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Routine vaccines across the life span, 2005.

Routine vaccines include those listed on the Recommended Childhood and Adolescent Immunization Schedule and the Recommended Adult Immunization Schedule. The disease burden, rationale for vaccination, efficacy, adverse reactions, and recommendations are discussed in relation to each vaccine. Pictures of vaccine-preventable diseases are included.

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Routine vaccination has made a tremendous impact on the burden of childhood diseases in the United States (TABLE 1). (1) The significance of this impact is so great that immunizations are considered one of the major medical achievements of the 20th century.

The categories of indications for vaccination are age, underlying medical conditions, and high-risk occupation or lifestyle. Routine vaccines indicated by age are discussed in this article; high-risk indications are discussed in the next article. Some important topics to consider when making decisions that concern routine use of vaccines include disease burden, rationale for vaccination, vaccine efficacy, adverse reactions, and official recommendations.

HEPATITIS B VACCINE

Each year, an estimated 78,000 persons in the United States are infected with hepatitis B virus, or HBV (down from 260,000 annually in the 1980s), and approximately 6000 persons die of HBV-related liver disease. Most of these deaths occur in persons with chronic HBV infection and are due to cirrhosis or primary hepatocellular carcinoma, which may affect adolescents and young adults. In fact, HBV infection is the second leading cause of cancer worldwide. The number of persons chronically infected with HBV in the United States, each of whom is potentially infectious, is estimated at 1.25 million, and the lifetime risk for acquiring HBV infection was estimated to be 5% prior to the introduction of hepatitis B vaccine. (2) Clearly, HBV infection remains a major health problem in this country.

HBV infection is much more likely to become chronic when acquired early in life than when acquired in adulthood: chronic HBV infection develops in 90% of those infected as infants, 30% to 60% of those infected before the age of 4 years, and only 5% to 10% of those infected as adults. (2) Although most acute HBV infections in the United States are contracted during adulthood because of high-risk behaviors, 36% of all persons in the United States with chronic HBV infection contracted the infection during childhood. Up to 25% of individuals infected with HBV as infants will die of HBV-related chronic liver disease as adults; therefore, a high number of years of potential life are lost.

Hepatitis B can be contracted from persons who are acutely or chronically infected with the virus. Transmission of HBV occurs primarily by blood exchange (eg, via shared needles during injection drug use) or by sexual contact. In 30% to 40% of hepatitis B cases, the source of infection is not identified. (3) Those cases may result from underreporting of injection drug use and sexual activity or unapparent contamination of skin lesions or mucosal surfaces. (Hepatitis B surface antigen [HBsAg] has been found in impetigo lesions and saliva of persons chronically infected with HBV and on toothbrush racks and coffee cups in their homes.) (4) Epidemiologic studies show that HBV can be transmitted between preschool-age children. (5,6)

Rationale for routine hepatitis B vaccination

Reasons to recommend routine infant vaccination against HBV include the following:

* Morbidity and mortality of HBV infection, especially when contracted in childhood, are high;

* Transmission of HBV infection from child to child, although relatively infrequent, has been reported among playmates, within schools and day-care centers, and among family members (5,6);

* Prior strategies focusing on immunization of high-risk persons have had little impact;

* No risk factor for HBV infection can be identified in at least 30% of infected persons (3);

* Those who engage in high-risk behaviors (eg, injection drug use) often are not compliant with the necessary 3-dose vaccination regimen; and

* Many become infected soon after beginning high-risk behaviors.

Routine vaccination of infants against HBV is as cost-effective as other commonly used preventive measures. (7) Based on direct medical expenses, the estimated cost per year of life saved is $1522 for routine vaccination of infants, but from a societal perspective, such vaccination is cost saving. (7)

The hepatitis B vaccines currently produced in the United States are manufactured by recombinant DNA technology using baker's yeast and do not contain human plasma. Preexposure vaccination results in protective antibody levels in more than 95% of all infants and children.

Duration of immunity. The duration of immunity in healthy persons is based on immunologic memory. Although with time antibody levels may diminish slowly following vaccination, most persons remain protected by the immunologic memory in B lymphocytes. Immunologic memory and the long incubation period of hepatitis B infection allow most immunized persons who have low titers to mount an anamnestic immune response if their system is challenged by HBV. A few persons who developed an adequate response to hepatitis B vaccine have developed HBV infection following exposure years after vaccination. However, none of these persons in the United States has become chronically infected or developed serious complications such as chronic liver disease. The issue of waning antibody levels in some healthy persons requires further study, but current data indicate excellent long-term efficacy with respect to preventing serious HBV infection in both infants and adults. Although some experts speculate that booster doses might be needed, they are not currently recommended. Of note, the duration of immunity in hemodialysis patients, in contrast to healthy persons, appears to persist only as long as the level of antibody to HBsAg is [greater than or equal to] 10 mIU/mL.

Factors affecting immunogenicity. Factors that affect immunogenicity include the number of doses administered, intervals between doses, age, underlying medical conditions, and genetics. Immunogenicity differs according to the number of doses received. After the third dose of hepatitis B vaccine, more than 95% of children seroconvert, ie, develop [greater than or equal to] 10 mlU/mL of anti-HBs. The third dose is required for optimal protection; furthermore, geometric mean titers improve with longer intervals between the second and third doses, supporting the concept that the vaccine series does not need to be restarted in those who experience a delay in its completion. Over 90% of healthy adults younger than 40 years of age seroconvert after being vaccinated. However, immunogenicity declines with age, dropping to 75% for 60-year-old recipients. Underlying medical conditions associated with a lower likelihood of seroconversion include prematurity with low birth weight, immunosuppression, renal failure, obesity, and tobacco use. Compared with full-term infants, unstable premature infants who weigh less than 2 kg at birth have lower seroconversion rates until they have gained weight and reached 30 days of age. Therefore, hepatitis B vaccination should be delayed until 1 month of age in preterm infants weighing less than 2 kg, unless the infant is born to a mother who is HBsAg-positive or whose HBsAg status is unknown, in which case hepatitis B vaccine should be given within 12 hours of birth (see article entitled Vaccine Schedules and Procedures, 2005 for schedule). (8)

Vaccine efficacy. Efficacy, ie, protection against HBV infection, is high (80% to 95%) for hepatitis B vaccines licensed in the United States when given to susceptible infants, children, and adults.

Adverse reactions

The most common adverse event after administration of hepatitis B vaccine is pain at the injection site, which occurs in 13% to 29% of adults and 3% to 9% of children. (2) Mild, transient systemic adverse events such as fatigue and headache have been reported in 11% to 17% of adults and 8% to 18% of children. Temperature higher than 37.7[degrees]C has been reported in 1% to 6% of vaccinees. Childhood hepatitis B vaccines in the United States are now free of thimerosal. A large US study found no association between hepatitis B vaccine and multiple sclerosis. (9)

Recommendations

The prevalence of HBV infection and its associated morbidity and mortality have led to the development of a comprehensive hepatitis B vaccination policy that includes recommendations for: (1) prevention of perinatal HBV infection, (2) routine vaccination of infants, (3) catch-up vaccination of adolescents not previously vaccinated, (4) catch-up vaccination of young children at high risk for infection, and (5) preexposure vaccination of adults based on lifestyle or environmental, medical, and occupational situations that place them at risk.

The Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP) recommend hepatitis B vaccination for all infants and catch-up vaccination for unvaccinated children and adolescents of any age. The hepatitis B vaccination schedule for infants depends on birth weight and the mother's HBsAg status; the dosage varies by age and indication (see article entitled Vaccine Schedules and Procedures, 2005).

Postvaccination testing for anti-HBs is recommended only when the results will affect the individual's subsequent medical care. Patients for whom such testing is recommended include dialysis patients, infants born to HBsAg-positive mothers, sexual contacts of persons chronically infected with HBV, and health care workers at high risk for percutaneous or permucosal exposure to body fluids. Testing should be performed 1 to 2 months after completion of the vaccine series, with the exception of infants born to HBsAg-positive mothers, who should be tested at 9 to 15 months of age. An adequate antibody response to vaccination is [greater than or equal to] 10 mlU/mL. Postvaccination testing is not indicated after routine vaccination of infants, children, adolescents, or persons at low risk for exposure, eg, public safety workers and health care workers who do not have contact with blood or blood-contaminated body fluids.

Revaccination is recommended for persons whose postvaccination level of antibody to HBsAg is <10 mlU/mL. Such persons should receive 3 doses on a 0-, 1-, and 6-month schedule. Antibody testing should be conducted again, 1 to 2 months after revaccination. Persons who do not respond after 2 series (6 doses) of hepatitis B vaccine should be counseled about universal precautions and the need for hepatitis B immune globulin if they are exposed to HBV. Testing such persons for HBsAg should be considered, since some already may be chronically infected. Hemodialysis and immunocompromised patients at risk for infection should have serologic tests annually and should be given a booster dose when antibody levels fall below 10 mlU/mL.

PERTUSSIS VACCINE

The majority of pertussis-related hospitalizations and serious complications occur in infants. About 21% of reported cases occur in infants <6 months of age who are too young to receive 3 doses of vaccine, and half occur in children younger than 5 years. (1) Most reported cases of pertussis in infants younger than 12 months require hospitalization. The case-fatality rate is 0.6% for infants younger than 12 months. Females are somewhat more likely to exhibit clinical pertussis than males, probably because girls have smaller airways. In some states, pertussis cases are increasing among adolescents and adults.

Complications of pertussis include pneumonia, seizures, encephalopathy, and permanent brain damage (COLOR CENTERFOLD, FIGURES 1 AND 2). Pneumonia occurs in about 15% and is the leading cause of death. Seizures occur in about 2% of cases. Encephalopathy, which may be caused by hypoxia or minute cerebral hemorrhages, occurs in 0.7% of cases, is fatal in approximately one third of those afflicted, and causes permanent brain damage in another third.

Pertussis is highly contagious: 70% to 100% of susceptible household contacts and 50% to 80% of susceptible school contacts will become infected following exposure to someone who is contagious. (11) A person is contagious from 7 days after exposure to 3 weeks after onset of symptoms. Pertussis is transmitted by respiratory droplets or occasionally by contact with freshly contaminated objects. Adults and adolescents are the primary source of pertussis infection for young infants. The reported incidence rate among adults and adolescents has risen recently, perhaps partly as a result of the use of polymerase chain reaction for improved diagnosis. The incubation period ranges from 5 to 21 days and is typically 7 to 10 days long. Immunity following pertussis disease lasts for many years and is possibly lifelong, negating the requirement for further immunization. Transplacental immunity wanes rapidly following birth.

Rationale for vaccination

Before pertussis vaccination of children became routine, peaks in whooping-cough incidence occurred approximately every 3 to 4 years, and virtually all children eventually were infected. Between 1925 and 1930, 36,013 persons in the United States died as a result of pertussis-related complications. More than 1 million cases of pertussis were reported in the United States from 1940 through 1945. (11) After pertussis vaccination became widespread in the mid-1940s, the incidence of pertussis dropped by more than 95%, although the number of pertussis cases has been increasing in recent years, reaching 9771 cases in 2002. (1)

Although quite effective in reducing pertussis disease, the whole-cell pertussis vaccine has had a number of adverse effects. Consequently, international efforts have been undertaken to develop an acellular vaccine with fewer adverse effects. Potential vaccine-target antigens important in disease production include (1) tracheal cytotoxin that destroys cilia, making it difficult to clear thickened mucus; (2) pertussis toxin (lymphocytosis-promoting factor), which interferes with immune-cell function, contributes to ciliary damage, and aids in attachment to respiratory epithelium; (3) filamentous hemagglutinin, which helps the bacteria attach to cilia of the respiratory tract; (4) pertactin (69-kd protein), which also enhances bacterial attachment to cilia; and (5) agglutinogens, which may aid persistent attachment to cilia. Acellular vaccines targeting one or more of these components were developed.

Vaccine efficacy. In studies conducted in Europe, the diphtheria, tetanus, acellular pertussis (DTaP) vaccines demonstrated efficacy rates ranging from 80% to 89%, compared with diphtheria, tetanus, whole-cell pertussis (DTP) vaccines, which demonstrated rates of efficacy ranging from 36% to 98% (TABLE 2). (12) However, comparing the various studies is difficult because of differences in study type, degree of blinding, case definition of pertussis, criteria for confirmation of pertussis infection, ethnicity of study population, number of children studied, timing of the vaccine schedule, and manufacturer of comparison whole-cell vaccine. Three vaccines are now licensed in the United States: SKB-3P (Infanrix), CB-2 (Tripedia), and CLL-4[F.sub.2] (DAPTACEL). Some combination vaccines include acellular pertussis vaccine. The first combination licensed was TriHIBit[R], in which the Haemophilus influenzae type b (Hib) vaccine ActHIB[R]) is reconstituted with the Tripedia[R] DTaP vaccine. TriHIBit[R] currently is licensed only for the fourth dose of the series and should not be used for earlier doses. Another combination vaccine, Pediarix[R], containing DTaP, hepatitis B, and inactivated poliovirus vaccines, is licensed for the primary series.

The protection afforded by pertussis vaccination wanes with time. For whole-cell DTP vaccines, protection against pertussis disease is lost by 12 years after the last dose. The duration of protection from acellular vaccines is not yet known, although cohorts from earlier trials show no loss of protection in 2- to 6-year follow-up periods.

Adverse reactions

The DTaP vaccines have approximately one quarter to half the number of common and uncommon adverse reactions associated with DTP vaccines (TABLE 3). Furthermore, the rates of adverse reactions to DTaP and pediatric DT are similar. (13) Minor adverse reactions associated with DTaP vaccination include localized edema at the injection site, fever, and fussiness.

Uncommon adverse reactions after DTaP vaccination are persistent crying for 3 or more hours, an unusually high-pitched cry, seizures, and hypotonic-hyporesponsive episodes. Most seizures that occur after DTaP vaccination are simple febrile seizures that do not have any permanent sequelae. Many experts state that on rare occasions a child might have an anaphylactic reaction to DTaP, and in these cases further doses of DTaP are contraindicated. Allegations of other serious adverse reactions, such as permanent neurologic damage, after a dose of DTP vaccine are controversial and have been discussed in depth elsewhere. (14,15) Rarely, temporary swelling of the entire limb (arm or leg) has occurred after administration of the fourth or fifth DTaP dose. Acellular pertussis vaccines currently produced in the United States have either no thimerosal or trace amounts of it.

Recommendations

The DTaP vaccine is recommended for all children because of the reduced risk for adverse reactions when compared with the DTP shot. Although 5 doses of pertussis vaccine are recommended, persons who receive their fourth dose on or after their fourth birthday do not need the fifth dose. Premature infants should be vaccinated with full doses at the appropriate chronological age, eg, 2 months, 4 months, etc. (8) Full doses should be used because fractional doses are not as immunogenic and might not lessen the risk for adverse reactions. Completing the recommended series is important for optimal efficacy.

TETANUS AND DIPHTHERIA TOXOIDS

Prior to widespread immunization, tetanus neonatorum caused hundreds of thousands of deaths worldwide. In contrast, only 25 cases of tetanus were reported in 2002 in the United States. (1) A person with tetanus experiences spasms of the muscles of mastication, (ie, trismus, or lockjaw) and of the back muscles (opisthotonos) (CENTERFOLD, FIGURE 3).

In the 1920s, about 14,000 deaths due to diphtheria were reported annually in the United States, compared with 1 case in 2002. Complications included myocarditis, heart failure, and neuritis. The tonsils are one of the most common sites of diphtheria infection (CENTERFOLD, FIGURE 4).

Recommendation

Adult tetanus and diphtheria toxoids (Td) are recommended for routine booster doses every 10 years for persons 7 years of age and older. An alternative schedule entails giving boosters during adolescence and at 50 years of age. (17) The Td vaccine contains about the same quantity of tetanus toxoid as the DTaP or pediatric DT vaccines but only one third to one eleventh as much diphtheria toxoid. Persons who have experienced an Arthrus-type hypersensitivity reaction or a fever >39.4[degrees]C (103[degrees]F) after a previous dose of tetanus toxoid probably have high serum antitoxin titers and should not be given a dose of Td more often than every 10 years. (11)

H INFLUENZAE TYPE B VACCINE

Prior to the development of effective vaccines, Hib caused invasive disease in about 1 of every 200 US children younger than 5 years. Hib was the most common cause of bacterial meningitis in this age group, with an incidence that peaked between the ages of 6 and 12 months. Even with appropriate treatment, Hib meningitis--the form taken by about two-thirds of cases of invasive Hib disease--carries a mortality rate of 2% to 5%. Neurologic sequelae, including hearing loss, vision loss, mental retardation, seizures, and motor and speech delays, are seen in 15% to 30% of survivors. Other manifestations of invasive Hib disease include epiglottitis with its 5%-10% mortality rate due to airway obstruction; cellulitis, especially facial, periorbital, and orbital locations; pneumonia; osteomyelitis; septic arthritis; bacteremia; and pericarditis. (11)

Rationale for vaccination

Because of the high mortality and complication rates of even properly treated Hib disease, the need for a vaccine was apparent for many years before a useful vaccine was developed. The Hib organism is encapsulated in a polysaccharide capsule. This capsule contributes to the virulence of Hib, and antibody directed against this polysaccharide provides protection against invasive disease. H inlCluenzae organisms that are unencapsulated commonly colonize the respiratory tract and cause sinusitis, otitis media, and bronchitis. Vaccines against Hib do not afford protection against these nontypable strains, or against the other strains of types of H influenzae (types a and c through f).

The polysaccharide antigen of the Hib capsule is linked to a protein to improve recognition by an infant's immature immune system. Four Hib vaccines that are immunogenic in infants as young as 6 weeks have been licensed since 1990. HibTITER (HbOC) links Hib polysaccharide to a mutant diphtheria protein; ActHIB and OmniHIB (PRP-T) use tetanus toxold; and PedvaxHIB (PRP-OMP) uses meningococcal group B outer membrane protein. (11) Two combination vaccines containing Hib also are available. COMVAX contains PRP-OMP as the Hib component and hepatitis B vaccine. It may be used in children who are at least 6 weeks old. TriHIBit contains PRP-T as the Hib component to reconstitute the DTaP (Tripedia), which is contained in a second vial. TriHIBit may be administered only as the fourth dose in the DTaP and Hib series for children who are at least 12 months of age.

Hib vaccine should not be given to children younger than 6 weeks because it can induce immune tolerance to the antigen. Such tolerance inhibits antibody formation and may increase the risk for disease.

Vaccine efficacy. Conjugate Hib vaccines are highly efficacious. The rate of clinical efficacy has been estimated to be between 95% and 100%. Not only has the incidence of invasive Hib disease dropped by more than 99% since the introduction of conjugate vaccine, but also the nasopharyngeal carriage rates among immunized children have dropped. The decrease in carriage rates helps protect unimmunized children against Hib disease.

Adverse reactions

No serious adverse reactions have been linked to Hib vaccine. Local reactions (tenderness, swelling, erythema) occur in 5% to 30% of recipients. Fever occurs in less than 5% of recipients. (11)

Recommendations

All infants should be immunized routinely against Hib disease. Routine immunization should begin at 2 months of age, and no earlier than 6 weeks of age. In general, unimmunized children have developed natural immunity to invasive Hib disease by 5 years of age, either through asymptomatic colonization or by acquiring cross-reactive antibodies to other organisms. Therefore, routine Hib immunization of children age 5 years and older is not recommended. However, exceptions to this recommendation do apply to children whose immunization has been delayed and who have an unusually high risk for invasive disease (eg, those with anatomic or functional asplenia and those with compromised immune systems).

PNEUMOCOCCAL CONJUGATE VACCINE

Streptococcus pneumoniae is a gram-positive diplococcus with a polysaccharide capsule that helps protect it from host-defense mechanisms; 90 capsular serotypes have been identified. Droplets from respiratory-tract secretions spread infection. Prior to the introduction of pneumococcal conjugate vaccine (PCV), S pneumoniae caused an estimated 3000 to 6000 cases of meningitis, 50,000 cases of bacteremia, and 500,000 cases of pneumonia in the United States. (18) Among children younger than 5 years, S pneumoniae previously caused about 17,000 cases of invasive disease, including 200 deaths annually. (19) Invasive disease consists of bacteremia, meningitis, or infection in a normally sterile site, excluding the middle ear and sinuses (CENTERFOLD, FIGURE 5). S pneumoniae is the most common bacterial cause of community-acquired pneumonia, sinusitis, and acute otitis media in young children. (19) After the tremendous success of Hib vaccines in reducing meningitis, S pneumoniae became the leading cause of bacterial meningitis in the United States.

Rationale for vaccination

Risk factors for invasive pneumococcal disease include age, race, recent use of antibiotics, day-care attendance, exposure to tobacco smoke, and chronic medical conditions; breastfeeding protects against the disease. (20,21) The incidence rates are highest among infants and elderly persons. Compared with Caucasians, rates are about two- to three-fold higher among African Americans and about three- to seven-fold higher among Alaska Natives and Native Americans (TABLE 4). (19) Children with sickle cell disease have high rates of pneumococcal disease; penicillin prophylaxis reduces the risk for pneumococcal disease in patients with sickle cell disease, but the rates are still elevated at about 1350 per 100,000 persons. (19) Additional predisposing risk factors include other sickle hemoglobinopathies, functional or anatomic asplenia, infection with human immunodeficiency virus, or HIV (eg, 9000 per 100,000 in HIV-infected children), and passive smoking. (20,21) Out-of-home day care increases the risk for invasive pneumococcal disease (by two- to three-fold) and for penicillin resistance. (20) Heightening the importance of immunizations is the increasing proportion of S pneumoniae that are resistant to antibiotics. In 1998, based on cases of invasive pneumococcal disease detected in the surveillance areas for the Active Bacterial Core, fully 24% of isolates had intermediate susceptibility or were resistant to penicillin. Some isolates are resistant to multiple antibiotics. Fortunately, resistance declined after the introduction of PCV, dropping to 21% in 2002.

Polysaccharide and conjugate pneumococcal vaccines. Currently, 2 vaccines that protect against pneumococcus are available: the 23-valent polysaccharide vaccine (Pneumovax[R] 23) and the 7-valent conjugate vaccine (Prevnar[TM]) licensed in 2000.

The older pneumococcal polysaccharide vaccine (PPV) contains T-independent antigens, which stimulate mature B-lymphocytes to produce effective antibody, but not T-lymphocytes. Thus, T-independent immune responses do not produce an anamnestic response upon challenge and may not be long-lasting. The vaccine is effective in older children and adults but not in children younger than 2 years because an infant's immune system does not respond well to such antigens. In fact, the serotypes that cause the majority of disease (ie, 6A, 14, 19F, and 23F) do not induce a good immune response from polysaccharide vaccine in children younger than 5 years. Finally, PPV does not reduce nasopharyngeal colonization of S pneumoniae, although the importance of this fact is debated.

A 7-valent immunogenic conjugate vaccine was licensed in the United States in 2000. (22,23) The carrier protein is CRM-197, which has been used in one Hib vaccine. The PCV, which does not contain thimerosal, was designed to cover the 7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) most common in children. These serotypes account for about 80% of invasive infections in children younger than 6 years but only 50% of infections in those age 6 and older. Obviously, PCV covers fewer serotypes than the 23-valent polysaccharide vaccine. However, the serotypes in PCV are more immunogenic than those in the polysaccharide vaccine. The PCV elicits a T-dependent immune response that leads to anamnestic response on rechallenge and is effective in infants. The vaccine also reduces nasopharyngeal carriage rates of S pneumoniae, which can create herd immunity.

Efficacy of PCV. A randomized, double-blind controlled trial was conducted at Northern Kaiser Permanente, California, in 1995-1998. In the primary efficacy analysis, the PCV's efficacy against invasive disease was 100%. In the follow-up analysis done 8 months later, the vaccine's efficacy against invasive disease was 94% for serotypes included in the vaccine in the intention-to-treat analysis and 97% for serotypes in the vaccine among all of the fully vaccinated. (24) The efficacy against all serotypes, including non-vaccine types, was 89%, suggesting some cross-protection among related serotypes. (24) In the intention-to-treat analyses, which are clinically more meaningful, the vaccine's efficacy rates were 11% against clinical pneumonia, 33% against clinical pneumonia with radiographic evidence of infiltrate, and 73% against pneumonia with radiographic evidence of consolidation [greater than or equal to]2.5 cm. (Of course, radiographic evidence of consolidation is more typical of pneumococcal pneumonia, whereas clinically diagnosed pneumonia often is caused by a virus. (24)) The vaccine also reduced middle ear ventilatory tube placement by 20.1% and antibiotic use by 5.3%. The number needed to vaccinate ("treat") was 411 to prevent a case of invasive disease, 239 to prevent a case of pneumonia, and 151 to prevent a case of invasive disease or pneumonia. Since the introduction of PCV, rates of invasive disease have dropped from 24 cases per 100,000 in 1999 to 13 cases per 100,000 in the United States in 2002. The largest decline was in children younger than 2 years, but decreases also occurred in adults, suggesting that some herd immunity was induced. (25)

Published analyses show that the vaccination of healthy infants would prevent more than 12,000 cases of meningitis and bacteremia and 53,000 cases of pneumonia. (26) The break-even price for PCV is $46 per dose from the societal perspective and $18 per dose from the health care payer's perspective. (25) The manufacturer's list price is about $61.65 per dose for the private sector, making it the most expensive routine infant immunization series to date. Actual prices vary by setting.

Adverse reactions

No serious adverse reactions are associated with PCV. When given with DTaP vaccine but at another site, fever [greater than or equal to]38[degrees]C occurs in 15% to 24% of those vaccinated with PCV, compared with 9% to 17% of those receiving the control vaccine (experimental meningococcal conjugate vaccine). (24) Among PCV vaccinees, 10% to 14% develop redness at the injection site and 15% to 23% develop tenderness at the injection site. (24) Fever higher than 39[degrees]C is uncommon, occurring in 1% to 2.5% of vaccinees.

Recommendations

Currently, the supply of PCV is adequate. The ACIP, the AAP, and the AAFP all recommend PCV for routine infant immunization. (19,27) In addition, the 3 organizations recommend catch-up vaccination for unvaccinated children between the ages of 24 and 59 months who are at high risk for invasive pneumococcal disease. Children at high risk are those with sickle cell disease, asplenia, HIV infection, chronic illness (eg, bronchopulmonary dysplasia, congenital heart disease, congestive heart failure, diabetes mellitus, and cerebrospinal fluid leaks), and immunocompromising conditions, including congenital immune or complement deficiencies, renal failure, nephrotic syndrome, and malignancies and treatment with immune-suppressive therapy (eg, solid organ transplantation) or radiation therapy. Children with sickle cell disease who have been given PCV should continue to receive penicillin prophylaxis.

Recommendations for catch-up vaccination of unvaccinated healthy children between the ages of 24 and 59 months vary by organization. The incidence of invasive pneumococcal disease decreases during childhood and the case for several different cutoff points can be made. Individual risk factors may help in deciding which recommendation to follow. As previously mentioned, risk factors for invasive pneumococcal disease include day-care attendance, passive smoking, and race. In accordance with the data for increased risk by race (TABLE 4), (19) the AAFP recommends catch-up vaccination of unvaccinated children age 24-59 months who are of Alaska Native, American Indian, or African American descent; the ACIP and AAP state that vaccination can be considered for these groups. The AAFP regards vaccination of children age 24-59 months who are in child-care settings or have had frequent or complicated acute otitis media in the previous year as optional.

PCV is not licensed for use in adults, and no efficacy data with respect to this vaccine are available for older children and adults. Since the serotypes change with age, only 50% of the serotypes that cause infection in older children and adults are covered by PCV, compared with 80%-90% for 23-valent PPV. Although the AAP allows use of PCV in older children up to 13 years of age who have high-risk conditions, it should not replace the PPV in older children or adults. (27)

POLIOVIRUS VACCINE

During the 20th century, poliomyelitis was a dreaded disease (CENTERFOLD, FIGURE 6). More than 18,000 paralytic cases occurred in 1954 in the United States (TABLE 1). (1) An outbreak of poliomyelitis that was due to a revertant virus (ie, mutated so no longer as attenuated) from oral poliovirus vaccine strain 1 occurred fairly recently in the Dominican Republic and Haiti. This outbreak demonstrates the need for continued vigilance to maintain high rates of vaccination. Poliovirus is an enterovirus that occurs in 3 serotypes. The virus is quite infectious, and 73% to 96% of those infected will transmit the virus to susceptible household contacts, depending on the contact's age. Transmission occurs primarily by the fecal-oral route, although oral-oral transmission can occur. After the virus enters the mouth, it multiplies in the pharynx and gastrointestinal tract before invading the bloodstream and, potentially, the central nervous system. The incubation period ranges from 3 to 35 days. (11)

The results of poliovirus infection, in decreasing order of likelihood, are subclinical infection (up to 95% of cases), nonspecific viral illnesses with complete recovery (about 5% of cases), nonparalytic aseptic meningitis (1% to 2% of cases), and paralytic poliomyelitis (less than 2% of cases). (11) The ratio of inapparent to paralytic illness is about 200:1 (range, 50:1 to 1000:1). (11) The case-fatality rate is 2% to 5% in children and 15% to 30% in adults.

Rationale for vaccination

Poliovirus vaccination programs have dramatically decreased disease incidence. Circulation of indigenous wild polioviruses ceased in the United States in the 1960s, (28) and the last case of wild poliomyelitis contracted in the United States was reported in 1979. The last case of poliomyelitis due to indigenous virus in the Americas occurred in 1991 in Peru, and in 1994, the Americas were declared free of indigenous poliomyelitis.

Two vaccines have been used in the United States: inactivated poliovirus vaccine (IPV) and oral poliovirus vaccine (OPV). The IPV, also known as the Salk vaccine, was licensed in 1955. An enhanced-potency IPV formulation became available in 1988 and is the IPV used in the United States today. The IPV cannot cause vaccine-associated paralytic poliomyelitis (VAPP); therefore, it is safe for immunocompromised persons and their contacts. The disadvantages of IPV are that it is administered by injection and that it reduces gastrointestinal immunity. In contrast, the OPV is easier to administer and induces early intestinal immunity. The main disadvantage of OPV is that the oral polioviruses can revert to a more virulent form and cause VAPP.

Adverse reactions

The overall risk for VAPP is quite small: between 1980 and 1994, 303 million doses of OPV were distributed and 125 cases of VAPP were reported, for a risk of 1 case per 2.4 million doses of OPV distributed. (11) VAPP occurred most often in healthy vaccine recipients (49 of 125 cases), and usually after the first dose of vaccine (1 case per 750,000 first doses). There were 40 cases among healthy contacts of vaccine recipients, 23 cases among immunodeficient vaccine recipients, and 7 cases among immunodeficient contacts of vaccine recipients. In 6 other cases, VAPP was community acquired. (11)

The rationale for the all-IPV schedule follows: (1) Exposure to indigenous wild poliovirus in the United States has ceased, and widespread circulation of indigenous wild polioviruses ceased in the 1960s. (2) OPV carries a slight risk for VAPP, whereas IPV does not cause VAPP or any other serious reactions. (3) The majority (61%) of parents prefer to have their child undergo more injections rather than face the risk for VAPP. (29) (4) It is easier to administer and store 1 vaccine, as opposed to stocking 2 vaccines and explaining the choices to patients and parents.

Recommendations

Poliovirus vaccination continues to be recommended because of outbreaks in other countries, ease of importation of wild virus, and the highly contagious nature of the virus. The all-IPV schedule is recommended for the United States. OPV, which is no longer recommended for routine use in the United States, is recommended by the World Health Organization for global eradication efforts and provides the earliest mucosal immunity. Prior to school entry, 4 doses of poliovirus vaccine generally are recommended; any combination of IPV and/or OPV is acceptable.

MEASLES, MUMPS, AND RUBELLA VACCINE

Throughout the 20th century, the burden of disease due to measles, mumps, and rubella ("German measles") dramatically declined because of widespread vaccination against these 3 viruses. (27) In the United States, the number of cases reported in 2002 dropped from annual peaks of 503,000 to 26 indigenous cases for measles, from 152,000 to 270 for mumps, and from 50,000 to 18 for rubella. (1,27) In patients with measles, cough, coryza, conjunctivitis, and sometimes Koplik's spots on the buccal mucosa precede the characteristic rash that appears about 14 days after exposure (CENTERFOLD, FIGURE 7). Measles can be severe and sometimes acutely fatal, with high fever and prostration. The disease may be complicated by a delayed fatal encephalopathy (subacute sclerosing panencephalitis), the onset of which tends to occur in early adolescence. Worldwide, measles is estimated to kill 1 million people per year. Mumps produces excruciating bilateral parotitis (CENTERFOLD, FIGURE 8) and sometimes pancreatitis, orchitis, cerebellar ataxia, or death. In contrast, mild rubella usually causes only posterior cervical adenopathy, arthralgia, and minimal rash; however, it can produce devastating fetal infection (CENTERFOLD, FIGURE 9).

[FIGURES 7-9 OMITTED]

Although the vaccines for these 3 viruses are extraordinarily effective in preventing these infections, (27) occasional outbreaks of all 3 illnesses have been reported in the United States. These include a 1989-1991 measles epidemic; outbreaks of rubella in 1994-1997, particularly among those age [greater than or equal to]20 years and generally among unimmunized persons in prisons, colleges, office buildings, or medical workplaces, who accounted for 65% of all cases; and occasional increases in mumps, (eg, 906 cases in 1995). (27) Measles cases often are imported (18 cases in 2002). (1) Outbreaks occur because the attack rate of this highly contagious virus among unvaccinated household contacts is 90% or higher. Infected persons may transmit the disease from 4 days prior to 4 days after the appearance of the rash.

Rationale for vaccination

The measles, mumps, rubella (MMR) vaccine is a successful combination of 3 live, attenuated viruses. Individual vaccine or any combination of vaccines is available, but expected combinations with varicella vaccine have yet to be approved. (27) Each individual vaccine contains neomycin, gelatin, sorbitol, and human albumin (all potential allergens). Measles and mumps vaccines are produced in chick cells, and rubella in human cells. The measles vaccine currently used in the United States (the Edmonston-Enders strain) contains live, highly attenuated virus.

The inadequacy of the protection afforded by the first dose of measles vaccine results from lack of initial seroconversion, usually due to the presence of higher initial titers of maternally acquired measles-neutralizing antibody, and waning immunity. Mothers who have acquired immunity as a result of wild viral disease, rather than through vaccination, confer higher initial levels of immunity to their infants, who then have protective antibody levels until about 11 months of age. In such cases, seroconversion rates are optimal when administration of MMR vaccine is delayed until children are 15 months old. Today, because maternal immunity to measles is due primarily to vaccination, the current duration of immunity transferred to infants has decreased to about 9 months of age, making vaccination at 12 months of age ideal. The growing incidence of measles at younger ages was noticed in 1990, when 26% of measles cases occurred in children who were younger than 16 months of age and whose immunity was inadequate, possibly due to waning maternally acquired antibody levels. In response to this change, the current ACIP recommendation is to give the first dose of MMR vaccine between the ages of 12 and 15 months. (27) Failure of seroconversion after the initial dose of measles vaccine occurs at a rate of 2% to 5%, necessitating a second vaccine dose. In comparison, the rate of secondary vaccine failure (waning immunity) is less than 0.2%. (27)

Vaccine efficacy. Following measles vaccination, seroconversion rates are 95% for children vaccinated at 12 months of age and 98% for children vaccinated at 15 months of age. (27) Antibody persists for at least 17 years, and immunity is probably lifelong in almost all vaccinated persons who initially seroconvert. Upon revaccination of the few whose antibody levels wane, secondary immune responses demonstrate persistent underlying immunity. After 2 doses, more than 99% of persons are immune. Vaccination of individuals who are already immune is not harmful.

Adverse reactions

Pain, irritation, and redness at the site of injection are common but mild. Delayed reactions to measles vaccine include fever that is usually below 38.8[degrees]C (102[degrees]F), occurring between days 7 and 12, or a rash of 2 to 5 days' duration, occurring between days 5 and 20. Adverse reactions to rubella vaccine include generalized lymphadenopathy in children and arthralgia in young women, with no reports of long-term arthritis. Adverse reactions to mumps vaccine include transient orchitis in young men. Measles vaccine does not cause autism. (27,30) Transient thrombocytopenia due to the measles component of the MMR vaccine (1 in 25,000 to 2 million) has been reported. (14,27) Some physicians report "arm syndrome" (brachial neuritis) or "catcher's crouch" (lumbar radiculoneuritis) as potential adverse reactions, (31) but reviews by the Institute of Medicine revealed either no evidence in the case of mumps vaccines, or insufficient evidence in the case of measles and rubella vaccines, for such allegations. (14,32)

Recommendations

The MMR vaccine is given routinely to all healthy children at age 12-15 months, with a second dose at age 4-6 years. A second dose is especially important for military recruits, college students, and susceptible health care personnel (see following article). Persons born before 1957 are assumed to have had measles and mumps but should not be assumed to be immune to rubella. Immunity to rubella must be proven via serum antibody tests, especially for women of childbearing age, or induced by vaccination. (27) Assurance of immunity by either vaccination or testing is especially important for unimmunized immigrants.

Persons who received killed measles vaccine, used in 1963 to 1967, or an unknown type of measles vaccine between 1963 and 1967 should receive 2 doses of live measles vaccine. Persons who received measles vaccine along with either immune globulin or measles immune globulin should be considered susceptible and revaccinated with at least one dose of measles vaccine, unless the measles vaccine type is known to be Edmonston B. It is preferable to receive the MMR vaccine, rather than 3 separate vaccines for measles, mumps, and rubella.

VARICELLA VACCINE

During childhood, the highly contagious varicellazoster virus (VZV) most often causes chickenpox, which is generally a self-limited and benign illness (CENTERFOLD, FIGURE 10). Prior to the introduction of varicella vaccine, roughly 4 million cases of VZV infection occurred annually in the United States, with a hospitalization rate of 5 cases per 1000 population and a death rate of 0.7 per 100,000. Because secondary attack rates are as high as 90% and because communicability via aerosol droplets begins 1 to 2 days prior to the appearance of the rash, prevention of spread requires a universal vaccination program. Partial utilization of the vaccine early on reduced wild-virus cases, leading to better herd immunity than expected. As a result, some children have had neither the vaccine nor the wild virus, leaving them potentially susceptible as adults, for whom chickenpox tends to be more severe. (33) Complications of chickenpox include secondary bacterial skin infection (both impetigo and invasive group A streptococcal disease) (CENTERFOLD, FIGURE 11), pneumonia, Reye's syndrome (now rare), encephalomeningitis, glomerulonephritis, thrombocytopenia, purpura fulminans, cerebellar ataxia, arthritis, and hepatitis. (27) Neonates only rarely are afflicted with the congenital varicella syndrome (limb atrophy and scarred skin). However, the threat of neonatal sepsis is present for those whose mothers are not immune to VZV and who develop VZV anywhere from 5 days before to 2 days after delivery, because maternal antibody levels are inadequate to protect the infant. The lifetime risk for the late complication of herpes zoster (shingles) is at least 10%.

[FIGURE 10-11 OMITTED]

Rationale for vaccination

VZV is most severe in neonates and in adults, the hospitalization rates of which are 103 and 65 per 10,000 cases, respectively, versus 23 per 10,000 for children between the ages of 1 and 4 years. However, the majority of individuals who are hospitalized each year for VZV-related complications tend to be in the latter group because VZV is so common at those ages. Most hospitalized individuals are immunologically normal, but many develop the secondary complications mentioned above, sometimes with fatal outcomes. Additional factors favoring a universal vaccine program include the cost of lost time from work or school and the burden of disease suffering. Routine vaccination is a cost-effective measure to reduce VZV morbidity and mortality. (34) Each dollar spent on universal immunization of children avoids approximately $5 in costs. (34)

Vaccine efficacy. The current varicella vaccine contains live attenuated virus (Oka strain) and is 97% effective against moderately severe and severe disease and 44% to 85% protective against any infection for at least 7 years. (35) When the disease does develop in vaccinees, it is usually mild with fewer than 30 pox lesions. (36) Although one outbreak study showed a vaccine effectiveness of only 44%, (37) a summary of 14 other published and unpublished studies presented at the February 2003 meeting of the ACIP showed efficacy rates of 71% to 100%. Outbreak studies are biased toward low estimates, as Fine and Zell have demonstrated. (38) A recent study conducted after the introduction of varicella vaccine in the United States found a substantial reduction in rates of hospitalization due to varicella and a large, significant reduction in cases of varicella among all age groups, including infants (who are not eligible for vaccination) and adults). (33) Vaccinated children with mild disease are less contagious than those with disease caused by wild virus. (39)

Because varicella vaccine is less immunogenic in older children and adults, a second dose is required in those age 13 years and older. The seroconversion rate in these individuals is 67% to 85% after 1 dose and 94% to 100% after the second dose, which is given 4 to 8 weeks later.

The long-term duration of vaccine-induced immunity is unknown. The concern that widespread vaccination of children would shift the disease burden to adults with waning antibody levels remains unsettled. One expert panel estimated that a child given 1 dose of varicella vaccine might have a 15% chance of eventual inadequate immunity over a lifetime. (40) Because of the decreasing incidence of wild varicella, waning antibody levels are less likely to be boosted from exposure in the community. Continued surveillance of vaccine-induced antibody levels is in progress. Protective antibody levels have persisted for longer than 20 years in Japan. (41) Results of studies have varied regarding the relation of likelihood of breakthrough chickenpox and the amount of time that has elapsed since vaccination. (42,43) Although some experts speculate that booster doses eventually may be required, mathematical models show that if the disease peak shifted to adults, with current therapy the overall hospitalization number and mortality would drop, even if immunity fails more rapidly than expected. (40) Thus, the overall decrease in hospitalization and severe disease favors universal childhood vaccination.

Adverse reactions

Local pain and erythema occur in 2% to 20% of children and 10% to 25% of adults after the first dose. Up to 47% develop local reactions with the second dose. From 4% to 10% develop a few (median of 5) varicella-like lesions 5 to 41 days after administration; these lesions last 2 to 8 days. A brief low-grade fever develops in 12% to 30% of vaccinees up to 42 days later. In rare cases, vaccine virus can be transmitted to healthy immunocompetent siblings and parents, especially if the vaccinee has developed a varicelliform rash or has had leukemia. No major ill effects have resulted from the vaccine. Rare hypersensitivity reactions to gelatin or neomycin have been reported. Those with previously unrecognized VZV infection or prior immunization are not at increased risk. To date, the risk for zoster is less among vaccinees than those who have been infected naturally.

Recommendations

The ACIP, AAFP, and AAP recommend that children between the ages of 12 months and 13 years receive 1 dose of VZV vaccine, unless they have a history of prior varicella infection. Vaccine on a 2-dose schedule, with the doses spaced 4 to 8 weeks apart, is recommended for adolescents ([greater than or equal to]13 years of age) and adults without a history of chickenpox. Adults and children can be assessed for immunity to varicella; one can start the assessment by asking them if they have had varicella. (35) About 70% to 90% of those without a history of chickenpox are actually immune. Although serologic tests may be cost-efficient, such tests are not required because the vaccine is well tolerated. Testing makes the most sense for children between the ages of 9 and 12 years whose VZV histories are uncertain because these children were born before varicella vaccination was available. Postvaccination serologic testing is unnecessary.

For adults without a history of chickenpox, the risk is highest among persons who live or work in settings where natural VZV is prevalent or transmission can occur: preschool, church-school, or elementary-school teachers; child-care staff; residents and staff members of correctional facilities and institutions for the developmentally delayed; military personnel; college students; nonpregnant women of childbearing age; international travelers; adolescents and adults living with young children; medical personnel, and family contacts of immunocompromised persons.

Households with immunocompromised persons require no special precautions unless the vaccinee develops a rash, after which direct contact should be avoided. Immunocompromised contacts who develop a rash may require antiviral therapy.

HEPATITIS A VACCINE

Hepatitis A is one of the most common vaccine-preventable diseases in the United States. Prior to the introduction of hepatitis A vaccine, the reported incidence of hepatitis A was highest among children 5-14 years of age. In the past, approximately one third of reported cases involved children younger than 15 years, but the more recent food-related outbreaks have involved adults. (46) Many children with unrecognized infection are the source of infection for others. Hepatitis A incidence varies by race and ethnicity, with the highest rates among American Indians and Alaska Natives and the lowest rates among Asians; rates among Hispanics are higher than among non-Hispanics. (46) These differences are most likely related to factors such as socioeconomic levels, resultant living conditions, and more frequent contact with persons from countries where hepatitis A is endemic.

Hepatitis A virus infection is acquired primarily via the fecal-oral route through either person-to-person contact or ingestion of fecally contaminated food or water. Depending on conditions, the virus can remain in the environment for months. (47)

The most frequently reported source of infection (12%-26%) is either household or sexual contact with a person who has hepatitis A. (48) International travel, especially to Mexico, accounts for an additional 4% to 6% of the infections. Cases associated with recognized food or waterborne disease outbreaks are increasingly common. (48) Notably, many persons with hepatitis A do not have an identified source for their infection. (48)

Hepatitis A virus is a picornavirus that causes infections in humans after a 28-day incubation period. The infections can be either asymptomatic or symptomatic. The symptomatic illness classically is characterized by an abrupt onset of symptoms that include fever, nausea, anorexia, malaise, and jaundice. Most infections in children younger than 6 years are asymptomatic. In contrast, infections in adults are symptomatic, with 70% of adults developing jaundice. The illness is usually self-limited and lasts less than 2 months. However, prior to widespread vaccination, an estimated 100 persons died each year as a result of acute liver failure due to hepatitis A. Although only 0.3% of all patients with acute hepatitis A develop fulminant hepatitis A, the rate is 1.8% among adults older than 50 years. (46) Persons with chronic liver disease are at increased risk for fulminant hepatitis A.

Rationale for vaccination

Both of the licensed vaccines are highly immunogenic in children age 2-18 years and in adults. Protective antibody levels develop in 94% to 100% of people one month after the first dose and essentially 100% after the second dose. (49) Available data indicate that hepatitis A vaccine is immunogenic in children younger than 2 years who do not have passively acquired maternal antibodies. Two doses of vaccine are recommended.

Vaccine efficacy. The efficacy of the hepatitis A vaccine is between 94% and 100%. Several studies have evaluated the vaccine's duration of protection; in both adults and children, protection has been demonstrated for at least 6 to 8 years. (50) Estimates of antibody persistence derived from kinetic models of antibody decline indicate that protection could persist for longer than 20 years. (51)

Adverse reactions

The most frequently reported side effects included soreness at the injection site, warmth at the injection site, and headache. Follow-up over a 5-year period of an estimated 65 million doses of hepatitis A vaccine administered worldwide did not find any serious adverse events among children or adults that definitely could be attributed to the vaccine.

Recommendations

The ACIP recommends vaccinating persons in groups shown to be at high risk for infection (eg, travelers to countries with high or intermediate disease endemicity, men who have sex with men, injection drug users, and persons with clotting-factor disorders), persons with chronic liver disease, and children living in communities with high rates of hepatitis A. The ACIP recommends routine vaccination of children in states, counties, or communities with rates that are at least twice the 1987-1997 national range (ie, [greater than or equal to] 20 cases per 100,000 population), including most of the western states. Consideration should be given to routine vaccination of children in states, counties, or communities with rates exceeding the 1987-1997 national average (ie, more than 10 but fewer than 20 cases per 100,000 population). (46) A CDC map shows these hepatitis A rates at www.cdc.gov/ncidod/diseases/ hepatitis/a/vax/index.htm.

MENINGOCOCCAL-DISEASE VACCINE

Neisseria meningitidis causes approximately 2200 to 3000 cases of invasive disease in the United States each year, with an annual incidence of 0.8 to 1.5 cases per 100,000 persons (CENTERFOLD, FIGURE 12). (52,53) N meningitidis is now the most common cause of bacterial meningitis in children and young adults in the United States and the second most common cause of community-acquired meningitis in adults. (54) Death occurs in 10% of cases; sequelae such as limb loss, neurologic disabilities, and hearing loss occur in another 11% to 19%. (52,53)

Disease transmission Neisseria meningitidis is a gram-negative diplococcus that colonizes the upper respiratory tract and is transmitted from person to person via respiratory-tract droplets. Although disease most often occurs in children <5 years old, about half of cases occur in people >16 years old. Most cases of meningococcal disease are sporadic and not linked to outbreaks. However, household, child-care, and nursery-school contacts are at increased risk for developing infection and are candidates for chemoprophylaxis during an outbreak. (27) Meningococcal disease also has occurred among international travelers, microbiology lab workers, and passengers on long-distance airplane flights.

Epidemiology of meningococcal disease

There are 13 serogroups of meningococci. (54) Serogroup A disease is rare in the United States, although it is the most common cause of meningococcal infection in sub-Saharan Africa. (53) Serogroup B accounts for more than 30% of cases of meningococcal disease and tends to occur in children younger than 2 years. Serogroup Y also accounts for about 30% of sporadic cases. (52) Serogroup C caused 26 of 42 outbreaks reported to state health departments from 1994 to 1997. (27)

Disease in college students. The incidence of meningococcal infection among Maryland college students was found to be similar to that among other persons of the same age, but students residing on campus had at least a three-fold greater relative risk of contracting meningococcal infection than did students living off campus. (55) Almost one quarter of meningococcal infections in 15-to-24-year-olds were fatal, possibly because of a high frequency of meningococcemia. (56) A nationwide survey of state health departments and college health centers found that the incidence of meningococcal disease for first-year students living in dormitories was 5.1 per 100,000, compared with 0.7 per 100,000 undergraduates and 1.4 per 100,000 18-to 23-year-olds in the general population. (57)

In addition to dormitory living, potential risk factors for meningococcal disease include white race, radiator heat, and recent upper respiratory infection. (52,55) A British university study found that the carriage rates for meningococci increased rapidly among students living in catered halls from 13.9% in October to 34.2% by December. (58) Being male, actively smoking, visiting hall bars and nightclubs, engaging in intimate kissing, and living in coed halls also were identified as risk factors for acquisition of meningococci. (58)

The devastation of meningococcal disease has prompted recommendations from the American College Health Association, the ACIP, and the AAP that students entering college be informed about the risks for meningococcal disease and the availability of a vaccine. (52) The majority of US states now mandate education about meningococcal disease and vaccine for students attending colleges and universities or for those full-time students residing on campus. Eleven of the 50 states currently mandate vaccination for these students.

Meningococcal polysaccharide vaccine

The quadrivalent meningococcal vaccine (Menomune[R]-A/C/Y/W-135, Aventis Pasteur) contains polysaccharide antigens to meningococci groups A, C, Y, and W-135. It is not effective in children younger than 2 years, but its efficacy is as high as 85% in school-age children and adults. (52) Immunity probably decreases 3 years after initial administration as measured by declining levels of antibody to groups A and C, especially in children younger than 5 years. (52) This vaccine does not confer protection against serogroup B disease, which is responsible for about 30% of all invasive meningococcal disease. (52)

Indications for vaccine use. In addition to dormitory residence, risk factors for meningococcal disease include functional or anatomic asplenia, underlying immune deficiencies, travel to hyperendemic areas such as sub-Saharan Africa, and employment in laboratories or industry where there is potential aerosol exposure to N meningitidis. (52) A single 0.5-mL dose is given subcutaneously. The multi-dose formulation of vaccine contains thimerosal and should not be given to anyone with anaphylactic sensitivity to this or any other constituent. Pain, tenderness, and redness at the injection site are the most common local reactions; fever, malaise, and headache occur in a small percentage of patients. Severe adverse events, including allergic reactions, seizures, and parasthesias, are rare, occurring in less than 0.1/100,000 doses.

Conjugated meningococcal vaccines

Conjugated vaccines are T-cell-dependent and stimulate immunologic memory. They usually provide a greater and longer duration of immunity than do standard polysaccharide vaccines. The meningococcal serogroup C conjugate vaccine first was used on a widespread basis in the United Kingdom and found to be over 90% efficacious in toddlers and teenagers. (59) A conjugated meningococcal vaccine containing polysaccharide serogroups A, C, Y, and W-135 conjugated to diphtheria toxoid has been submitted to the US Food and Drug Administration. A small, initial study of this vaccine demonstrated it to be immunogenic in adults and acceptably tolerated. (60)

PNEUMOCOCCAL POLYSACCHARIDE VACCINE

Prior to the introduction of PCV, S pneumoniae caused an estimated 3000 to 6000 cases of meningitis, 50,000 cases of bacteremia, and 500,000 cases of pneumonia in the United States. (18) Today it accounts for a major proportion of invasive bacterial disease (bacteremia, meningitis, etc.) in all age groups but is especially dangerous for persons age [greater than or equal to] 65 years, with an attack rate of 50 to 83 cases per 100,000 persons per year. (18,16) African Americans, Alaska Natives, American Indians, and persons with certain chronic diseases, immunocompromise, or asplenia are at increased risk. (18,19) Cigarette smoking and passive smoke inhalation are also risk factors for pneumococcal infections, but asthma alone is not. (18,19) In those older than 70 years, the mortality rate climbs to 55%-60%. (11) Despite these data, the current immunization rate for elderly persons of 63% remains well below the Healthy People 2010 goal of 90% for noninstitutionalized elderly.

Rationale for vaccine

PPV contains 23 polysaccharide antigens (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F) that cover 80% to 90% of the serotypes of invasive pneumococci in children older than 2 years and adults, so it provides broader coverage than the 7-valent PUg. (27,61) The duration of immunity following a single dose is unknown but is at least 9 years in immunocompetent individuals. (62)

Vaccine efficacy. In case-control studies, PPV has a 56% to 81% efficacy against invasive pneumococcal disease, with better protection against the serotypes included in the vaccine and in immunocompetent persons. (18) The vaccine may be less effective against nonbacteremic pneumococcal pneumonia. (11,62) However, in a meta-analysis of randomized controlled trials of older PPVs, the vaccine was 66% effective against definitive pneumococcal pneumonia and 83% against definitive pneumococcal pneumonia for vaccine serotypes. (63) PPV is cost-effective. (64)

Adverse reactions

Primary vaccination and revaccination with PPV are extremely safe. (65) One article suggests that 11% of revaccinees, compared with 3% of first-time vaccinees, develop large 10.2-cm (4-in) local reactions if a second PPV is given more than 4 years after the first. (65) However, these reactions are self-limited, generally last 3 days or less, and leave no residua. Other reactions include pain at the injection site and, rarely, fever or myalgia. (18) Repeat vaccinations given less than 5 years after prior administration are likely to have a higher incidence of local side effects.

Recommendations

PPV is recommended for all persons age 65 years and older and for those age 2 years and older with certain high-risk conditions, as outlined in the following article. Opportunities to vaccinate include routine office visits, occasions when influenza vaccine is being administered, and hospitalization once patients have been stabilized. To stress the importance of the latter point, one study showed that 60% of persons [greater than or equal to] 65 years old hospitalized for pneumonia had been discharged from the hospital within 4 years of readmission. (66) As of October 2002, qualified facility personnel may administer pneumococcal and/or influenza vaccine without a physician's order. Some states have passed statutes mandating that hospitals offer these 2 vaccines to all inpatients.

For persons who received PPV prior to age 65 years, one revaccination at age [greater than or equal to] 65 years is indicated when 5 or more years have elapsed since the first dose (TABLE 5). Antibody levels significantly increase after this second vaccination but reach somewhat lower levels than with primary vaccination. Antibody levels do not increase after a third dose of PPV.

VACCINE SHORTAGES

Due to manufacturing problems, quality-improvement projects, increased demand, and/or manufacturer withdrawal from vaccine production, shortages of vaccines have occurred, including, most recently, shortages of conjugated pneumococcal and influenza vaccines. For advice on how best to manage potential future shortages, the practitioner should consult the CDC's National Immunization Information Hotline at (800) 232-2522 or the CDC's National Immunization Program at www.cdc.gov/nip.
TABLE 1

Impact of routinely used vaccines on number of cases
of vaccine-preventable childhood diseases

Vaccine-preventable                        Number of Cases
Disease                          Year *    in That Year

Hepatitis B                       1989     132,000
Haemophilus influenzae type b
  Invasive disease                1986      13,014
  Meningitis                                  8676
Poliomyelitis
  All types                       1954      56,784
  Paralytic                                 18,308
Measles                           1964     458,083
Rubella                           1970      57,686

Vaccine-preventable              Number of          Number of Cases
Disease                          Deaths             Reported in 2002

Hepatitis B                      5820 ([dagger])    7996
Haemophilus influenzae type b
  Invasive disease               531                34
  Meningitis                     354
Poliomyelitis                                       0
  All types                      --
  Paralytic                      --
Measles                          380                26
Rubella                          --                 18 ([double
                                                      dagger])

* The year preceding widespread use of specified vaccine.

([dagger]) Includes an estimated 320 deaths from acute hepatitis B
virus (HBV) infection and an estimated 5500 deaths from chronic HBV
infection.

([double dagger]) 18 cases of rubella and 1 case of congenital rubella
syndrome.

Adapted from Centers for Disease Control and Prevention. MMWR Morb
Wkly Rep. 2004;51:1-84.

TABLE 2

Study sites, vaccines, vaccination schedules, and efficacy estimates
used to evaluate efficacy of acellular pertussis vaccine when
administered in infancy

                Acellular          Vaccine Composition
                Pertussis
Site of Study   Vaccine            PT   FHA   Pn   Fim

Italy           Infanrix[TM]       X    X     X
                (SKB-3P)
Germany         Infanrix[TM]       X    X     X
                (SKB-3P)
Stockholm,      DAPTACEL           X    X     X    X (types
Sweden          (CLL-4[F.sub.2])                   2 and 3)
Munich,         Tripedia[R]        X    X
Germany         (CB-2)

                                          Schedule Studied
Site of Study   Trial Type                (months)

Italy           Randomized double-blind   2,4,6
Germany         Household contact with    3,4,5
                passive surveillance
Stockholm,      Randomized double-blind   2,4,6
Sweden
Munich,         Case-control study with   3,5,7
Germany         passive surveillance

                Vaccine Efficacy Against
                [greater than or equal to] 21 Days ofCough

                DTaP, %                         DTP,* %
Site of Study   (95% Cl)                       (95% Cl)

Italy           84 (76-90) ([dagger])          36(14-52)

Germany         89 (77-95) ([dagger])          98(83-100)

Stockholm,      85 (81-89)                     48(37-58)
Sweden
Munich,         80 (59-90) ([double dagger])   95(81-99)
Germany

PT = pertussis toxin; FHA = filamentous hemmagglutin; Pn = pertactin;
Fim = fimbriae; DTap = pediatric dse of diphtheria toxoid and tetanus
toxoid and acellular pertussus vaccine; DTP = pediatric dose of
diphtheria toxoid and tetanus toxoid and whole-cell pertussis vaccine;
CI = confidence interval.

* The whole-cell vaccines differed; some are not available in the
United States.

([dagger]) Efficacy against [greater than or equal to] 21 days of
paroxysmal cough with culture or serologic confirmation.

(double dagger)] Efficacy against [greater than or equal to] 21 days of
any cough and confirmation by culture or link to culture; positive
household contact.

Note: Pediarix (DTaP-hepatitis B vaccine-inactivated polio vaccine)
contains the same formula as Infanrix.

Modified from Centers for Disease Control and Prevention. MMWR Recomm
Rep. 1997;46:6.

TABLE 3

Percent of infants with mild or local reactions by
the third evening after pertussis vaccination
at ages 2, 4, and 6 months

                               Temperature
                               [greater than
                               or equal to]     Swelling   Severe
Vaccine                        37.8[degrees]C   >20 mm     Fussiness *

Aventis/Biken/CB-2/
  Tripedia[R]                  24.5             3.7        3.7
Aventis/CLL-4[F.sub.2]/
  DAPTACEL                     32.8             4.4        3.6
SmithKline Beecham/SKB-3P/
  Infanrix[TM]                 31.6             5.8        5.0
Overall for 13 DTaP vaccines   24.5             4.2        4.7
DTP vaccines overall           60.4             22.4       12.4

DTaP = pediatric dose of diphtheria toxoid and tetanus toxoid and
acellular pertussis vaccine;

DTP = pediatric dose of diphtheria toxoid and tetanus toxoid and
whole-cell pertussis vaccine.

* Fussiness was classified as severe when the infant cried persistently
and could not be comforted.

Modified from Decker MD, et al. Pediatrics:
1995;96(suppl) 557-566.

TABLE 4

Number of cases (per 100,000 population) of invasive
pneumococcal disease in various US pediatric populations

                            African        Alaska
Age Group    All Races *    Americans *    Natives    Navajo

0-5 mo        73            163            277        629
6-11 mo      228            542            598        629
12-23 mo     184            441            453        557
24-35 mo      65            116            125         73
36-47 mo      27             46             56         73
48-59 mo      14             21             73         73
5-9 y          6              9
10-19 y        3              5

             Children  With
             Sickle Cell
             Disease ([dagger])    Children
Age Group                          With HIV

0-5 mo       6380                  4500
6-11 mo      6380                  4500
12-23 mo     6340                  5500
24-35 mo     5720                  9900
36-47 mo      900                  5100
48-59 mo     1450                  2500
5-9 y
10-19 y

HIV = human immunodeficiency virus.

* Active Bacterial Core Surveillance/Emerging Infections Program
Network for the US, 2000.

([dagger]) No vaccine or penicillin prophylaxis.

Modified from Centers for Disease Control and Prevention. MMWR Recomm
Rep. 2000;49:5. Public domain.

TABLE 5

Indications for revaccination with pneumococcal polysaccharide
vaccine

Indication                      Timing of Single Revaccination

Children at increased risk *
  for severe pneumococcal
  infection
  Age 2-10 y                    Revaccinate in 3-5 y
  Age >10 y                     [greater than or equal to] 5 y
Adults [greater than or
  equal to] 65 y and
  received first dose prior
  to age 65                     [greater than or equal to] 5 y
Bone marrow transplant
  patients                      12 mo and 24 mo following transplant
Chemotherapy and radiation
  therapy patients              3 mo after discontinuation of therapy

* Risk factors for severe pneumococcal infection:

1) Functional or anatomic asplenia

2) Conditions associated with rapidly decreasing antibody levels,
especially:
Renal failure or transplantation
Nephrotic syndromes

3) HIV infection

4) Immunosuppression, including malignant neoplasm, especially:
Leukemia
Hodgkin's disease
Lymphoma

5) Sickle cell disease

6) Children with chronic disease: cardiovascular, pulmonary
(not asthma), diabetes mellitus, cirrhosis, or cerebrospinal
fluid leaks.


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SPECIAL TOPIC

Prevention of perinatal HBV infection

The Advisory Committee on Immunization Practices, American College of Obstetricians and Gynecologists, American Academy of Pediatrics, and US Preventive Services Task Force recommend screening of all pregnant women for HBsAg, optimally at an early prenatal visit. According to published calculations, screening all pregnant US women would detect about 22,000 HBsAg-positive women each year and prevent chronic HBV infection in 6000 neonates annually. (10) Women whose initial HBsAg test result is negative but who are at high risk for HBV infection (eg, women who use injection drugs, have been recently diagnosed with a sexually transmitted disease, have multiple sexual partners, or have had hepatitis during pregnancy) should be tested again for HBsAg late in pregnancy. Infants born to HBsAg-positive mothers should receive, at separate sites, both hepatitis B vaccine and 0.5 mL of hepatitis B immune globulin within 12 hours of birth.

SPECIAL TOPIC

Pertussis in adolescents and adults

Although adults and adolescents are the primary source of pertussis infection in young infants, (16) the morbidity rate from pertussis among older persons is low. No acellular vaccines have been licensed for use in persons 7 years of age or older, although is at least 2 such vaccines are being developed.

SPECIAL TOPIC

Hib and young immunized children

In the rare event that an immunized child develops Hib disease before the age of 24 months, a complete series of Hib vaccination should be started during the convalescent phase of the illness to help prevent subsequent episodes of Hib disease. Such children clearly do not have an adequate amount of protective antibody, and naturally acquired Hib disease does not reliably induce immunity in the very young.

SPECIAL TOPIC

Measles outbreaks, postexposure, prophylaxis, and treatment

Either the MMR or measles vaccine may be given for epidemic control as early as 6 months of age. However, this dose does not count as the first dose of vaccine; 2 additional doses of MMR vaccine must be given later, as routinely scheduled. Unvaccinated persons age 12 months and older who are exposed to measles should be given measles vaccine (usually as MMR)if it can be administered within 72 hours of exposure. Immunoglobulin, 0.25 mL/kg/dose (max 15 mL) given intramuscularly, may be utilized to control measles for exposed immunocompromised persons if given within 6 days of exposure. Vitamin A therapy reduces measles morbidity and mortality. (27)

If a patient receives antibody or blood products (including RhoGAM), a sufficient amount of time must be allowed prior to administration of MMR vaccine; otherwise the vaccine may not be effective. The amount and type of product will determine how much time (at least 3 months but no longer than 9 months, depending on the product)is required. (11,27)

SPECIAL TOPIC

Postexposure prophylaxis

Varicella vaccine is effective in preventing or modifying varicella if given within 3 days (and possibly up to 5 days) of exposure to wild varicella. (44,45) Varicella-zoster immune globulin (VZIG)is indicated for immunosuppressed patients who have been exposed to varicella. It also is indicated during early pregnancy for susceptible exposed mothers and for infants of mothers who develop chickenpox 5 days before to 2 days after delivery at 125 units/10 kg (max 625 units; min 125 units). Ideally, VZIG should be given intramuscularly within 96 hours of exposure.

SPECIAL TOPIC

New vaccines

Development of new vaccines against a number of diseases is progressing well. Vaccines that may be available later this decade include meningococcal conjugate vaccine, acellular pertussis vaccine for adolescents and adults, human papillomavirus vaccine, herpes zoster vaccine, and, for dialysis patients, Staphylococcus aureus vaccine.

RICHARD KENT ZIMMERMAN, MD, MPH; DONALD B. MIDDLETON, MD; ILENE TIMKO BURNS, MD, MPH; RICHARD D. CLOVER, MD; AND SANFORD R. KIMMEL, MD Pittsburgh, Pennsylvania; Louisville, Kentucky; and Toledo, Ohio

From the Department of Family Medicine and Clinical Epidemiology, School of Medicine (RKZ, DBM, ITB) and the Department of Behavioral and Community Health Sciences, Graduate School of Public Health (RKZ), University of Pittsburgh; Renaissance Family Practice (ITB); Department of Family and Community Medicine, University of Louisville School of Medicine (RDC); and the Department of Family Medicine, Medical College of Ohio (SRK). Address correspondence to Richard Kent Zimmerman, MD, MPH; Department of Family Medicine and Clinical Epidemiology; University of Pittsburgh School of Medicine; 3518 Fifth Ave; Pittsburgh, PA 15261; Phone: (412) 383-2354; Fax: (412) 383-2245; E-mail: zimmer+@pitt.edu.
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Title Annotation:Clinical Review
Author:Zimmerman, Richard Kent; Middleton, Donald B.; Burns, Ilene Timko; Clover, Richard D.; Kimmel, Sanfo
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Jan 1, 2005
Words:13667
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