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.

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.)

Vaccine Production

Vaccine production is primarily a responsibility of private industry. Most of the vaccines recommended routinely for children are produced by only one of the vaccine manufacturers. Only Hib, HepB, HPV, rotavirus, MCV4, diphtheria and tetanus toxoids and acellular pertussis (DTaP), and tetanus and diphtheria toxoids and acellular pertussis (Tdap) vaccines for adolescents and adults have multiple manufacturers. IPV as an IPV-only vaccine has only 1 manufacturer, but IPV also is available in combination products DTaP-HepB-IPV, and DTaP-IPV from another manufacturer. Influenza vaccine for children ≤2 yr of age is produced by 2 manufacturers. MMR, MMRV, varicella, PCV13, and Td vaccines also are produced by manufacturers.

Vaccine Policy

There are 2 major committees that make vaccine policy recommendations for children: the Committee on Infectious Diseases (COID) of the AAP (the Red Book Committee) and the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC). At least annually, the AAP, the ACIP, and the American Academy of Family Physicians (AAFP) issue a harmonized childhood and adolescent immunization schedule (www.cdc.gov/vaccines/recs/schedules/default.htm). The COID consists primarily of academic pediatric infectious disease specialists with liaisons from practicing pediatricians, professional organizations, and government agencies including the FDA, CDC, and National Institutes of Health (NIH). Recommendations of the COID must be approved by the AAP Board of Directors. The ACIP consists of 15 members who are academic infectious disease experts (for both children and adults), family physicians, state and local public health officials, nurses, and consumers. The ACIP also has extensive liaison representation from major medical societies, government agencies, managed care, and others. The AAP recommendations are published in the Red Book and in issues of Pediatrics. The ACIP recommendations, available at www.cdc.gov/vaccines/pubs/ACIP-list.htm, are official only after approval by the CDC director, which leads to publication in the Morbidity and Mortality Weekly Report (MMWR).

Vaccine Financing

Between 55 and 60% of vaccines routinely administered to children and adolescents <19 yr of age are purchased thorough a contract negotiated by the federal government with licensed vaccine manufacturers. There are 3 major sources of funds that can purchase vaccines through this contract.

The greatest portion comes from the Vaccines for Children (VFC) program, a federal entitlement program. The VFC program covers children on Medicaid, children without any insurance (uninsured), and Native Americans and Alaska Natives. In addition, children who have insurance but whose insurance does not cover immunization (underinsured) can be covered through VFC, but only if they go to a federally qualified health center (FQHC) (http://www.cms.gov/center/fqhc.asp). In contrast to other public funding sources that require approval of discretionary funding by legislative bodies, VFC funds are immediately available for new recommendations provided the ACIP votes the vaccine and the recommendation for its use into the VFC program, the federal government negotiates a contract, and the Office of Management and Budget (OMB) apportions funds. The VFC program can provide free vaccines to participating private providers.

The second major federal funding source is the 317 Discretionary Federal Grant Program to states and selected localities. These funds must be appropriated annually by Congress, but in contrast to VFC, they have not had eligibility requirements for use. The third major public source of funds is state appropriations. The VFC program itself does not cover vaccine administration costs. Medicaid covers the administration fees for children enrolled in that program. Parents of other children eligible for VFC must pay administration fees out of pocket, although there is a stipulation in the law that no one eligible for the program can be denied vaccines because of inability to pay the administration fee. The Affordalde Care Act may lead to changes in financing.

Vaccine Safety Monitoring

Monitoring vaccine safety is the responsibility of the FDA, CDC, and vaccine manufacturers. A critical part of that monitoring depends on reports to the Vaccine Adverse Event Reporting System (VAERS). Adverse events following immunization can be reported by calling 1-800-822-7967 or completing a VAERS form that can be obtained from www.vaers.hhs.gov. Individual VAERS case reports may be helpful in generating hypotheses about whether vaccines are causing certain clinical syndromes, but in general they are not helpful in evaluating the causal role of vaccines in the adverse event. This is because most clinical syndromes that follow vaccination are similar to syndromes that occur in the absence of vaccination. For causality assessment, epidemiologic studies are often necessary, comparing the incidence rate of the adverse event after vaccination with the rate in the unvaccinated. A statistically significant higher rate in the vaccinated would be consistent with causation.

The Vaccine Safety Datalink (VSD) consists of inpatient and outpatient records of some of the largest managed-care organizations in the USA and facilitates causality evaluation. In addition, the clinical immunization safety assessment network (CISA) has been established to advise primary care physicians on evaluation and management of adverse events (www.cdc.gov/vaccinesafety/Activities/CISA.html). The Institute of Medicine (IOM) has reviewed independently a variety of vaccine safety concerns (available at www.iom.edu/imsafety and Table 165-4). In no instance did the IOM find that evidence favored acceptance of a causal link between the postulated adverse event and vaccines.

Table 165-4 INSTITUTE OF MEDICINE IMMUNIZATION SAFETY REVIEW COMMITTEE REPORTS, 2001-2004

Data from http://www.iom.edu/imsafety.

* Reviews relationship of vaccines to asthma, diabetes, and heterologous infections.

From Cohn AC et al: Immunizations in the US: a rite of passage, Pediatr Clin North Am 52:669–693, 2005.

The National Vaccine Injury Compensation Program (NVICP), established in 1988, is designed to compensate persons injured by vaccines in the childhood and adolescent immunization schedule. The program is funded through an excise tax of $0.75 per disease prevented per dose. As of 2010, all of the routinely recommended vaccines that protect children against 16 diseases are covered by this program. The NVICP was established to provide a no-fault system. There is a table of related injuries and time frames. All persons alleging injury from covered vaccines must first file with the program. If the injury meets the requirements of the table, compensation is automatic. If not, the claimant has the responsibility to prove causality. If compensation is accepted, the claimant cannot sue the manufacturer or physician administering the vaccine. If the claimant rejects the judgment of the compensation system, he or she can enter the tort system, but this has only occurred rarely. Information on the NVICP is available at 1-800-338-2382 and www.hrsa.gov/vaccinecompensation/. All physicians administering a vaccine covered by the program are required by law to give the approved Vaccine Information Statement (VIS) to the child’s parent or guardian at each visit before administering vaccines. Information on the VIS can be obtained from www.cdc.gov/vaccines/pubs/vis/default.htm.

Vaccine Delivery

To ensure potency, vaccines should be stored at recommended temperatures before and after reconstitution (www.cdc.gov/vaccines/recs/storage/default.htm). Expiration dates should be noted, and expired vaccine should be discarded. Lyophilized vaccines often have long shelf lives. However, the shelf life of reconstituted vaccines generally is short, ranging from 30 min for the varicella vaccine to 8 hr for the MMR vaccine.

All vaccines have a preferred route of administration, which is specified in package inserts and in AAP and ACIP recommendations. Most inactivated vaccines, including DTaP, HepA, HepB, Hib, TIV, PCV13, MCV4, and Tdap, are administered IM. In contrast, the commonly used live-attenuated vaccines, MMR, MMRV and varicella, should be dispensed SC and rotavirus vaccine is administered orally. IPV and PPS23 (pneumococcal polysaccharide vaccine) can be given IM or SC. For IM injections, the anterolateral thigh muscle is the preferred site for infants and young children. The recommended needle length varies depending on age and size: inch for newborn infants, 1 inch for infants 2-12 mo of age, and 1- inches for older children. For adolescents and adults, the deltoid muscle of the arm is the preferred site for IM administration with needle lengths of 1- inches depending on the size of the patient. Most IM injections can be made with 23-25 gauge needles. For SC injections, needle lengths generally range from to inches with 23-25 gauge needles.