimmune diseases. Although millions of lives are saved by vaccines each year and countless cases of postinfection disability are averted, some segments of the public are increasingly unwilling to accept any risk whatsoever of vaccine-associated complications (severe or otherwise), and resistance to vaccination is growing. No medical procedure is absolutely risk-free, and the risk to the individual must always be balanced with benefits to the individual and to the population at large. This dichotomy poses two essential challenges for the medical and public health communities with respect to vaccines: (1) to create more effective and ever-safer vaccines, and (2) to educate patients and the general public more fully about the benefits as well as the risks of vaccine use. Because immunity to infectious diseases is acquired only by infection itself or by immunization, sustained vaccination programs for each birth cohort will continue to be necessary to control vaccine-preventable infectious diseases until and unless their etiologic agents can be eradicated from every region of the world. An unwavering scientific and public health commitment to immunization is essential in countering public distrust and political pressure to legislate well-intentioned but ill-informed vaccine safety laws in response to the concerns of organized antivaccine advocacy groups. Ironically, it is the public health success of vaccines that has created a significant part of the problem: because the major fatal and disabling diseases of childhood are only rarely seen today in the United States, parents and young practitioners most likely will never have seen tetanus, diphtheria, Haemophilus influenzae disease, polio, or measles. Under these circumstances, the risks of immunization can easily (if erroneously) be perceived to outweigh the benefits, and this perception can be fueled by inaccurate information, poor science, and zealous advocacy. Caregivers must be prepared to educate parents about the importance of childhood immunization and to address their concerns effectively. The medical community must also appreciate public concern about the sheer number of vaccines now licensed and the attendant fear that the more vaccines are administered, the more likely it is that complications and adverse immunologic consequences will occur. More than 50 biologic products are presently licensed in the United States, and dozens of antigens (many of them components of vaccine-combination products) are recommended for routine immunization of infants, children, adolescents, and adults (Figs. 3-1 and 3-2). Moreover, new vaccines are continually becoming available—e.g., human papillomavirus (HPV) vaccine for use in adolescent girls to prevent cervical cancer (Chap. 86) and a herpes zoster vaccine to prevent zoster (Chap. 81). Still other vaccines are used in special situations, including responses to outbreaks (e.g., polio), prophylaxis in travelers (e.g., yellow fever), and fulfillment of regional requirements (e.g., Japanese B encephalitis). Of course, for many serious infectious agents, such as eukaryotic pathogens (protozoa and helminths) and HIV, effective and safe vaccines remain only a hope for the future. Current concern about the potential for a human pandemic of H5N1 avian influenza, against which a vaccine product is lacking, underscores the lag time between emerging public health needs and vaccine development programs. The U.S. government’s document Healthy People 2010 Objectives for the Nation includes a set of immunization indicators. The goals are for 80% of children to receive diphtheria–tetanus–acellular pertussis (DTaP), poliovirus, measles-mumps-rubella (MMR), H. influenzae type b (Hib), and hepatitis B vaccines and for 90% of adults to receive influenza and pneumococcal vaccines by 2010. Unfortunately, even these modest goals may not be attained in the United States.


IMPACT OF IMMUNIZATION
The epidemiologically appropriate use of vaccine resulted in the global eradication of smallpox, permitting the cessation of routine smallpox vaccination. Unfortunately, recent concerns about the potential use of smallpox virus for bioterrorism have led to renewed consideration of the need for routine smallpox immunization and for a new, effective, and much safer smallpox vaccine. Immunization has eliminated naturally transmitted polio-myelitis from the Western Hemisphere, Europe, and the western Pacific. However, polio has recrudesced in some countries in Africa, the Middle East, and parts of Asia because of interruption (for a variety of reasons) of immunization programs. Measles, which affected nearly 100% of children in the prevaccination era, has been effectively eliminated from most of the Western Hemisphere by widespread immunization; a global campaign to reduce measles mortality rates elsewhere is underway. The virtual elimination of rubella and congenital rubella syndrome, neonatal tetanus, and diphtheria in the United States is entirely due to vaccination.The introduction of Hib conjugate vaccines for immunization of infants has all but eliminated invasive Hib infections (including meningitis and pneumonia) among children <5 years of age. This vaccine both elicits durable immunity by the time maternal-derived antibodies dissipate and reduces nasopharyngeal carriage of Hib, thus diminishing the risk of transmission. The introduction of polyvalent pneumococcal polysaccharide conjugate vaccine is beginning to have a significant impact on serious invasive pneumococcal diseases, including otitis media. Vaccine has reduced the incidence of varicella by 70–87% in high-coverage areas. In short, vaccines work.

DEFINITIONS
The terms vaccination and immunization are often used interchangeably, although technically the former denotes the administration of a vaccine, whereas the latter refers to the induction or provision of immunity by any means, active or passive. Thus vaccination does not guarantee immunization, and immunization may not involve vaccine.  


PRINCIPLES OF IMMUNIZATION
The immune system, composed of a variety of cell types and soluble factors, is geared toward the recognition of and response to “foreign” substances termed antigens.Vaccines convey antigens from living or killed microorganisms (or protein or carbohydrate molecules derived from these antigens) to elicit immune responses that are generally protective but can occasionally backfire and cause harm to the recipient. Specific immune responses, which interrupt the infectious process, generally take the form of immunoglobulin proteins called antibodies and/or activated immune cells that recognize particular antigens from an infectious agent. Immunity is medically induced by active or passive immunization. Active immunization— i.e., the administration of a vaccine—induces immunity that is usually long-lasting and is sometimes life-long. In contrast, passive immunization—i.e., the administration of exogenously produced immune substances or of protective products made in animals—elicits temporary immunity that dissipates with the turnover of the administered protective substances. Used together, the two methods can produce a complementary effect; this is the case, for example, with the coadministration of hepatitis B vaccine and hepatitis B immune globulin.Caution is required, how- 27 ever: the combination of active and passive immunization can also interfere with the development of immunity— e.g., when measles vaccine is administered within 6 weeks of measles immunoglobulin. When multiple species or serotypes of an organism exist and share common, cross-reactive antigens, vaccination may induce broad immunity to all or most of the related forms or may result in serotype-specific immunity against the immunizing strain alone. One of the virtues of whole-organism vaccines is their potential to contain all the protective antigens of the organism. This advantage is balanced by the possibility of adverse responses to reactive but nonprotective antigens present in the mix. Because the immune response is genetically controlled, all individuals cannot be expected to respond identically to the same vaccine. Additional vaccine constituents affect immunogenicity, efficacy, and safety and may render one formulation superior to another formulation of the same antigens (see “Adjuvants” later in the chapter).


Approaches to Active Immunization
The two standard approaches to active immunization are (1) the use of live, generally attenuated infectious agents (e.g., measles virus); and (2) the use of inactivated agents (e.g., influenza virus), their constituents (e.g., Bordetella pertussis), or their products, which are now commonly obtainable through genetic engineering (e.g., hepatitis B vaccine). For many diseases (e.g., poliomyelitis), both live and inactivated vaccines have been employed, each offering advantages and disadvantages. Live attenuated vaccines consisting of selected or genetically altered organisms that are avirulent or dramatically attenuated, yet remain immunogenic, typically generate long-lasting immunity. These vaccines are designed to cause a subclinical or mild illness and an immune response that mimics natural infection.They offer the advantage of microbial replication in vivo, which simulates natural infection; they may confer life-long protection with one dose; they can present all potential antigens, including those made only in vivo, thus overcoming immunogenetic restrictions in some hosts; and they can reach the local sites most relevant to the induction of protective immunity. Nonliving vaccines typically require multiple doses and periodic boosters for the maintenance of immunity. The exceptions to this rule are the pure polysaccharide vaccines, whose effects cannot be boosted by additional exposures because polysaccharides do not elicit immunologic memory. Nonliving vaccines administered parenterally fail to induce mucosal immunity because they lack a delivery system that can effectively transport them to local mucosal antigen-processing cells. Nonetheless, nonliving parenteral vaccines can be extremely efficacious. For example, hepatitis A vaccine appears to be effective in nearly 100% of recipients. Currently available nonliving vaccines consist of inactivated whole organisms (e.g., plague vaccine), detoxified protein exotoxins (e.g., tetanus toxoid), recombinant protein antigens (e.g., hepatitis B vaccine), or carbohydrate antigens—either soluble purified capsular material (e.g., serotype-specific Streptococcus pneumoniae polysaccharides) or polysaccharide conjugated to a protein carrier to induce a memory response (e.g., Hib polysaccharide conjugated to a suitable protein moiety). Despite their many advantages, live vaccines are not always preferable. For example, after several decades of extensive use, live oral polio vaccine (OPV) is no longer recommended in the United States because of the rare but real risk of vaccine-associated polio due to reversion to virulence. However, the WHO continues to recommend OPV for use in the developing world because of lower costs and logistical advantages.


Approaches to Passive Immunization
Passive immunization is generally used to provide temporary immunity in a person exposed to an infectious disease who has not been actively immunized; this situation can arise when active immunization is unavailable (e.g., for respiratory syncytial virus) or when active immunization simply has not been implemented before exposure (e.g., for rabies). Passive immunization is used in the treatment of certain illnesses associated with toxins (e.g., diphtheria), as well as for some snake and spider bites, and as a specific or nonspecific immunosuppressant [Rho(D) immune globulin and antilymphocyte globulin, respectively].Three types of preparations can be used in passive immunization: (1) standard human immune serum globulin for IM or IV administration; (2) special immune serum globulins with a known content of antibody to specific agents (e.g., hepatitis B virus or varicellazoster immune globulin); and (3) specific animal antisera and antitoxins. Postexposure Immunization For certain infections, active or passive immunization soon after exposure can prevent or attenuate disease expression. Recommended postexposure immunization regimens are shown in Table 3-1. For example, giving either measles immune globulin within 6 days of exposure or measles vaccine within the first few days after exposure may prevent symptomatic infection. Nonimmune pregnant women exposed to rubella can minimize clinical illness by postexposure passive immunization; however, this measure may fail to prevent viremia and infection of the fetus and thus may be followed by the congenital rubella syndrome. Proper immunization for tetanus plays an important role in dirty-wound management. The need for active immunization—with or without passive immunization—depends on the wound’s condition and the patient’s immunization history.Tetanus is rare among persons with documented receipt of a primary series of tetanus toxoid doses.Tetanus immune globulin is helpful in patients with clinical tetanus, but survivors must be actively immunized since the disease does not stimulate protective levels of antitoxin antibody. Administration of rabies immune globulin plus rabies vaccine in the immediate postexposure period is highly effective in preventing disease. Similarly, for persons who have not been actively immunized, administration of hepatitis A immune globulin within 2 weeks of exposure to hepatitis A virus is likely to prevent clinical illness. Evidence also supports the efficacy of human hepatitis B immune globulin in preventing disease after exposure. Although no high-titer preparation is available for postexposure protection against non-A, non-B hepatitis, standard human immune serum globulin is efficacious.VariZIG, a highly purified preparation of human antibody to varicella-zoster virus (VZV), is licensed in Canada for the prevention of varicella in nonimmune pregnant women who are exposed to infected individuals. At the time of this writing, this product is available in the United States from the Centers for Disease Control and Prevention (CDC) under an investigational new drug (IND) protocol or under an expanded-access program through the U.S. Food and Drug Administration.

THE IMMUNE RESPONSE
Although many constituents of infectious microorganisms and their products (e.g., exotoxins) are or can be rendered immunogenic, only some stimulate protective immune responses that can prevent infection and/or clinical illness or (as in the case of rotavirus) can attenuate illness, providing protection against severe disease but not against infection or mild illness. The immune system is complex, and many factors—including antigen composition and presentation, as well as host characteristics— are critical for stimulation of the desired immune responses.

The Primary Response
The primary response to a vaccine antigen includes an apparent latent period of several days before immune responses can be detected.Although the immune system is rapidly activated, it takes 7–10 days for activated B lymphocytes to produce enough antibody to be detected in the circulation.The primarily IgM antibodies seen initially are rapidly produced but have only a low affinity for the antigen. After the first week, high-affinity IgG antibodies begin to be produced in quantity; this switch from IgM to IgG production requires the participation of CD4+ T-helper lymphocytes—the “middle men” of the immune response. Because precursors for T cells mature within the thymus gland, antigens that stimulate T cells are referred to as T or thymus-dependent antigens. Circulating antigenspecific T lymphocytes that implement cell-mediated immune responses are identified in the peripheral bloodstream only after several days but begin to increase in number immediately after antigenic stimulation. Activation of these responses typically requires corecognition of the antigen by specific molecular species of human leukocyte antigen (HLA), the major histocompatibility complex, which is present on the surface of lymphocytes and macrophages. Some individuals cannot respond to one or more antigens, even when repeatedly exposed, because they do not have the genes for the particular HLA type involved in antigen recognition, processing, and presentation for an immune response. This situation is known as primary vaccine failure.

The Secondary Response
Stronger and faster humoral or cell-mediated responses are elicited by a second exposure to the same antigen and are detectable within days of the “booster” dose.The secondary response depends on immunologic memory induced by the primary exposure and is characterized by a marked proliferation of IgG antibody–producing B lymphocytes and/or effector T cells. Pure polysaccharide antigens, such as the first-generation pneumococcal vaccine, evoke immune responses that are independent of T cells and are not enhanced by repeated administration. However, conjugation of the same polysaccharide to a suitable protein converts the carbohydrate antigen into one that is T cell–dependent and able to induce immunologic memory and secondary responses to reexposure. Although levels of vaccine-induced antibodies may decline over time, revaccination or infection generally elicits a rapid (anamnestic) protective secondary response consisting of IgG antibodies, with little or no detectable IgM.Thus a lack of measurable antibody in an immunized individual does not necessarily indicate secondary vaccine failure. Similarly, the mere presence of detectable antibodies after immunization does not ensure clinical protection: the level of circulating antibody may need to exceed a threshold value in order to mediate protection (e.g., 0.01 IU/mL for tetanus antitoxin).


Mucosal Immunity
Some pathogens are confined to and replicate only at mucosal surfaces (e.g., Vibrio cholerae), whereas others first encounter the host at a mucosal surface before they invade systemically (e.g., influenza virus). A distinctive immunoglobulin, secretory IgA, is produced at mucosal surfaces and is adapted to resist degradation and to function at these sites. Vaccines may be specifically designed to induce secretory IgA and thereby to block the essential initial steps in disease pathogenesis that occur on mucosal surfaces. Given its complexity, mucosal immunology has become a separate branch of the field of immunology.

Measurement of the Immune Response
Immune responses to vaccines are often gauged by the concentration of specific antibody in serum. Although seroconversion (i.e., transition from antibody-negative to antibody-positive status) serves as a dependable indicator of an immune response, it does not necessarily correlate with protection unless serum antibody is the critical mechanism in vivo and the levels achieved are sufficient (e.g., against measles). In some instances, serum antibody correlates with clinical protection but does not directly mediate it (e.g., vibriocidal serum antibodies in cholera).

Herd Immunity
Successful vaccination protects immunized individuals from infection, thereby decreasing the percentage of susceptible persons within a population and reducing the possibility of infection transmission to others. At a definable prevalence of immunity, an infectious organism can no longer circulate freely among the remaining susceptibles. This indirect protection of unvaccinated (nonimmune) persons is called the herd immunity effect; through this effect, vaccination programs may confer societal benefits that exceed individual costs. The level of vaccine coverage needed to elicit herd immunity depends on the patterns of interaction among individuals within the population and the biology of the specific infectious agent. For example, measles virus and VZV have high transmission rates and require a higher level of vaccine coverage for herd immunity than do organisms with lower transmission rates, such as S. pneumoniae. Wherever herd immunity for poliomyelitis and measles has been induced with vaccines, transmission of infection has ceased; however, herd immunity may wane if immunization programs are interrupted (as was the case for diphtheria in the former Soviet Union) or if a sufficient percentage of individuals refuse to be immunized because of a fear of vaccine-related adverse events (as occurred for pertussis in the United Kingdom and Japan). In either setting, the loss of herd immunity has led to renewed circulation of the organism and subsequent large outbreaks with serious consequences.

PRINCIPLES OF VACCINE USE
Route of Administration

Microbes differ in their routes of infection, patterns of transmission, and predispositions for certain age groups. The route of vaccine administration (oral, intranasal, intradermal, transdermal, subcutaneous, or intramuscular) takes these factors into account in order to maximize protection and minimize adverse events.Vaccine development is more a pragmatic undertaking than an exact science, guided only in part by immunologic principles and shaped largely by the results of clinical trials. Although vaccines can theoretically be given by any route, each vaccine has unique characteristics adapted to a particular route and, in practice, must be given by the licensed route, for which optimal immunogenicity and safety have been documented. For example, vaccines containing adjuvants are designed for injection into the muscle mass. Mucosal administration of vaccines designed for parenteral administration may not induce good systemic responses because such vaccines do not induce mucosal secretory IgA. Administration of hepatitis B vaccine into the gluteal rather than the deltoid muscle may fail to induce an adequate immune response, whereas SC rather than IM administration of DTaP vaccine increases the risk of adverse reactions. Injectable biologicals should be administered at sites where the likelihood of local, neural, vascular, or tissue injury is minimized.

Age
Because age influences the response to vaccines, schedules for immunization are based on age-dependent responses determined empirically in clinical trials. The presence of high levels of maternal antibody and/or the immaturity of the immune system in the early months of life impairs the initial immune response to some vaccines (e.g., measles and pneumococcal polysaccharide vaccines), but not to others (e.g., hepatitis B vaccine). In the elderly, vaccine responses may be diminished because of the natural waning of the immune system, and larger amounts of an antigen may be required to produce the desired response (e.g., in vaccination against influenza). In contrast, in some age groups, the use of substandard amounts of antigen is sufficient for immunity induction and reduces the risk of adverse effects (e.g., a reduced dose of diphtheria toxoid for persons ≥7 years of age). Age-related adverse events are discussed in a later section.

Target Populations and Timing of Administration
Disease attack rates differ across the human life span, and the timing of immunization must consider these variations along with the age-specific response to vaccines, the durability of the immune response, and the logistics for optimal identification and vaccination of the groups at risk. Aside from immunologic parameters, many factors are involved, including demographic features; thus vaccination programs are really as much community as individual endeavors. Schedules for immunization are ultimately derived from careful consideration of the many relevant variables and may ultimately depend on the best opportunities to reach the target groups (e.g., infancy, school entry, puberty, college enrollment, military induction, entry into the workplace). Health care workers administering vaccines or caring for patients with vaccine-preventable diseases have a special responsibility to be adequately immunized themselves and to take all necessary precautions to minimize the risk of spreading infection (e.g., hand washing between immunizations or other interactions with patients). Catchup immunization schedules for infants and children through the age of 18 years have been approved by the CDC (Fig. 3-3). For common and highly communicable childhood diseases such as measles, the target population is the universe of susceptible individuals, and the time to immunize is as early in life as is feasible and effective. In the industrialized world, immunization with live-virus vaccine at 12–15 months of age has become the norm because the vaccine protects >95% of children immunized at this age and there is little measles morbidity or mortality among infants <1 year of age. In contrast, under crowded conditions in the developing world, measles remains a significant cause of death among young infants. For optimal benefit in this situation, it is necessary to immunize early enough to narrow the window of vulnerability between the rapid decline of maternal antibody 4–6 months after birth and the development of vaccine-induced active immunity; this choice must be made despite the less efficient immune response in children <1 year old. Invasive infections due to Hib (meningitis, pneumonia, and epiglottitis) occur primarily in young children, with rates rising sharply after the disappearance of maternally derived antibody. First-generation Hib polysaccharide vaccines often failed when administered during infancy because very young children cannot respond to pure polysaccharides. This problem has been overcome by conjugating the capsular polysaccharide with a protein to create a T cell–dependent antigen, to which infants effectively respond. In contrast, rubella is primarily a threat to the fetus rather than to infants and young children. The ideal strategy would be to immunize all women of reproductive age before they became pregnant. Because it is difficult to ensure this type of coverage, rubella is included in a combination vaccine with measles and mumps (MMR) that is administered during infancy and boosted at the age of 4–6 years. It is recommended that pregnant women be screened for rubella antibodies and that seronegative women be given rubella vaccine after delivery. Similar considerations apply to the use of the vaccine against HPV that was recently approved in the United States and is intended primarily to prevent cervical cancer in women. Accordingly, it is recommended that the vaccine be given at the age of 11–12 years (or as early as 9 years), so that all are immunized before becoming sexually active. Some vaccines, such as the influenza and polyvalent pneumococcal polysaccharide products, were originally formulated to prevent pneumonia hospitalizations and deaths among the elderly.These products have been consistently underused, in large part because physicians and otherwise-healthy older individuals ignore the recommendations, but also because vaccines continue to be thought of as interventions for infants and children. There is considerable debate about alternative strategies to reduce the burden of these diseases in the elderly by indirectly protecting them through childhood vaccination, which would reduce transmission. The development of new vaccines and the exploitation of new routes of administration may facilitate this approach; examples include the development of pneumococcal conjugate vaccines and the administration of influenza vaccine by the intranasal route, respectively.The pneumococcal conjugate vaccine has made it possible to immunize young infants at risk of pneumococcal pneumonia, meningitis, and otitis media, but whether immunity will persist or will need boosting in adulthood remains to be determined. What is clear is that the number of recommended vaccines and the strategies for their deployment are undergoing constant revision.

Adjuvants
The immune response to some antigens is enhanced by the addition of adjuvants—nonspecific boosters of immune responses. Adjuvants include aluminum salts or, in the case of polysaccharides such as the polyribose phosphate oligosaccharide of Hib, a carrier protein to which the polysaccharide is conjugated. Adjuvants are essential to the efficacy of a number of inactivated vaccines, including diphtheria and tetanus toxoids, acellular pertussis vaccine, and hepatitis B vaccine; they also appear to be required for enhancement of the response to killed H5N1 avian influenza vaccines. The mechanism by which adjuvants enhance immunogenicity is not well defined, but appears to relate to the ability of the adjuvant to activate antigen-presenting cells, frequently through stimulation of Toll-like receptors. Other reported mechanisms for adjuvant effects include rendering of soluble antigens into a particulate form, the mobilization of phagocytes to the site of antigen deposition, and the slowing down of antigen release in order to prolong stimulation of the immune response. Identification of new adjuvants that are safe, more effective, and inexpensive is a high priority for vaccine researchers and manufacturers.

USE OF VACCINES RECOMMENDATIONS FOR USE
Two or more vaccines should not be mixed in the same syringe in an effort to diminish the number of needle sticks unless such a practice is specifically endorsed by licensure. Disposable needles and syringes must be safely discarded to prevent inadvertent needle stick injury. Although the importance of using a new syringe and needle for each vaccine recipient is obvious, reuse of contaminated equipment is a common reality in resource-poor settings. One-time-use, “autodestruct” needles and syringes have been designed to prevent this practice, but their use adds to the cost of vaccine delivery. Wherever effective primary health care systems ensure access to medical services for the majority and the population is educated about the need for and efficacy of vaccines, coverage rates for basic immunizations are usually high, regardless of the route of vaccine administration or the number of doses necessary. However, without systematic attention to the completion of multiple-dose vaccine schedules, coverage rates for second, third, and booster doses may drop off, and the efficacy of immunization may be significantly diminished.

RISK ASSESSMENT
Vaccines are considered safe when the risk of use is judged to be acceptable in relation to the benefits. For vaccines given to healthy individuals for diseases that are no longer common, acceptable risks are set at very low levels— indeed, far lower than for most medical products. However, “safety” does not and cannot ever mean “zero risk.” The determination of safety is thus based on a scientific assessment of the data and a considered judgment of all the issues involved, including benefits and risks. Communities and individuals may differ, both among themselves and from health care professionals, in how they perceive the risks, benefits, and acceptability of vaccines and in how they judge the amount of uncertainty that is tolerable. Some parent advocacy groups, such as those that oppose mandatory vaccination, feel that no amount of risk is acceptable, especially for childhood vaccines.

SOURCES OF IMMUNIZATION RECOMMENDATIONS
Harmonized recommendations for vaccine use in the United States are developed by several professional groups. Schedules for immunization of children and adolescents and of adults are shown in Figs. 3-1 and 3-2, respectively. Vaccines recommended for special use are shown in Table 3-2. As noted above, the number of licensed vaccines and the strategies for their best use change constantly as new products, new indications, and new information become available. The Advisory Committee on Immunization Practices (ACIP) regularly amends immunization recommendations to reflect the evolution of vaccines and vaccination policy in the United States. Changes for 2006 include the following points: • To implement standing orders to administer hepatitis B vaccine—soon after birth and before hospital discharge—to all infants except those with documented hepatitis B–negative mothers; • To target adults at high risk for hepatitis B vaccination; • To use a new tetanus toxoid/reduced-dose diphtheria toxoid plus acellular pertussis combination vaccine (Tdap) formulated for adolescents and adults in place of Td; FIGURE 3-3 (CONTINUED) administered ≥28 days after the first dose. 9. Hepatitis A vaccine (HepA). (Minimum age: 12 months) HepA is recommended for certain groups of children, including in areas where vaccination programs target older children. See MMWR 2006;55(No. RR-7):1–23. 10. Tetanus and diphtheria toxoids vaccine (Td) and tetanus and diphtheria toxoids and acellular pertussis vaccine (Tdap). (Minimum ages: 7 years for Td, 10 years for BOOSTRIX, and 11 years for ADACEL) Tdap should be substituted for a single dose of Td in the primary catch-up series or as a booster if age appropriate; use Td for other doses. A 5-year interval from the last Td dose is encouraged when Tdap is used as a booster dose. A booster (fourth) dose is needed if any of the previous doses were administered at age <12 months. Refer to ACIP recommendations for further information. See MMWR 2006;55(No. RR-3). 11. Human papillomavirus vaccine (HPV). (Minimum age: 9 years) Administer the HPV vaccine series to females at age 13–18 years if not previously vaccinated. To provide meningococcal conjugate vaccine (MCV4) 35 to all children at 11–12 years of age, to unvaccinated adolescents at age 15, and to all college freshmen living in dormitories; • To administer hepatitis A vaccine to all children at 1 year of age; • To administer three doses of the newly licensed rotavirus vaccine at 2, 4, and 6 months of age, with the first dose given by 12 weeks of age and the last by 32 weeks of age; • To immunize children 6 months to 5 years of age with influenza vaccine and to expand routine use of the vaccine for their household contacts and out-of-home caregivers; • To administer Tdap to protect health care personnel from pertussis and to reduce their potential to transmit nosocomial infections, assigning the highest priority to those who have direct contact with infants <1 year old; and • To administer HPV vaccine routinely to girls at 11–12 years of age.

VACCINES FOR ROUTINE USE
Infants and Children
It is current practice for all children in the United States to receive DTaP, poliovirus, MMR, Hib, hepatitis B, and varicella vaccines and to receive pneumococcal conjugate, hepatitis A, and rotavirus vaccines in the absence of specific contraindications (Fig. 3-1; www.cdc.gov/vaccines/vpd-vac/vaccines-list.htm). Annual influenza seasonal vaccine is recommended for all children 6 months to 5 years old and to other children who have certain risk factors or who reside with persons with certain chronic disorders. In several European countries, meningococcal C conjugate vaccine is routinely recommended for children.


Teenagers
It is now recommended that all adolescents routinely receive quadrivalent meningococcal conjugate vaccine for serogroups A, C,Y, and W135 and the new-formulation Tdap vaccine. Girls should be given HPV vaccine, ideally at the age of 11–12 years, but certainly before becoming sexually active (Fig. 3-1; www.cdc.gov/vaccines/recs/schedules/ teen-schedule.htm).

Adults, Including College Students 
Immunization recommendations for adults (≥18 years old) fall into four categories: (1) routine vaccines for all adults; (2) vaccines for high-risk exposure groups (health care and other institutional workers, prisoners, students, military personnel, travelers to endemic areas, injection drug users, and men who have sex with men); (3) vaccines for persons at high risk for severe outcomes of infection (pregnant women; the elderly; persons with chronic medical conditions, including diabetes, alcoholism, immunodeficiency, and renal, hepatic, respiratory, or cardiac disease); and (4) vaccines for household contacts of persons in group 3. Because a substantial proportion of adults in the United States no longer have protective levels of antibodies to tetanus or diphtheria, all adults should receive routine booster doses of Td every 10 years. For those under age 65 years, one-time substitution of Tdap suitable for adults (Adacel, Sanofi-Pasteur) in place of the usual Td booster is recommended. Pregnant women who received their last Td booster >10 years previously may receive Td during the second or third trimester; those boosted <10 years previously (and as recently as 2 years before) should receive Tdap after delivery.Adults who have contact with infants <12 months of age should receive a single dose of Tdap—ideally at least 2 weeks before contact begins—if the most recent Td booster was ≥2 years earlier. If not previously immunized, adults require a primary immunizing course of Td. Young adults without laboratory evidence or a reliable history of past vaccination or disease should be immunized against measles, mumps, rubella, and varicella. A second dose of MMR vaccine is recommended for groups with a higher risk of exposure and for health care workers with certain other indications. Unless they have documented proof of immunity, rubella vaccine should be given to all nonpregnant women of childbearing age. Rubella-susceptible pregnant women should be vaccinated as early as possible in the postpartum period. Live-virus vaccines, such as MMR and varicella vaccines, are contraindicated in pregnant women and immunosuppressed individuals. Routine immunization against polio (with inactivated vaccine) is not recommended for adults unless they are at particular risk of exposure because of travel to the remaining endemic areas. College students, particularly freshmen living in dormitory settings, are at increased risk of meningococcal meningitis, as are military recruits; individuals in both of these groups should be offered the meningococcal polysaccharide or conjugate vaccine for serogroups A,C,Y, and W-135. Current recommendations also include influenza vaccine for routine annual administration to individuals with chronic illness at any age, to persons living in the same household as chronically ill individuals, and to all adults >50 years of age. Polyvalent pneumococcal polysaccharide vaccine is similarly recommended for adults ≥65 years of age and for all chronically ill persons. Hepatitis B vaccine should be given to adults at high risk from clinical, occupational, behavioral, or travel exposures, including patients undergoing hemodialysis, routine recipients of clotting factors, health care workers exposed to potentially infected blood or blood products, individuals living and working in institutions for the mentally handicapped, travelers to highly endemic countries, persons at excess risk for sexually transmitted diseases, injection drug users, and household contacts of known carriers of hepatitis B surface antigen. Hepatitis A vaccine is recommended for these same groups and for persons with clotting disorders or chronic liver disease. There are a number of other special-use vaccines whose administration is related to travel and occupational exposures (e.g., Japanese B encephalitis, typhoid fever, yellow fever, and rabies); specific recommendations for the use of these vaccines in the United States can be found at www.cdc.gov/nip/recs/adult-schedule.htm.

Simultaneous Administration of Multiple Vaccines
There are no contraindications to the simultaneous administration of multiple individual vaccines, although the use of licensed combination vaccines can significantly reduce the required number of injections during the first 2 years of life. Combination DTaP/Hib vaccine should not be used for primary immunization of infants because it results in a blunted, suboptimal response to Hib; the combination may be used for booster immunizations. Simultaneous administration of the most widely used live and inactivated vaccines has not resulted in impaired antibody responses or in elevated rates of adverse reactions. In fact, this approach increases the likelihood that a child will ultimately be fully immunized. The simultaneous administration of vaccines is useful in any age group when the potential exists for exposure to multiple infectious diseases during travel to endemic countries. Live-virus vaccines may be given together on the same day; if this approach is not feasible, an interval of at least 30 days should be allowed to avoid interference in the response to one or another of the administered vaccine strains. Because high doses of immune globulin can inhibit the efficacy of measles and rubella vaccines, an interval of at least 3 months is recommended between the administration of immune globulin and that of MMR vaccine or its components. However, postpartum vaccination of rubella-susceptible women should not be delayed because of the administration of anti-Rho(D) immune globulin or any other blood product during the last trimester or at delivery. Should the administration of an immune globulin preparation become necessary after vaccination, it should be postponed, if at all possible, for at least 14 days to allow time for vaccine-virus replication and development of immunity. In general, there is little interaction of immune globulin with inactivated vaccines, and postexposure passive prophylaxis can be given together with hepatitis B vaccine or tetanus toxoid, resulting in both immediate and long-lasting protection. Adverse Events Vaccines are generally very safe. Serious adverse events proven to be due to currently licensed vaccines are rare. Concerns about vaccine safety have at times become inflated in conjunction with complacency about the consequences of infections no longer routinely transmitted in the United States. As a result, some parents have refused to have their infants and children immunized. An adverse reaction or vaccine side effect is an untoward vaccine effect that is extraneous to the vaccine’s primary purpose (to produce immunity). An adverse event can be either a true vaccine reaction or an event whose occurrence is temporally related to a vaccine dose but is entirely unrelated to the vaccine itself. As vaccines are routinely administered through childhood, coincidental events are inevitable. Because our understanding of the underlying biologic mechanisms that cause adverse events remains limited, a few highly publicized claims— unsubstantiated by validated data or analysis—can easily heighten the suspicion that some or all vaccines routinely cause unacceptable adverse events. Antivaccine advocacy groups actively encourage the avoidance of immunization because they believe that vaccines cause certain disorders (e.g., autism). This situation presents a challenge to physicians and public health officials who must educate parents and practitioners about vaccine benefits and risks. It is true that modern vaccines, although remarkably safe and effective, are associated with adverse events in some recipients and that these events range from frequent and mild to rare and serious or even life-threatening.The decision to recommend a vaccine involves an assessment of the risks of disease and its complications for those who remain unimmunized and the benefit-to-risk ratio of vaccination itself. Because these factors may change over time, the balance between societal benefits and individual risks must be continually evaluated. Valid and invalid contraindications to childhood immunization and appropriate precautions in the use of specific vaccines are reported by the CDC (Table 3-3); updated information can be found at www.cdc.gov/vaccines/recs/ vac-admin/downloads/contraindications_guide.pdf. A putative link between measles immunization and autism has been the subject of intense international controversy. The Institute of Medicine of the U.S. National Academies of Science has issued four recent reports whose findings (1) fail to support hypotheses that vaccines are associated with multiple sclerosis, neurodevelopmental disorders (e.g., autism), or immune dysfunction; (2) provide no evidence for a temporal association of these conditions with vaccination; and (3) elucidate no biologically plausible basis for the purported relationships. An illuminating example is the case of Rotashield, a rhesus reassortant rotavirus vaccine, which was introduced for routine use in the United States in the late 1990s.Within 9 months of its introduction, cases of intussusception were reported by the CDC to be temporally associated with the administration of the initial vaccine dose.This report led first to the cessation of the vaccine’s use and subsequently to its withdrawal from the market and the discontinuation of its production. The withdrawal of the vaccine in the United States made its use impossible in developing countries, where the risk of any increase in intussusception would have been dramatically outweighed by the benefit of decreased rotavirus mortality rates. It is now apparent that the susceptibility to intussusception is age related, with virtually no events in children <90 days of age. Almost a decade later, a new rotavirus vaccine has been licensed in the United States and recommended for routine use beginning at ≤2 months of age. In the interim, some 4–5 million infants have died of rotavirus diarrhea in the developing world; most of these deaths could have been prevented by the original rhesus rotavirus vaccine.  Vaccine components, including protective antigens, 39 animal proteins introduced during vaccine production, and antibiotics or other preservatives or stabilizers, can certainly cause allergic reactions in some recipients.These reactions may be local or systemic, including urticaria and serious anaphylaxis.The most common extraneous allergen is egg protein derived from the growth of measles, mumps, influenza, and yellow fever viruses in embryonated eggs. Gelatin, used as a heat stabilizer, has been implicated in rare but severe allergic reactions. Local or systemic reactions (probably due to antigen-antibody complexes) can result from the too-frequent administration of vaccines such as Td or rabies vaccine. Because live-virus vaccines can interfere with tuberculin test responses, necessary tuberculin testing should be done either on the day of immunization or at least 6 weeks later.

USE OF VACCINES IN SPECIAL CIRCUMSTANCES
Breast Feeding
Neither killed nor live vaccines affect the safety of breast feeding for either mother or infant. Breast-fed infants can be immunized on a normal schedule. Even premature infants can be immunized at their appropriate chronologic age. Seroconversion in response to hepatitis vaccine at birth may be impaired in some premature infants with birth weights of <2000 g. By a chronologic age of 1 month, however, premature infants—regardless of initial birth weight or gestational age—are as likely to respond adequately to vaccines as older and larger infants.

Occupational Exposure
Immunization recommendations for most occupational groups remain to be developed. Specific practices for the immunization of U.S. health care workers against hepatitis B are mandated by the Occupational Safety and Health Administration. Persons employed in caring for patients with chronic diseases can transmit influenza and should be vaccinated annually, independent of age. Rubella is transmitted to and from health care workers in medical facilities, particularly in pediatric practice. Health care workers who might transmit rubella to pregnant patients should be documented to be immune to rubella; susceptible individuals should be promptly immunized. Persons providing health care are also at greater risk from measles and varicella than the general public, and those who are likely to come into contact with measles- and varicella-infected patients should be documented to be immune or be immunized.

HIV Infection and Other Medical Conditions
Limited studies in HIV-infected individuals have found no increase in the risk of adverse events from the use of live or inactivated vaccines. It is not surprising that immune responses may not be as vigorous in immunocompromised individuals as in those with a normal immune system; therefore, persons known to be infected with HIV should be immunized with recommended vaccines in the same manner as individuals with a normal immune system and as early in the course of their disease as possible, before immune function becomes significantly impaired. If MMR immunization is indicated, HIV-infected patients may receive the standard attenuated vaccine; if polio vaccination is required, these patients and their household contacts should receive inactivated polio vaccine. Albeit prudent, it is not necessary to test for HIV before making decisions about the immunization of asymptomatic individuals from known HIV risk groups. Live attenuated vaccines are contraindicated in other immunocompromised patients, including those with congenital immunodeficiency syndromes, those who have undergone splenectomy, and those who are receiving immunosuppressive therapy. Passive immunization with immunoglobulin preparations or antitoxins can be considered in individual cases, either as postexposure prophylaxis or as part of the treatment of established infection.

Travel 
The International Sanitary Regulations allow countries to impose requirements for yellow fever and killed cholera vaccines as a condition for admission, even though the latter vaccine is not an effective public health tool.Travelers should know whether these vaccines are required for entry into the countries on their itinerary to avoid being turned back or immunized on the spot, with the inherent danger of unsafe injections in poor developing countries. Infants, children, and adults should have all routine immunizations updated before traveling, especially to developing countries, with particular attention to polio, measles, and DTaP or Tdap, depending on age. Immunity to hepatitis A and hepatitis B is advisable for travelers. Special-use vaccines (Table 3-2), including rabies, typhoid, Japanese B encephalitis, and plague vaccines, should be considered for those individuals who expect to go beyond the usual tourist routes or to spend extended periods in rural areas in disease-endemic regions. Most U.S. cities have travel clinics that maintain up-to-date epidemiologic information and can provide the appropriate vaccines.The CDC maintains a useful website for travelers (www.cdc.gov/travel ).

CURRENT CONTROVERSIES
Even though vaccines are very safe and serious adverse events proven to be due to licensed vaccines are rare, the recent rise in the reporting of autism spectrum disorders has led some parents of affected children to claim that thimerosal—used as a preservative—is the cause of the problem. No study has yet implicated thimerosal or the vaccines in which it has been used as a likely cause of these disorders; however, fully 50% of cases before the Vaccine Injury Compensation Program concern autism allegedly due to mercury. In 1999, thimerosal was removed from single-dose formulations of recommended childhood vaccines in the United States; the exception is influenza vaccine, for which thimerosalfree preparations have been in short supply.There is no evidence that the frequency of autism diagnoses has changed since the discontinuation of thimerosal use, but further observation is necessary. It is important to resolve these controversies, particularly because it may be difficult to ensure product sterility in developing countries— where multidose vials of vaccine are most cost-effective— without the use of preservative. Disparities in vaccine coverage among the majority and minority communities in the United States persist. Reasons for underimmunization include limited access to health care, lack of insurance, assignment of a low priority to preventive measures, and insufficient knowledge about vaccines and the importance of being vaccinated. The persistence of wild poliovirus in immunocompromised individuals and the reversion of live poliovirus vaccine to virulence in several communities have catalyzed debate about whether it really is possible to eradicate poliovirus from the world (thus allowing the cessation of immunization) or whether the best that can be hoped for is the worldwide elimination of clinical disease, with continued routine immunization to keep the risk low. The addition of new, individually injectable vaccines to the childhood immunization schedule has heightened parental concerns about multiple injections at a single clinic visit. The continued development and testing of vaccine combinations aim to mitigate these concerns. Even when multiple injections are required, providers must make every effort to administer all indicated vaccines at each visit.


DELIVERY OF VACCINES
Over the past 25 years, considerable progress has been made to ensure that every child in the United States is fully immunized by the time of school entry. All 50 states now require immunization for school entry, and most have laws addressing attendance at preschools and day-care centers. Despite the dramatic impact of immunization and of other improvements in health care on the incidence of vaccine-preventable illness in the United States, many children still are not fully immunized, both in poor communities with inadequate health services and in affluent communities where parental concern about potential adverse events may exceed concern about now-uncommon diseases. The failure to vaccinate preschool children was largely responsible for the resurgence of measles in the United States in 1989–1991, with >55,000 cases and >130 measles-related deaths. Outbreaks of pertussis, mumps, and congenital rubella syndrome have occurred wherever immunization rates among preschool children are low. Although indigenous transmission of polio, measles, and rubella has been eliminated in the United States, the risk of imported infection and spread to vaccine-naïve susceptible persons persists.

ACCESS TO IMMUNIZATION
Four major barriers to infant and childhood immunization have been identified within the health care system: (1) low public awareness and lack of public demand for immunization, (2) inadequate access to immunization services, (3) missed opportunities to administer vaccines, and (4) inadequate resources for public health and preventive programs. National outreach and educational campaigns promote parental awareness of the value of vaccination and encourage health care providers to use every opportunity to vaccinate the children in their care.

HANDLING OF VACCINES
Vaccines must be handled and stored with care. Attention to the entire “cold chain”—from storage, shelf life, reconstitution, and shelf life after reconstitution and opening— is essential to ensuring that clients receive potent vaccines. Vaccines should be kept at 2°–8°C and, with the exception of varicella vaccine and live attenuated influenza vaccine, should not be frozen.The latter two vaccines should be kept frozen at −15°C. Measles vaccine must be protected from light, which inactivates the virus.

STANDARDS FOR IMMUNIZATION PRACTICE
National standards of immunization for childhood, adolescent, and adult practice have been established to define common policies and practices for public health clinics and physicians’ private offices (Table 3-4).These standards represent the most desirable immunization practices and highlight the need to distinguish between valid contraindications and conditions that are often considered to be but are not in fact contraindications (www.cdc.gov/vaccines/recs/vac-admin/downloads/ contraindications_guide.pdf). Among the valid contraindications applicable to all vaccines are a history of anaphylaxis or other serious allergic reactions to a vaccine or vaccine component and the presence of a moderate or severe illness, with or without fever. Infants who develop encephalopathy within 72 h of a dose of DTP or DTaP should not receive further doses; those who experience a “precaution” event should not normally receive further doses. Because of theoretical risks to the fetus, pregnant women should not receive MMR or varicella vaccine. Diarrhea, minor respiratory illness (with or without fever), mild to moderate local reactions to a previous dose of vaccine, the concurrent or recent use of antimicrobial agents, mild to moderate malnutrition, and the convalescent phase of an acute illness are not valid contraindications to routine immunization. Failure to vaccinate children because of these conditions is increasingly viewed as a missed opportunity for immunization.

CONTROL OF VACCINE-PREVENTABLE DISEASE
A continuing task of public health practice is to maintain individual and herd immunity, and the job is not over once a population is fully vaccinated. Rather, it is imperative to immunize each subsequent generation as long as the threat of the reintroduction of the disease from anywhere in the world persists. Ongoing surveillance and prompt reporting of disease to local or state health departments are essential to this goal, ensuring a continuing awareness of the possibility of vaccine-preventable illness. Nearly all vaccinepreventable diseases are notifiable, and individual case data are routinely forwarded to the CDC. These data are used to detect outbreaks or other unusual events that require investigation and to evaluate prevention and control policies, practices, and strategies.

 
INTERNATIONAL CONSIDERATIONS

Since the establishment of the Expanded Programme on Immunization (EPI) by the WHO in 1981 and the involvement of UNICEF in the program’s implementation, levels of coverage for the recommended basic children’s vaccines (bacille Calmette-Guérin, poliomyelitis, DTP/DTaP, and measles) have risen from 5% to ∼80% worldwide, although coverage does not necessarily translate into protective immunity. Each year, at least 2.7 million deaths from measles, neonatal tetanus, and pertussis and 200,000 cases of paralysis due to polio are prevented by immunization. Despite the successes of this program, many vaccine-preventable diseases remain prevalent in the developing world. Measles, for example, continues to kill an estimated 500,000 children each year, and diphtheria, whooping cough, polio, and neonatal tetanus still occur at unacceptably high rates. An estimated 20–35% of all deaths of children are due to vaccine-preventable diseases. In addition to the antigens included in the EPI for routine use in the developing world, others (hepatitis B, Hib, Japanese B encephalitis, yellow fever, meningococcal, mumps, and rubella) are used regionally, depending on disease epidemiology and resources.The rationale for inclusion of hepatitis B vaccine in Africa and Asia is to prevent the subsequent development of hepatocellular carcinoma, which is strongly linked with the persistence of hepatitis B virus from early childhood. The delivery of vaccines in mass campaigns on national immunization days, superseding even civil wars and insurgencies, has resulted in the cessation of transmission of poliomyelitis in the Western Hemisphere, the western Pacific, and Europe and in the virtual elimination of clinical measles from the Western Hemisphere. Periodic vaccination campaigns complement routine infant and childhood vaccination services under the rubric “catch up, follow up, and keep up.” Despite these successes, concerns remain about the adequacy of long-term strategies to ensure continuity, the impact of vaccine campaigns on the provision of routine services, and unsafe injection practices. Because infectious diseases know no geographic or political boundaries, uncontrolled disease anywhere in the world poses a threat to the United States, even without bioterrorism.Vaccines offer the opportunity to effectively control and even eliminate some diseases through individual and herd protection. Vaccines also represent the best societal hope for stopping the pandemic of HIV infection throughout the world and for efficiently controlling malaria and tuberculosis. Issues of cost, liability, risk, and profitability limit the interest of the pharmaceutical industry in the development of vaccines for infectious diseases of the poor.