Active Immunization

Vaccine Content

Biologic agents used to induce active immunization include vaccines and toxoids. Traditionally, a vaccine is defined as a suspension of live (usually attenuated) or inactivated microorganisms, or fractions thereof, which is administered to induce immunity and prevent infectious diseases or their sequelae; efforts to develop vaccines to increase the immune response to cancers or to treat diseases including diabetes mellitus necessitate reconsideration of this definition. Live, attenuated vaccines traditionally have been developed by means of serial passage (in culture or animals) of an initially pathogenic bacteria or virus strain with selection for strains that are less pathogenic for humans but that induce protective immunity (e.g., measles, mumps, and rubella [MMR] vaccine). Live, attenuated vaccines also can be developed with use of reassortants of attenuated animal or human virus strains with virus coat antigens from pathogenic strains (e.g., cold-adapted influenza, rotavirus vaccines). Inactivated vaccines can consist of the following: (1) whole organisms inactivated by heat, formalin, or other agents (e.g., polio, hepatitis A, rabies vaccines); (2) purified protein (e.g., acellular pertussis, influenza, and meningococcal serogroup B vaccines) or polysaccharide antigens (e.g., pneumococcal, meningococcal, and intramuscular typhoid vaccines) from whole organisms; (3) purified antigens produced by genetically altered organisms (e.g., hepatitis B and human papillomavirus [HPV] vaccines produced by yeast); (4) chemically modified antigens, such as polysaccharides conjugated to carrier proteins to increase immune response (e.g., conjugated Hib, pneumococcal, and meningococcal vaccines); or (5) messenger RNA encoding protein(s) of the organism, which then are transcribed in the cytoplasm of cells near the site of infection to express the antigen and then stimulate the immune response. Toxoids are bacterial toxins produced in bacterial culture that have been rendered nontoxic but retain the ability to stimulate formation of antitoxin.

Vaccine and toxoid preparations also contain other constituents intended to enhance immunogenicity and stability but that can be responsible for adverse reactions. Such constituents include the following: (1) suspending fluid, which can be saline or complex fluids containing constituents derived from the biologic system or medium in which the vaccine is produced (e.g., egg or serum proteins); (2) preservatives, stabilizers, or antimicrobial agents, which are used to inhibit bacterial growth in viral cultures or the final product or to stabilize antigens (e.g., mercurials, phenols, albumin, glycine, neomycin); and (3) adjuvants, which enhance response to inactivated antigens (e.g., aluminum phosphate, aluminum hydroxide, mixed aluminum salts). Concern about the theoretical possibility of adverse effects from cumulative exposure to mercury in the environment has led to removal of thimerosal as a preservative from most US vaccines recommended for children. The only vaccines administered to children that contain thimerosal as a preservative are some influenza vaccines (multidose vials). Physicians should be knowledgeable about the constituents of each vaccine, which are described in vaccine package inserts ( https://www.fda.gov/vaccines-blood-biologics/vaccines/vaccines-licensed-use-united-states ).

Immunologic Basis of Response to Vaccines

The two major approaches to active immunization are (1) live, attenuated vaccines and (2) inactivated or detoxified agents or their purified components, or the messenger RNA encoding these inactive agents. For some diseases, such as poliomyelitis and influenza, both approaches have been used.

Live, attenuated vaccines have the advantage of producing a complex immunologic response simulating natural infection. Because replication of the organism and processing of antigens mimic those of the natural pathogen, both humoral and cell-mediated responses can be generated to a variety of antigens. Generally, immunity induced by a single dose of a live, attenuated vaccine is long-lasting, possibly lifelong. However, the strength of response, particularly the humoral response, usually is less robust than the response following natural infection, and detectable antibodies can wane with time, resulting in some potential loss of protection. Induction of immunity by live vaccines can be inhibited by passive antibody, whether from transplacental acquisition from the mother or receipt of immunoglobulin-containing blood products. Thus, optimal response depends on ensuring that passive antibody levels have declined prior to vaccination (e.g., primary measles vaccination at 12 months of age instead of earlier, delay of measles vaccination after administration of blood products). In addition, because response may be only 90%–95% after a single dose, a 2-dose or multiple-dose regimen may be necessary to induce higher levels of protection in the community and prevent spread of disease if the population is exposed (community protection).

Inactivated or purified antigen vaccines induce response only to components present in the vaccine. Multiple doses, usually three or more, are generally necessary to induce satisfactory antibody levels that persist for long periods of time; booster doses at longer intervals (e.g., 10 or more years for tetanus and diphtheria toxoids) sometimes are required to ensure lasting protection. The nature of vaccine responses depends on antigen type. Protein and glycoprotein antigens usually induce both humoral immunity and memory (response through helper T lymphocytes) after multiple doses, as evidenced by more rapid, broad, and intense (anamnestic) response to successive doses. Polysaccharide antigens by themselves induce only humoral antibody without T-lymphocyte stimulation and fail to induce an anamnestic response with repeated antigenic challenge. This limitation can be overcome by conjugation of polysaccharides to protein carriers to induce both a stronger immune response in younger children and immunologic memory.

Immune Response to Active Immunization

The general mechanism by which a long-term protective memory immune response is induced requires activation of T lymphocytes by antigen-presenting cells, which then provide help to B lymphocytes to develop into antibody-producing plasma cells (i.e., T-lymphocyte–dependent response). ^, Polysaccharide antigens bypass T-lymphocyte help (i.e., T-lymphocyte–independent response) and induce B-lymphocyte differentiation directly, but they do not induce immunologic memory. Initiation of a T-lymphocyte–dependent antibody response occurs by activation of naïve CD4 ⁺ helper T lymphocytes in response to antigen-presenting cells, generally dendritic cells. This interaction occurs through recognition of the major histocompatibility complex (MHC) on the antigen-presenting cells by the T-lymphocyte receptor and by secretion of cytokines that are necessary for maturation of naïve CD4 ⁺ helper T lymphocytes to differentiate toward a helper T-lymphocyte 1 (Th1) or Th2 response. Th1 responses are predominantly cell-mediated, whereas Th2 responses are predominantly humoral. In the presence of interleukin-12 (IL-12), Th1 response is differentiated and is associated with secretion of IL-2 and interferon γ (IFNγ). In the presence of IL-4, Th2 response is differentiated and is associated with secretion of IL-4 and IL-5. These two cytokines are essential for differentiation and maturation of B lymphocytes into antibody-secreting plasma cells. A small subset of CD4 ⁺ T lymphocytes does not differentiate into effector cells; instead, these T-lymphocytes mature to become long-lived memory cells, which form the nucleus of the secondary immune response on reexposure to antigen. The overall response is regulated by a further class of CD4 ⁺ T lymphocytes (Treg).

In a primary response, naïve B lymphocytes recognize a specific antigenic epitope on native antigen through the immunoglobulin receptor on the surface of the B lymphocyte, and they differentiate into antibody-secreting cells in response to help from CD4 ⁺ Th2 lymphocytes. A given B lymphocyte is activated by a T-lymphocyte responding to the same antigen. B-lymphocyte proliferation and maturation then occur in a clonal manner, and during this process, immunoglobulin (Ig) class switching (from IgM to IgG and IgA) and affinity maturation also occur. Antigen-specific plasma cells develop and secrete large amounts of clonal antibody.

The polyclonal response to a given immunogen reflects the sum of the multiple individual clonal B-lymphocyte responses that result in an antibody response. A few activated B lymphocytes mature into long-lived memory B lymphocytes, which form the basis of the rapid secondary response on the next encounter with antigen. Some plasma cells acquire the capacity to migrate toward long-term survival niches mostly located within the bone marrow, from where they may produce antibodies during extended periods. ^, The duration of antibody responses reflects the number or quality, or both, of long-lived plasma cells generated by immunization. The mechanism of maintenance of these lymphocytes is an area of active research because the ability to mount a strong secondary response after many years is a critical component of the adaptive immune response.

Initiation of the specific immune response to a pathogen depends on the innate immune response, which is rapid, does not exhibit memory, and historically has been considered nonspecific. However, discovery of germline-encoded pattern recognition receptors has led to an understanding that specific molecular structures are recognized by pathogen-associated molecular patterns. These specific structures include Toll-like receptors (TLRs), which are membrane associated, and nucleotide-binding oligomerization domain (NOD)-like receptors, which are found in the cytoplasm and include the NALP family of receptors (member of the nucleotide-binding domain and leucine-rich repeat containing gene family) and others, all of which contribute to immune activation by inducing proinflammatory cytokines, which in turn modulate the adaptive immune response. TLRs and NOD-like receptors are found on antigen-presenting lymphocytes and recognize a wide variety of molecules commonly found in pathogens. TLR4 binds lipopolysaccharide and TLR5 binds flagellin, both common bacterial components. The NALP3 inflammasome is activated by aluminum and has been shown to be the pathway through which aluminum adjuvants enhance immunogenicity.

Antibodies produced in response to immunization can mediate protection by a variety of extracellular mechanisms including (1) direct neutralization of bacterial toxin, (2) facilitation of intracellular digestion of bacteria by phagocytes (opsonization), (3) initiation of or combination with the complement pathway to cause lysis, or (4) sensitization of macrophages to promote phagocytosis. Antibodies cannot readily reach the intracellular space, which is the site of viral and some bacterial replication. However, antibodies are effective against many viral diseases by interacting with a virus before initial intracellular penetration occurs (neutralization) and by preventing locally replicating virus from disseminating from the site of entry to an important target organ, as in spread of poliovirus from the intestine to the central nervous system or spread of rabies from a puncture wound to peripheral neural tissue. Antigen-specific cytotoxic T-lymphocyte–mediated responses are important components of the response to viral infections.

The cell-mediated immune response also has an innate and memory effector arm. Natural killer (NK) cells recognize virally infected cells in a nonspecific manner, without generation of memory. Activated NK cells secrete a variety of soluble mediators, including IFNs that kill virus-infected cells and ILs that modulate differentiation and response of CD4 ⁺ helper T lymphocytes. Cytotoxic CD8 ⁺ T lymphocytes require the help of CD4 ⁺ T lymphocytes (generally Th1) to differentiate and mature. CD8 ⁺ cytotoxic T lymphocytes are an important part of the immune response to intracellular bacteria and viruses. As viruses replicate in a cell, viral proteins are processed and presented on the cell surface as an MHC class I/peptide complex. The complex is recognized by cytotoxic T lymphocytes. As with CD4 ⁺ T lymphocytes, a small subset develops into long-lived memory CD8 ⁺ T lymphocytes capable of rapid reactivation as part of a secondary immune response.

Rarely, vaccination can result in immune responses that alter the course of natural infection detrimentally. For example, killed measles vaccine, a formalin-inactivated vaccine administered to some children in the US from 1963 to 1967, sensitized some vaccine recipients so that when exposed to wild virus, they developed an atypical measles infection with enhanced severity of disease. The prevailing theory has been that failure of formalin-inactivated vaccine to produce response to the measles virus fusion protein led to altered immune response and atypical disease on subsequent challenge. More recent theories suggest that killed measles virus failed to induce high-avidity antibody, and immune-complex deposition was the major determinant of atypical measles.

Following primary immunization with inactivated antigens, antibody response develops in 2–6 weeks but can be incomplete even after two doses; after effective priming, booster responses occur within 4–14 days. The initial response usually is IgM antibodies, followed within weeks by IgG antibodies. For example, response to live vaccines requires one incubation period, followed by several weeks to months for development of a strong immune response. Response to measles vaccination usually is maximal by 6 weeks, but in younger children, antibody levels can continue to rise for several months. However, protection against measles begins much earlier, and some evidence suggests that disease can be prevented even when vaccine is administered within 72 hours of exposure.

Determinants of Response

Vaccine immunogenicity and response are determined by characteristics of the vaccine and the host. Vaccine dose, presence of an adjuvant, route and site of administration, timing of doses, and vaccine handling can affect response. Vaccine doses are adjusted before licensure to ensure a high level of response (generally >90% of subjects); adjuvants permit a better response with a lower dose of inactivated antigen. The route of vaccine administration (e.g., intradermal, subcutaneous, intramuscular, or mucosal) can determine the strength and nature of the immune response. Mucosal administration (intranasal or oral) stimulates higher levels of mucosal IgA antibodies that can inhibit disease transmission with greater effectiveness than parenteral administration, which induces limited or no mucosal response. Intradermal vaccination with lower antigen doses can induce antibody responses similar to responses induced by intramuscular or subcutaneous administration of larger doses, but intradermal vaccine is more difficult to deliver precisely and, in practice, achieves less predictable responses.

Intramuscular injections should be administered in the anterior thigh (infants and toddlers) or deltoid muscle (children and adults); injection into the buttocks can produce lower antibody response, which has been documented for hepatitis B and rabies vaccines in adults, probably as a result of delivery of vaccine into adipose tissue. ^, Vaccines with adjuvants should be administered into a muscle because subcutaneous or intradermal injection can induce local irritation, inflammation, granuloma formation, or skin discoloration.

Timing of doses of killed vaccines is important; a minimal interval of 1 month between primary doses is usual, as is delay of a fourth or reinforcing dose for 10 months or longer after the first dose to enhance response and duration of antibody persistence. The recommended routes and sites of administration and timing of doses are devised to ensure optimal effectiveness in disease prevention and should be used.

Host Factors

Intrinsic factors in the host that affect immune response include genetic factors, age, nutritional or disease status, primary or secondary immunodeficiency, sex, pregnancy, and smoking. ^, Although genetic factors such as MHC polymorphism are known to affect both cellular and humoral immune response at a molecular level for some vaccines, the precise mechanisms are unknown. Evaluating how host genetic markers alter vaccine response could identify differences that predict successful or adverse vaccine outcome. Studies of the expression of genetic information modified on a molecular level can reveal how environmental influences affect innate and adaptive immune responses. These considerations combined with system vaccinology approaches may lead to better understanding of immune responses. ^{, ,} Age is an important factor in response to immunization. With killed vaccines, neonates generally do not develop as brisk a response as older infants or children (e.g., with hepatitis B), and with certain vaccines, too-early immunization can result in a suboptimal response or development of tolerance or interference (diphtheria and tetanus toxoids and acellular pertussis [DTaP]; inactivated poliovirus vaccine [IPV]; Hib conjugates). For live (and some killed) vaccines, inhibition of response by maternal antibodies determines the optimal timing for vaccination in early childhood (measles, hepatitis A). Generally, response to all vaccines is excellent in young children, adolescents, and young adults but diminishes with increasing age. In adults, smoking decreases response to hepatitis B vaccine. ^, Extreme debilitation, primary or secondary immunodeficiency disorders (including diseases or treatments that cause immunosuppression), and some chronic diseases (renal disease, diabetes mellitus) can diminish immune response. For people with such conditions, inactivated vaccines can be recommended, although higher or more frequent doses may be required; live vaccines are contraindicated for some immunocompromising conditions because of the risk of disseminated disease and possible death caused by the vaccine organism. ^,

Measurement of Response

Ideally, reliable laboratory tests should be available to measure the presence and strength of each of the major effectors of protection against the disease for which the vaccination is administered. In routine practice, many different assays are available to assess the presence, absence, and level of antibodies. These include enzyme immunoassay (EIA), complement fixation, and immunofluorescent techniques. Assays for functional antibody, including neutralization or opsonophagocytosis, generally are performed in reference or research laboratories, as are assays for T-lymphocyte function. CD4 ⁺ Th1 and Th2 lymphocytes and CD8 ⁺ lymphocytes generally are characterized by their cytokine profiles by using assays such as enzyme-linked immunospot (ELISpot) or intracellular cytoplasmic staining.

For certain diseases, including hepatitis B, poliovirus, rubella, and measles, reliable assays exist, and antibody levels that correlate with protection are known. For other diseases, such as pertussis and HPV infection, no serologic correlates of protection have been defined. Development of improved laboratory methods to measure protection and to permit rapid diagnosis of acute disease continues to be a priority of vaccine-preventable disease control programs.

Vaccine Licensure and Approval

Before testing a vaccine in humans, a manufacturer files an investigational new drug (IND) application with the FDA, followed by three phases of clinical trials that are performed to study vaccine safety, immunogenicity, and efficacy. ^, On completion of the prelicensure clinical trials, the following steps generally occur for a vaccine to become available and used: (1) the manufacturer applies for a Biologics Licensure Application (BLA) with the FDA; (2) the FDA licenses the vaccine; (3) the Advisory Committee on Immunization Practices (ACIP), the Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics (AAP), and other professional medical societies make recommendations for use of the vaccine; and (4) financing is secured for the public and private sectors ( Fig. 6.1 ).

Following FDA licensure of a new vaccine, information about the vaccine is reviewed by the ACIP. The ACIP consists of 15 voting, nongovernment members appointed by the US Department of Health and Human Services for 4-year terms. In addition to the 15 voting members, ACIP includes 8 ex officio members who represent other federal agencies with responsibility for immunization programs in the US, and 30 non-voting representatives of liaison organizations that bring related immunization expertise. To formulate recommendations, the ACIP establishes subject-specific work groups to review and synthesize data months to years before presentation to the ACIP, where votes are taken on vaccine use. Data considered in making recommendations are subjected to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) process ( https://www.cdc.gov/vaccines/acip/recs/grade/index.html ). ACIP recommendations are not official until approved by the CDC director and published in the Morbidity and Mortality Weekly Report (MMWR) ( https://www.cdc.gov/vaccines/acip/committee/charter.html ). Given that new vaccines and updated recommendations appear often, the reader is advised to follow the ACIP website for new recommendations at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/index.html .

Following vaccine licensure, monitoring for rare adverse events continues for some vaccines through formal phase IV trials conducted by the manufacturer, which often are required and monitored by the FDA. In addition, post-marketing surveillance for adverse events is performed and permits detection of new or unanticipated adverse events. Physician and manufacturer reporting of certain adverse events observed after vaccine administration is required by the National Childhood Vaccine Injury Act for vaccines covered under the Vaccine Injury Compensation Program. The importance of post-marketing surveillance was demonstrated following licensure and wide use of tetravalent rhesus rotavirus vaccine for infants in the US in 1999. Surveillance of adverse events detected cases of intussusception within 1 week after receipt of the first or second doses of the rhesus rotavirus vaccine. Follow-up studies determined that risk of intussusception was approximately 1 case per 10,000 doses of vaccine administered. Subsequently, the vaccine was withdrawn from distribution, and the recommendation for universal use in infants in the US was withdrawn. Currently there is a universal recommendation for infants for two other rotavirus vaccines.

Disease Reduction

Childhood immunization programs have substantially reduced the occurrence of vaccine-preventable diseases in the US ( Table 6.1 ). Declines exceed 90% for all diseases for which universal vaccination has been well implemented, with the exception of hepatitis B, which remains an important clinical disease in adults not reached by universal vaccine programs, and pertussis. ^, Smallpox has been eradicated, poliomyelitis resulting from indigenous WPV has not occurred since 1979 in the US, and endemic rubella has been declared eliminated in the US. ^, Fewer than 10 cases each of diphtheria and tetanus (DT) in children are now reported each year and indigenous transmission of measles has been interrupted, notwithstanding the 2018–2019 measles outbreak in the New York area. Wide use of Hib conjugate vaccines has reduced Hib disease by >98% in the US and in some European countries. Use of pneumococcal conjugate vaccines (PCVs) has led to marked reductions in invasive pneumococcal disease (IPD) among vaccinated children as well as unvaccinated young infants, adolescents, and adults. Building on the success of the program to date, the US Public Health Service established 2010 goals to eliminate indigenous transmission of measles, rubella and congenital rubella syndrome (CRS), mumps, diphtheria, poliomyelitis, Hib disease in children <5 years of age, and tetanus in people <35 years of age, and to reduce hepatitis B in people 2–18 years old by 90%. These goals were achieved for diphtheria, measles, rubella, congenital rubella, poliomyelitis, and hepatitis B. The Healthy People 2020 objectives included specific goals for disease reduction and vaccination coverage. ( http://www.healthypeople.gov/2020/topics-objectives/topic/immunization-and-infectious-diseases/objectives).49

Proposed objectives for Healthy People 2030 include 4 doses of DTaP and 1 dose of MMR by the age of 2 years, maintaining two-dose coverage of MMR for children in kindergarten, and increasing the percentage of persons 6 months old and older vaccinated annually against influenza ( https://www.healthypeople.gov/sites/default/files/Report%207_Reviewing%20Assessing%20Set%20HP2030%20Objectives_formatted%20EO_508_05 ).

Vaccination Coverage

Vaccination coverage among preschool children has increased steadily after the measles resurgence that began in 1989 and stimulated unprecedented efforts to improve delivery of immunization. From 2016 through 2018, coverage with 3 doses of DTaP, poliovirus, and hepatitis B virus vaccines and 1 dose of MMR and varicella vaccines among children by 24 months of age each reached or exceeded 90%. School laws are often expanded to include newly recommended vaccines. In 2018, 88.9% of adolescents received 1 dose of Tdap, 85.1% received dose of MenACWY, and 53.1% of adolescent females and 44.3% of adolescent males were up-to-date with the HPV vaccine series. In 2019 90.2% of adolescents received 1 dose of Tdap, 88.9% received 1 dose of MenACWY, and 56.8% of adolescent females and 51.8% of adolescent males were up-to-date with the HPV vaccine series.

Vaccine Administration

Immunization Schedules

The CDC, AAP, American Academy of Family Physicians (AAFP), American College of Obstetricians and Gynecologists (ACOG), and American College of Nurse Midwives (ACNM) annually publish harmonized childhood and adolescent immunization schedules. The ACIP, AAFP, ACOG, ACNM, and American College of Physicians also publish an annual adult immunization schedule ( www.cdc.gov/vaccines ). The ACIP, with input from many liaison organizations, periodically reviews the schedules to ensure consistency with new vaccine developments and policies. The first harmonized childhood immunization schedule was published in 1995 and recommended 6 vaccines containing antigens against 9 infectious diseases. Since November 2010, vaccines have been recommended universally in the childhood and adolescent immunization schedule to protect against 16 infectious diseases ( Figs. 6.2 to 6.4 ). The harmonized schedule specifies the recommended and acceptable timing for each dose of universally recommended vaccine and for vaccines recommended for children and adolescents in selected high-risk populations.

Since its inception, the US immunization program has focused on immunization of infants and young children. In 1996, following growing concern about morbidity associated with vaccine-preventable diseases in the difficult-to-reach adolescent population, the ACIP recommended expanding efforts to immunize adolescents by establishing a routine immunization visit at 11 through 12 years of age. In addition to providing Td and previously missed vaccinations, the report emphasized that this visit should be used to provide other important preventive health services. A decade ago the addition of several newer vaccines for adolescents (i.e., MenACWY, Tdap, and HPV) stimulated a reappraisal of approaches that continues to effectively and efficiently increase the proportion of adolescents who receive newly recommended vaccines and develop ways to integrate these approaches into other adolescent health, education, and development programs.

Interchangeability of Vaccines

Available data support interchangeability of most vaccines produced by different manufacturers to prevent the same disease. The response to a 3-dose series using different Hib conjugate vaccines equals or exceeds response when the same vaccine is used for all doses. The ACIP and AAP recommend that, when feasible, the same vaccine should be used for the primary series but that 3 doses of any vaccine are sufficient. ^, Data are limited regarding safety, immunogenicity, and efficacy of using acellular pertussis (as DTaP) vaccines from different manufacturers for successive doses of the pertussis series. Data suggest that 2 of the current DTaP preparations can be used interchangeably for the first 3 doses of the DTaP series without affecting safety or immunogenicity. When the specific product is not known or not available, any DTaP vaccine should be used to continue or complete the series. Similarly, the series of hepatitis A vaccine does not have to include the same brand of vaccine for both doses. However, the two MenB vaccine products are not interchangeable. The same MenB vaccine product must be used for all doses on the MenB series.

Vaccine Safety and Compensation for Vaccine Injury

In 1986, the National Childhood Vaccine Injury Act was enacted to create a compensation program for families affected by childhood vaccine-associated adverse events and help ensure safety of the vaccine supply ( Table 6.2 ).

Vaccination in Special Situations