The widespread prevention of disease by vaccination is among the greatest achievements of humankind. The ability to defend children against infectious diseases has followed aggressive immunization programs using effective vaccines. Underlying all of pediatric medicine is the conviction that it is better to prevent disease than to treat it, and it is this that compels us to create new vaccines and provide them to vulnerable children. The newest vaccine to be developed and licensed in the United States has proven effective in protecting infants from invasive pneumococcal disease.
Streptococcus pneumoniae is an extremely successful pathogen that kills more than 1 million children each year worldwide.1 Pneumococcal disease is prevalent, often difficult to promptly or reliably identify, and commonly severe. S. pneumoniae is responsible for numerous clinical syndromes and is a major cause of life-threatening pneumonia, bacteremia, meningitis, and acute otitis media. Pneumococcal antibiotic resistance is increasing such that approximately 25% of the invasive isolates obtained through active surveillance conducted by the Centers for Disease Control and Prevention are penicillin resistant. More than 75% of nasopharyngeal isolates from children living in some communities are penicillin resistant. S. pneumoniae strains that can survive in the presence of vancomycin have been isolated from clinical samples2 and it is feared that widespread vancomycin resistance will emerge. To counter these important problems, polysaccharide-protein conjugate vaccines have been developed for use in infants.
On February 17, 2000, the first of these pneumococcal vaccines was licensed in the United States and recommended for routine use in all infants by advisory committees. Approximately 20 million doses of the heptavalent pneumococcal conjugate vaccine have been distributed. The safety, immunogenicity, and efficacy data supporting the recommendations for widespread use of this vaccine in children are presented in this article, along with an update on the effectiveness of the vaccine in reducing invasive disease.
PNEUMOCOCCAL POLYSACCHARIDE VACCINES
Much of the pathogenicity of S. pneumoniae is attributed to its polysaccharide capsule, a defense against phagocytosis shared with other encapsulated bacteria. This defense is overcome when capsule-specific antibodies generated by the infected host bind to pneumococcal capsular polysaccharides, resulting in opsonin-dependent phagocytosis and clearance of the organism. Anti-pneumococcal capsular antibody and an active phagocytic mechanism allow for immunity to infection. The induction of an anti-pneumococcal antibody response can be achieved by injection of polysaccharide antigens, which was successfully employed in the development of the first licensed pneumococcal vaccines. This effort has been greatly complicated by the discovery that there are at least 90 distinct capsular pneumococcal serotypes.3 A polysaccharide vaccine providing coverage for each of these pneumococcal serotypes would have to include 90 or more distinct polysaccharides - effectively a combination of 90 different vaccines.
The observation that pneumococcal serotypes are not found equally distributed in disease isolates allowed investigators to develop a pneumococcal vaccine consisting of 14 purified capsular polysaccharide antigens responsible for 68% of invasive infections at that time. In 1977, this 14valent pneumococcal polysaccharide vaccine was licensed in the United States. This vaccine was improved by the addition of 9 more purified polysaccharide antigens to include pneumococcal serotypes causing more than 85% of invasive disease in the United States.
This reformulation resulted in the current 23valent pneumococcal capsular polysaccharide vaccine that was licensed in 1983. This vaccine has proven effective in the prevention of pneumococcal meningitis and bacteremia in children older than 5 years and adults.4 Retrospective studies demonstrate significant efficacy of this vaccine for prevention of invasive pneumococcal disease in children older than 2 years who have had a splenectomy.5 The use of the 23-valent pneumococcal polysaccharide vaccine has been recommended for patients older than 2 years who are at high risk for invasive pneumococcal disease.6
GENERAL PRINCIPLES OF THE POLYSACCHARIDEPROTEIN CONIUGATE VACCINES
The 23-valent capsular polysaccharide vaccine is not effective in children younger than 2 years - the group with the highest incidence of invasive pneumococcal infections.4,7'8 Antibody responses are not reliably induced by the capsular polysaccharides in this age group. The immune response occurs without T-cell involvement (T cell independent) that is necessary for high-level antibody production and the establishment of immunologic memory.9,10 The inability to respond to polysaccharide antigens observed in neonates and infants is poorly understood and is the subject of ongoing investigation.
Enhanced immune responses to bacterial polysaccharide antigens can be induced in young children if the polysaccharides are coupled to carrier proteins that can be processed and presented to T cells bearing receptors specific for the protein complex. The T cells exposed to polysaccharideprotein conjugates are able to promote vigorous antigen-specific B-cell proliferation and memory cell maturation.9'10 This concept of polysaccharide-protein conjugation has been successfully applied to the clinically important pathogen Haemophilus influenzae type b (Hib).11"14 Hib polysaccharide capsule antigen (polyribosylribitol phosphate, or PRP), similar to the pneumococcal polysaccharide antigens, fails to provoke a protective antibody response in vaccinated infants. This limitation was overcome by conjugating PRP to immunogenic proteins able to elicit T-cell immunity. Proteins used in licensed Hib vaccines include an outer membrane protein complex of Neisseria meningitidis, a mutant nontoxic diphtheria toxin (CRM197), diphtheria toxoid, and tetanus toxoid. Although each of these possess somewhat different immunologic properties, all evoke protective antibody and memory responses in vaccinated infants.15
The introduction of the Hib polysaccharideprotein conjugate vaccines for widespread use has represented an extraordinary medical advance. Prior to their introduction, an estimated 20,000 cases of invasive Hib disease occurred in the United States each year; now fewer than 100 cases are seen per year.16 The overwhelming effectiveness of the Hib conjugate vaccines offered great hope for the success of the pneumococcal conjugates. Prior to routine vaccination of all infants in the United States with the Hib conjugate vaccine, the organism caused a large burden of disease in children, comparable to the burden of pneumococcal disease (Figure).
THE PNEUMOCOCCAL POLYSACCHARIDE-PROTEIN CONIUGATE VACCINES
As noted, a substantial number of pneumococcal serotypes are clinically important, and these serotypes vary by geographic region. The development of a pneumococcal polysaccharide-protein conjugate vaccine has involved the creation of several serotype-specific vaccines used in combination, each consisting of selected capsular polysaccharides that are attached to an immunogenic carrier protein. As with the earlier polysaccharide vaccines, a restricted number of serotypes have been targeted for inclusion.
It is important to consider that significant cross-protection exists for some pneumococcal serotypes not included in a vaccine preparation due to antigenic similarity (eg, 6A and 6B). Careful analysis of epidemiologic data suggested that a conjugate vaccine directed against serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F could prevent 86% of bacteremia cases and 83% of meningitis cases in children younger than 6 years living in the United States.17,18 The currently licensed vaccine is composed of polysaccharideprotein conjugates directed against these 7 pneumococcal serotypes. The addition of serotypes 1, 3, 5, and 7F could broaden coverage to allow prevention of more than 90% of invasive infections in the United States and provide protection against serotypes more prevalent in developing countries.19 The effectiveness of any vaccination program directed against S. pneumoniae will require periodic reassessment based on ongoing surveillance of serotypes responsible for invasive pneumococcal disease.
Figure. Comparison of the incidence of Streptococcus pneumoniae and Haemophilus influenzae type B (Hib) invasive disease in the United States prior to the use of polysaccharideprotein conjugate vaccines against these organisms.
Pneumococcal Conjugate Vaccines That Have Entered Clinical Trials*
The proteins chosen for conjugation to pneumococcal polysaccharides have been those previously used in the production of the Hib conjugate vaccines: diphtheria and tetanus toxoids, the meningococcal outer membrane protein complex, and the diphtheria protein CRM197 (Table). The magnitude and kinetics of the immune responses to each of the polysaccharide conjugate vaccines varies with the serotype and proteins used in the conjugation process. The remainder of this article focuses on the licensed 7-valent pneumococcal conjugate vaccine conjugated to the mutant diphtheria protein CRM197.
More than 20,000 children have received pneumococcal conjugate vaccines with no severe systemic or life-threatening reactions reported.2027 Local reactions at the injection site of the licensed 7-valent pneumococcal polysaccharide-protein conjugate were found to be less than those seen with the combination diphtheria and tetanus toxoids and whole cell pertussis vaccine when these vaccines were given simultaneously at different sites.25
Approximately 20 million doses of the vaccine have been distributed since licensure. Data on vaccine safety continue to be collected through the Vaccine Adverse Events Reporting System (VAERS), established by the U.S. Department of Health and Human Services. All events severe enough to require the patient to seek medical attention that are temporally associated with the administration of any licensed vaccine should be reported to the VAERS (1-800-822-7967). At this time, as with the Hib conjugate vaccines, all available data suggest that pneumococcal conjugate vaccines are safe.
The immunogenicity of pneumococcal polysaccharide-protein conjugates in healthy, vaccinated infants has been clearly demonstrated.28 Most children studied have received the vaccine at 2, 4, 6, and 12 to 15 months of age. Statistically significant increases in polysaccharide-specific antibody titers were observed after vaccination to all serotypes studied. However, as mentioned earlier, the geometric mean titers of the capsular antibody responses differed among the various serotypes. In other studies, induction of immunologic memory was confirmed in children primed with the conjugate vaccine and boosted with the 23-valent polysaccharide vaccine 1 year later. Functional opsonophagocytic activity of vaccineinduced antibodies has also been demonstrated.2930 Additionally, anti-pneumococcal mucosal immunity is believed to result following vaccination based on the findings that specific mucosal IgA antibody responses are detected,31 salivary anticapsular antibody responses have been documented,32 and pneumococcal nasopharyngeal carriage rates are decreased in vaccinated subjects.24'3334
The effort to evaluate the immunogenicity of the pneumococcal polysaccharide-protein conjugate vaccines in children at high risk for invasive disease has been of special interest. Rates of invasive pneumococcal disease among the children of various Native American communities are much higher than those of non-Native American children. The serotype-specific antibody response to pneumococcal conjugate vaccine serotypes increased significantly in vaccinated infants of several Native American communities.30 Infants with sickle cell disease immunized with pneumococcal conjugate vaccine and boosted at 24 months with 23-valent polysaccharide vaccine have similarly been shown to generate anticapsular antibody and anti-pneumococcal opsonic activity.35
Efficacy for Prevention of Invasive Pneumococcal Disease In Healthy Children
The prevention of invasive pneumococcal disease, including meningitis and bacteremia, was a primary goal of pneumococcal vaccine development. S. pneumoniae causes more than 50% of cases of bacterial meningitis in the United States.14 More than 8% of children with pneumococcal meningitis die36,37 and survivors are often left with severe neurologic deficits and hearing loss. Pneumococcal bacteremia is an important cause of high fever in children younger than 36 months and can progress to meningitis and invasive disease.
Efficacy of the pneumococcal conjugate vaccine for the prevention of invasive pneumococcal disease was studied at Northern California Kaiser Permanente. In this trial, 37,830 infants were randomly assigned to either the 7-valent pneumococcal conjugate vaccine or the control vaccine, N. meningitidis serotype C capsular polysaccharideprotein conjugate. Children were defined as having invasive pneumococcal disease if they had an acute illness that was consistent with pneumococcal infection and was associated with isolation of S. pneumoniae from a normally sterile body fluid. Three children vaccinated with the 7-valent pneumococcal conjugate vaccine experienced invasive pneumococcal disease caused by serotypes included in the vaccine. In contrast, 49 children in the control group vaccinated with meningococcal conjugate vaccine suffered invasive disease caused by pneumococcal vaccine serotypes. These data yielded a vaccine efficacy of 94% (range, 80% to 99%) for prevention of invasive pneumococcal disease for vaccine serotypes.38 There were sufficient cases to evaluate the serotype-specific efficacy against 4 of the 7 vaccine serotypes. Point estimates for serotype specific efficacy ranged from 87% for serotype 19F to 100% for serotypes 14, 18C, and 23F.38
Recent data were presented from Northern California Kaiser Permanente on surveillance for invasive pneumococcal disease in more than 200,000 children younger than 5 years who have received the 7-valent pneumococcal conjugate vaccine since licensure. The vaccine appears to be highly effective in reducing the overall disease burden in children younger than 5 years, with no evidence of a compensatory increase in pneumococcal disease caused by non-vaccine serotypes.39
Efficacy for Prevention of Pneumonia in Healthy Children
S. pneumoniae causes an estimated 500,000 cases of pneumonia annually in the United States alone40 and is a major cause of childhood mortality from lower respiratory tract infections worldwide.1 The impact of vaccination on the incidence of pneumonia in young children was also evaluated in the Kaiser Permanente trial. When all children enrolled in the trial were evaluated, the pneumococcal vaccine group had fewer cases of pneumonia for all definitions of pneumonia compared with the control group.38 Vaccine efficacy was 11.4% (range, 1.3% to 21%) for the prevention of clinically diagnosed pneumonia, 33% (range, 7.5% to 52%) for the prevention of clinically diagnosed pneumonia for which an abnormality on chest radiograph was detected, and 73% (range, 38% to 88%) for the prevention of clinically diagnosed pneumonia in which a chest radiograph showed pulmonary consolidation greater than 2.5 cm.
In a recent study of children ages 12 to 35 months attending day care centers, it was reported that recipients of a pneumococcal conjugate vaccine showed reduced incidence of upper respiratory tract infections, lower respiratory tract problems, and otitis media.41 Additionally, reductions in illness correlated with reduced antibiotic use in vaccinated children. Characterization of the overall effect of the pneumococcal polysaccharide-protein conjugate vaccines on childhood respiratory disease and antibiotic use will be the focus of future studies.
Efficacy for Prevention of Otitis Media in Healthy Children
Given that S. pneumoniae is an important cause of otitis media, it is of great interest to learn what protection against this disease has resulted from widespread use of the pneumococcal protein conjugate vaccine. In the United States, acute otitis media results in more than 24 million office visits each year, with an estimated total annual cost of more than $5 billion.42·43 The prevention of even a small percentage of the 7 million U.S. cases of otitis media thought to be attributable to S. pneumoniae annually40 would represent a considerable cost savings and reduction in the burden of pediatric disease.
Two efficacy studies were completed to examine the prevention of otitis media. In one trial conducted in Finland in 1,662 infants, a 7-valent pneumococcal protein conjugate vaccine was administered at 2, 4, 6, and 12 months of age.44 Each infant diagnosed as having otitis media underwent tympanocentesis for specific bactériologie confirmation. The pneumococcal vaccine was found to be 34% (range, 21% to 45%) efficacious in preventing pneumococcal otitis media of all serotypes and 57% (range, 44% to 67%) efficacious in preventing otitis media caused by pneumococcal serotypes included in the vaccine. Vaccine efficacy in preventing any case of otitis media, irrespective of etiology, was 6% (range, -4% to 16%). The Kaiser Permanente study also investigated vaccine efficacy for the prevention of physician-diagnosed otitis media; tympanocentesis was not included in this trial. This vaccine's efficacy for preventing clinically diagnosed otitis media was found to be 6% (range, 3.9% to 8.7%).38 Even this modest reduction becomes significant when we consider that 6% of 7 million U.S. cases of acute otitis media is 420,000.
It is important to emphasize during a discussion of pneumococcal vaccination and otitis media that the basis for the recommendation for widespread use of the pneumococcal polysaccharide-protein conjugate vaccine was its efficacy against invasive pneumococcal disease. Evidence is accumulating that the pneumococcal conjugate vaccines will afford children some protection against otitis media, but the complete characterization of this protection awaits future studies.
Efficacy for Prevention of Invasive Pneumococcal Disease in Children at Increased Risk of Invasive Disease
The pneumococcal polysaccharide-protein conjugate vaccine is recommended for all children 24 to 59 months old who are at high risk for invasive disease caused by S. pneumoniae. In the United States, certain groups of Native American children, children with sickle cell disease or other types of functional or anatomic asplenia, or children who are infected with human immunodeficiency virus experience rates of S. pneumoniae infection of more than 150 per 100,000 cases per year. Also believed to be at increased risk are children with other immunodeficient states, including immunosuppressive therapy, chronic cardiac or pulmonary disease, chronic renal disease (including nephrotic syndrome), and diabetes mellitus,6,45 as well as premature and low-birthweight infants. The efficacy of the pneumococcal polysaccharide-protein conjugate vaccine for the prevention of invasive vaccine serotype disease among Navajo and White Mountain Apache children was found to be 86.4% (range, 40.3% to 96.9%) in a study of 8,292 children during a 2year period.46 An examination of the efficacy of the vaccine for invasive pneumococcal disease among 4,314 premature and 1,762 low-birthweight infants revealed that all cases of invasive pneumococcal disease were seen in unvaccinated control patients, yielding a calculated efficacy of 100%.47
Additional clinical trials are planned that will assess the efficacy of pneumococcal conjugate vaccines in preventing disease in immunocompromised persons and the elderly. There is optimism that the impact of the pneumococcal polysaccharide-protein conjugate vaccines on the care of children at increased risk for invasive disease will be substantial. How this vaccine program will influence standing recommendations for antimicrobial pneumococcal prophylaxis in highrisk children is unclear, but studies designed to answer these important questions are ongoing.
The ability of S. pneumoniae to alter capsular polysaccharide expression by recombination48 has strengthened interest in vaccines directed against pneumococcal proteins.49,50 Immunization with pneumococcal noncapsular antigens, such as pneumococcal surface protein A and others, might induce protection against all serotypes of the pneumococcus. The use of such a vaccine either instead of or as a complement to a polysaccharide-based vaccine could potentially improve protection against pneumococcal serotypes more broadly. These vaccines are being evaluated.51 Surveillance of clinical pneumococcal isolates through the coming years will provide direction for improvement of pneumococcal vaccines. Additionally, data from long-term studies will guide decisions about the necessity and timing of booster vaccinations.
S. pneumoniae is the most common cause of invasive bacterial disease in children. The pneumococcal polysaccharide-protein conjugate vaccines significantly reduce disease caused by S. pneumoniae and represent a major advance in the prevention of life-threatening childhood disease.
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Pneumococcal Conjugate Vaccines That Have Entered Clinical Trials*