Immunization Practices

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Chapter 165 Immunization Practices

Immunization is one of the most beneficial and cost-effective disease-prevention measures. As a result of effective and safe vaccines, smallpox has been eradicated, polio is close to worldwide eradication, and measles and rubella are no longer endemic in the USA. The incidence of most other vaccine-preventable diseases of childhood has been reduced by ≥99% from the annual morbidity prior to development of the corresponding vaccine (Table 165-1). An analysis of effective prevention measures recommended for widespread use by the U.S. Preventive Services Task Force reported that childhood immunization received a perfect score, based on clinically preventable disease burden and cost-effectiveness.

Table 165-1 REPRESENTATIVE 20TH CENTURY MORBIDITY, CASES IN 2009, AND CHANGE

Immunization is the process of inducing immunity against a specific disease. Immunity can be induced either passively through administration of antibody-containing preparations or actively by administering a vaccine or toxoid to stimulate the immune system to produce a prolonged humoral and/or cellular immune response. As of 2011, infants, children, and adolescents routinely are vaccinated against 16 diseases in the USA: diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b (Hib) disease, hepatitis A (HepA), hepatitis B (HepB), measles, mumps, rubella, rotavirus, varicella, pneumococcal disease, meningococcal disease, and influenza. Human papillomavirus (HPV) vaccine has been recommended routinely for girls 11-12 yr of age, with catch-up for females through 26 yr of age. One of the HPV vaccines, HPV4, is recommended for permissive use in males age 11 through 18 yr for prevention of genital warts.

Passive Immunity

Passive immunity is achieved by administration of preformed antibodies to induce transient protection against an infectious agent. Products used include immunoglobulin (IG) administered intramuscularly (IM); specific or hyperimmune IG preparations administered IM; intravenous IG (IVIG); specific or hyper-immunoglobulin preparations administered IV; antibodies of animal origin; monoclonal antibodies; and subcutaneous (SC) human IG, which has been licensed to treat patients with primary immunodeficiencies. Passive immunity also can be induced naturally through transplacental transfer of maternal antibodies (IgG) during gestation. Maternally derived transplacental antibodies can provide protection during an infant’s first month of life and longer during breast-feeding. Protection for some diseases can persist for as long as a year after birth.

The major indications for passive immunity are to provide protection to immunodeficient children with B-lymphocyte defects who have difficulties making antibodies, persons exposed to infectious diseases or who are at imminent risk of exposure where there is not adequate time for them to develop an active immune response to a vaccine, and persons with an infectious disease as part of specific therapy for that disease (Table 165-2).

Table 165-2 IMMUNE GLOBULIN AND ANIMAL ANTISERA PREPARATIONS

PRODUCT	MAJOR INDICATIONS
Immune globulin for intramuscular injection	Replacement therapy in primary immunodeficiency disorders
	Hepatitis A prophylaxis
	Measles prophylaxis
Intravenous mmunoglobulin (IVIG)	Replacement therapy in primary immune-deficiency disorders
	Kawasaki disease
	Immune-mediated thrombocytopenia
	Pediatric HIV infection
	Hypogammaglobulinemia in chronic B-cell lymphocytic leukemia
	Hematopoietic cell transplantation in adults to prevent graft-versus host disease and infection
	May be useful in a variety of other conditions
Hepatitis B immune globulin (IM)	Postexposure prophylaxis
Hepatitis B immune globulin (IM)	Prevention of perinatal infection in infants born to HBsAg⁺ mothers
Rabies immune globulin (IM)	Postexposure prophylaxis
Tetanus immune globulin (IM)	Wound prophylaxis
Tetanus immune globulin (IM)	Treatment of tetanus
Varicella-zoster immune globulin (VZIG) (IM) or IVIG	Postexposure prophylaxis of susceptible people at high risk for complications from varicella
Cytomegalovirus IVIG	Prophylaxis of disease in seronegative transplant recipients
Palivizumab (monoclonal antibody) (IM)	Prophylaxis for infants against respiratory syncytial virus (RSV) (Chapter 252)
Vaccinia immune globulin (IV)	Prevent or modify serious adverse events following smallpox vaccination due to vaccinia replication
Botulism IVIG human	Treatment of infant botulism
Diphtheria antitoxin, equine	Treatment of diphtheria
Trivalent botulinum (A,B,E) and bivalent (A,B) botulinum antitoxin, equine	Treatment of food and wound botulism

From Passive immunization. In Pickering LK, Baker CJ, Kimberlin DW, et al, editors: Red book 2006: report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, IL, 2009, American Academy of Pediatrics.

Intramuscular Immunoglobulin

IG is a sterile antibody-containing solution, usually derived through cold ethanol fractionation of large pools of human plasma from adults. Antibody concentrations reflect the infectious disease exposure and immunization experience of plasma donors. IG contains 15-18% protein, is predominantly IgG, and is administered intramuscularly. Intravenous use of human intramuscular IG is contraindicated. IG is not known to transmit infectious agents, including viral hepatitis and HIV. The major indications for IG are replacement therapy for children with antibody deficiency disorders, and for passive immunization for measles and hepatitis A.

For replacement therapy, the usual dose of IG is 100 mg/kg or 0.66 mL/kg monthly. The usual interval between doses is 2-4 wk depending on trough IgG concentrations. In practice, IVIG has replaced IMIG for this indication. IG can be used to prevent or modify measles if administered to susceptible children within 6 days of exposure (usual dose, 0.25 mL/kg for immunocompetent children, 0.5 mL/kg for immunocompromised children; maximum dose 15 mL) and to prevent or modify HepA if administered to children within 14 days of exposure (usual dose, 0.02 mL/kg). IG also may be administered for prophylaxis of HepA for persons traveling internationally to HepA-endemic areas (0.06 mL/kg) and for children too young for HepA vaccination (<1 yr of age). In children <12 mo of age, adults >40 yr of age, and susceptible children and adults with underlying immunodeficiencies or chronic liver disease, IG is preferred over hepatitis A immunization. In people 12 mo-40 yr of age, HepA immunization is preferred over IG for postexposure prophylaxis and for protection of people traveling to areas where HepA is endemic.

The most common adverse reaction to IG is pain and discomfort at the injection site and, less commonly, flushing, headache, chills, and nausea. More-serious adverse events are rare and have included chest pain, dyspnea, anaphylaxis, and systemic collapse. Patients with selective IgA deficiency can produce antibodies against the trace amounts of IgA in IG preparations and develop reactions after repeat doses. These reactions can include fever, chills, and a shocklike syndrome. Because these reactions are rare, testing for selective IgA deficiencies is not recommended.

Intravenous Immunoglobulin

IVIG is prepared from adult plasma donors using alcohol fractionation and is modified to allow IV use. IVIG is predominantly IgG and is tested to ensure minimum antibody titers to diphtheria, HepB, measles, and polio. Liquid and powder preparations are available. The major recommended indications for IVIG are replacement therapy for immunodeficiency disorders; treatment of Kawasaki disease to prevent coronary artery abnormalities and shorten the clinical course; prevention of serious bacterial infections in children with HIV; prevention of serious bacterial infections in persons with hypogammaglobulinemia in chronic B-cell leukemia; immune-mediated thrombocytopenia; and prophylaxis of infection following bone marrow transplantation. IVIG may be helpful for patients with severe toxic shock syndrome, Guillain-Barré syndrome, and anemia caused by parvovirus B19. IVIG is used for many other conditions based on clinical experience. It may be used for varicella postexposure if varicella-zoster immune globulin is not available.

Reactions to IVIG range from 1 to 15%. Some of these reactions appear to be related to the rate of infusion and can be mitigated by decreasing the rate. Such reactions include fever, headache, myalgia, chills, nausea, and vomiting. More serious reactions rarely have been reported, including anaphylactoid events, thromboembolic disorders, aseptic meningitis, and renal insufficiency.

Specific Immune Globulin Preparations

Hyperimmune globulin preparations are derived from donors with high titers of antibodies to specific agents and designed to provide protection against those agents (see Table 165-2).

Hyperimmune Animal Antisera Preparations

Animal antisera preparations are derived from horses. The IG fraction is concentrated using ammonium sulfate, and some products are further treated with enzymes to decrease reactions to foreign proteins. As of 2011, 2 horse antisera preparations are available for humans: diphtheria antitoxin, which is used to treat diphtheria, and botulinum antitoxin, which is available for use in adults with botulism but is not used in infants for whom botulism IVIG (Baby-BIG), a human-derived antitoxin, is licensed. Great care must be exercised before administering animal-derived antisera because of the potential for severe allergic reactions. This includes testing for sensitivity before administration; desensitization, if necessary; and treating potential reactions, including febrile events, serum sickness, and anaphylaxis.

Monoclonal Antibodies

Monoclonal antibodies are antibody preparations produced against a single antigen. They are mass-produced from a hybridoma, created by fusing an antibody-producing B cell with a fast-growing immortal cell such as a cancer cell. A major monoclonal antibody used in infectious diseases is palivizumab, which can prevent severe disease from respiratory syncytial virus (RSV) among children ≤24 mo of age with chronic lung disease (CLD, also called bronchopulmonary dysplasia), with a history of premature birth or with congenital heart lesions or with neuromuscular diseases. The American Academy of Pediatrics (AAP) has developed specific recommendations for use of palivizumab (Chapter 252). RSV-IVIG, a hyperimmune globulin formulated for intravenous administration, is no longer produced in the USA. Monoclonal antibodies also are used to prevent transplant rejection and to treat some types of cancer and autoimmune diseases. Monoclonal antibodies against interleukin 2 (IL-2) and tumor necrosis factor-α (TNF-α) are being used as part of the therapeutic approach to patients with a variety of malignant and autoimmune diseases.

Serious adverse events associated with palivizumab primarily are rare cases of anaphylaxis and hypersensitivity reactions. Adverse reactions to monoclonal antibodies directed at modifying the immune response, such as antibodies against IL-2 or TNF, can be more serious, such as cytokine release syndrome, fever, chills, tremors, chest pain, immunosuppression, and infection with various organisms, including mycobacteria.

Active Immunization

Vaccines are defined as whole or parts of microorganisms administered to prevent an infectious disease. Vaccines can consist of whole inactivated microorganisms (e.g., polio and HepA), parts of the organism (e.g., acellular pertussis, HPV, and HepB), polysaccharide capsules (e.g., pneumococcal and meningococcal polysaccharide vaccines), polysaccharide capsules conjugated to protein carriers (e.g., Hib, pneumococcal, and meningococcal conjugate vaccines), live-attenuated microorganisms (measles, mumps, rubella, varicella, rotavirus, and live-attenuated influenza vaccines), and toxoids (tetanus and diphtheria) (Table 165-3). A toxoid is a modified bacterial toxin that is made nontoxic but is still able to induce an active immune response against the toxin.

Table 165-3 CURRENTLY AVAILABLE VACCINES IN THE USA BY TYPE

PRODUCT	TYPE
Anthrax vaccine adsorbed	Cell free filtrate of components including protective antigen
Bacille Calmette-Guérin (BCG) vaccine	Live-attenuated mycobacterial strain used prevent tuberculosis in very limited circumstances
Diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine	Toxoids of diphtheria and tetanus and purified and detoxified components from Bordetella pertussis
DTaP with Haemophilus influenzae type b (DTaP/Hib)	DTaP and Hib polysaccharide conjugated to tetanus toxoid
DTaP–hepatitis B–inactivated polio vaccine (DTaP-HepB-IPV)	DTaP with hepatitis B surface antigen produced through recombinant techniques in yeast with inactivated whole polioviruses
DTaP with IPV and Hib (DTaP-IPV/Hib)	DTaP with inactivated whole polio viruses and Hib polysaccharide conjugated to tetanus toxoid
DTaP and inactivated polio vaccine (DTaP-IPV)	DTaP with inactivated whole polio viruses
Hib conjugate vaccine (Hib)	Polysaccharide conjugated to either tetanus toxoid or meningococcal group B outer membrane protein
Hepatitis A vaccine (HepA)	Inactivated whole virus
Hepatitis A-hepatitis B vaccine (HepA-HepB)	Combined hepatitis A and B vaccine
Hepatitis B vaccine (HepB)	HBsAg produced through recombinant techniques in yeast
Hepatitis B-Hib vaccine (Hib-HepB)	Combined hepatitis B–Hib vaccine; the Hib component is polysaccharide conjugated to meningococcal group B outer membrane protein
Human papillomavirus vaccine (bivalent) (HPV2) and (quadrivalent) (HPV4)	The L1 capsid proteins of HPV types 6, 11, 16, 18 and to prevent cervical cancer and genital warts (HPV4) and types 16 and 18 to prevent cervical cancer (HPV2)
Influenza virus vaccine inactivated (TIV)	Trivalent (A/H₃N₂, A/H₁N₁, and B) split and purified inactivated vaccine containing the hemagglutinin (H) and neuraminidase (N) of each type and other components
Influenza virus vaccine live, intranasal (LAIV)	Live-attenuated, temperature-sensitive, cold-adapted trivalent vaccine containing the H and N genes from the wild strains reassorted to have the 6 other genes from the cold-adapted parent
Japanese encephalitis vaccine	Inactivated whole virus that is purified
Measles, mumps, rubella (MMR) vaccine	Live-attenuated viruses
Measles, mumps, rubella, varicella (MMRV) vaccine	Live-attenuated viruses
Meningococcal conjugate vaccine against serogroups A, C, W135, and Y (MCV4)	Polysaccharide from each serogroup conjugated to diphtheria toxoid or CRM 197
Meningococcal polysaccharide vaccine against serogroups A, C, W135, and Y (MPSV4)	Polysaccharides from each of the serogroups
Pneumococcal conjugate vaccine (13 valent) (PCV13)	Pneumococcal polysaccharides conjugated to a nontoxic form of diphtheria toxin CRM197
Pneumococcal conjugate vaccine (13 valent) (PCV13)	Contains 13 serotypes that accounted for >80% of invasive disease in young children prior to vaccine licensure.
Pneumococcal polysaccharide vaccine (23 valent) (PPSV23)	Pneumococcal polysaccharides of 23 serotypes responsible for 85-90% of bacteremic disease in the USA
Poliomyelitis (inactivated, enhanced potency) (IPV)	Inactivated whole virus
Rabies vaccines (human diploid and purified chick embryo cell)	Inactivated whole virus
Rotavirus vaccines (RV5 and RV1)	Bovine rotavirus pentavalent vaccine (RV-5) live reassortment attenuated virus, and human live-attenuated virus (RV1)
Smallpox vaccine	Vaccinia virus, an attenuated pox virus that provides cross-protection against smallpox
Tetanus and diphtheria toxoids, adsorbed (Td, adult use)	Tetanus toxoid plus a reduced quantity of diphtheria toxoid compared to diphtheria toxoid used for children <7 yr of age
Tetanus and diphtheria toxoids adsorbed plus acellular pertussis (Tdap) vaccine	Tetanus toxoid plus a reduced quantity of diphtheria toxoid plus acellular pertussis vaccine to be used in adolescents and adults and in children 7 through 9 yr of age who have not been appropriately immunized with DTaP
Typhoid vaccine (polysaccharide)	Vi capsular polysaccharide of Salmonella typhi
Typhoid vaccine (oral)	Live-attenuated Ty21a strain of Salmonella typhi
Varicella vaccine	Live-attenuated Oka strain
Yellow fever vaccine	Live-attenuated 17D strain

Data from Centers for Disease Control and Prevention: U.S. vaccine names (website). www.cdc.gov/vaccines/about/terms/USvaccines.html. Accessed March 4, 2011.

Immunizing agents can contain a variety of other constituents besides the immunizing antigen. Suspending fluids may be sterile water or saline but could be a complex fluid containing small amounts of proteins or other constituents derived from the biologic system used to grow the immunobiologic. Preservatives, stabilizers, and antimicrobial agents are used to inhibit bacterial growth and to prevent degradation of the antigen. Such components can include gelatin, 2-phenoxyethanol, and specific antimicrobial agents. Preservatives are added to multidose vials of vaccines, primarily to prevent bacterial contamination on repeated entry of the vial. In the past, many vaccines for children contained thimerosal, a preservative containing ethyl mercury. Beginning in 1999, removal of thimerosal as a preservative from vaccines for children was begun as a precautionary measure in the absence of any data on harm from the preservative. This objective was accomplished by switching to single-dose packaging. The only vaccines in the recommended schedule for young children that contain thimerosal as a preservative are some preparations of influenza vaccine. Adjuvants are used in some vaccines to enhance the immune response. In the USA, the only adjuvants currently licensed by the Food and Drug Administration (FDA) to be part of vaccines are aluminum salts and ASO4, an adjuvant that contains aluminum hydroxide and monophosphoryl lipid A. Vaccines with adjuvants should be injected deep into muscle masses to avoid local irritation, granuloma formation, and necrosis associated with SC or intracutaneous administration.

Vaccines can induce immunity by stimulating antibody formation, cellular immunity, or both. Protection induced by most vaccines is thought to be mediated primarily by B lymphocytes, which produce antibody. Such antibodies can inactivate toxins, neutralize viruses, and prevent their attachment to cellular receptors, facilitate phagocytosis and killing of bacteria, interact with complement to lyse bacteria, and prevent adhesion to mucosal surfaces by interacting with the bacterial cell surface.

Most B-lymphocyte responses require the assistance of CD4 helper T lymphocytes. These T lymphocyte–dependent responses tend to induce high levels of functional antibody with high avidity, mature over time from primarily an IgM response to long-term persistent IgG, and induce immunologic memory that leads to enhanced responses upon boosting. T lymphocyte–dependent vaccines, which include protein moieties, induce good immune responses even in young infants. In contrast, polysaccharide antigens induce B-lymphocyte responses in the absence of T-lymphocyte help. These T lymphocyte–independent vaccines are associated with poor immune responses in children <2 yr of age, short-term immunity, and absence of an enhanced or booster response on repeat exposure to the antigen. To overcome problems of plain polysaccharide vaccines, polysaccharides have been conjugated, or covalently linked, to protein carriers, converting the vaccine to a T lymphocyte–dependent vaccine. In contrast to plain polysaccharide vaccines, conjugate vaccines induce higher avidity antibody, immunologic memory leading to booster responses on repeat exposure to the antigen, long-term immunity, and herd immunity by decreasing carriage of the organism. As of 2009 in the USA, there were licensed conjugate vaccines to prevent Hib and pneumococcal and meningococcal diseases.

Serum antibodies may be detected as soon as 7-10 days after injection of antigen. Early antibodies are usually of the IgM class that can fix complement. IgM antibodies tend to decline as IgG antibodies increase. The IgG antibodies tend to peak approximately 1 mo after vaccination and with most vaccines persist for some time after a primary vaccine course. Secondary or booster responses occur more rapidly and result from rapid proliferation of memory B and T lymphocytes.

Assessment of the immune response to most vaccines is performed by measuring serum antibodies. Although detection of serum antibody at levels considered protective after vaccination can indicate immunity, loss of detectable antibody over time does not necessarily mean susceptibility to disease. Some vaccines induce immunologic memory, leading to a booster or anamnestic response on exposure to the microorganism, leading to protection from disease. In some instances, cellular immune response is used to evaluate immune status. For some vaccines (e.g., acellular pertussis), there is no accepted serologic correlate of protection.

Live-attenuated vaccines routinely recommended for children and adolescents include measles, mumps, and rubella (MMR); rotavirus; and varicella. In addition, a cold-adapted live-attenuated influenza vaccine (LAIV) is available as an alternative to the trivalent inactivated influenza vaccine (TIV) for children 2-18 yr of age who do not have conditions that place them at high risk for complications from influenza. Live-attenuated vaccines tend to induce long-term immune responses. They replicate, often similar to natural infections, until an immune response shuts down reproduction. Most live vaccines are administered in 1- or 2-dose schedules. The purpose of repeat doses, such as a second dose of the MMR vaccine, is to induce an initial immune response in persons who failed to respond to the first dose.

The remaining vaccines in the recommended schedule for children and adolescents are inactivated vaccines. Inactivated vaccines tend to require multiple doses to induce an adequate immune response and are more likely to need booster doses to maintain that immunity than live-attenuated vaccines. However, some inactivated vaccines appear to induce long-term immunity, perhaps life-long immunity, after a primary series, including HepB vaccine and inactivated polio vaccine (IPV).

Vaccination System in the USA

Vaccine Development

Basic scientific knowledge about an organism, its pathogenesis, and the immune responses thought to be associated with protection are financed primarily through government sponsorship of academic research, although private industry plays a major role (Fig. 165-1). Private industry usually assumes the lead role for guiding potential vaccine candidates through preclinical testing in humans into human clinical trials. There are three phases of prelicensure clinical trials: phase I, involving generally <100 participants to gauge safety and dosing; phase II, involving several hundred or more participants to refine safety and dosing; and phase III or pivotal trials that can involve thousands or tens of thousands of participants. Phase III trials are the major basis for licensure. Following successful clinical development, the sponsor applies to the FDA for vaccine licensure. Estimates for the cost of development for each vaccine range to $800 million or more. Following licensure by the FDA, postlicensure monitoring is performed on hundreds of thousands to millions of people to monitor safety and effectiveness.

Figure 165-1 Vaccine development and testing.

(Modified from Pickering LK, Orenstein WE: Development of pediatric vaccine recommendations and policies. Semin Pediatr Infect Dis 13[3]:148–154, 2002.)