Pediatric Annals

Pneumococcal Vaccines: Present and Future

Timothy R Peters, MD; Kathryn M Edwards, MD

Abstract

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…

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.

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.

Table

TABLEPneumococcal Conjugate Vaccines That Have Entered Clinical Trials*

TABLE

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.

Vaccine Safely

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.

Vaccine Immunogenlcity

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.

FUTURE DIRECTIONS

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.

CONCLUSIONS

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.

REFERENCES

1. Stansfield SK. Acute respiratory infections in the developing world: strategies for prevention, treatment and control. Pediatr Infect Dis }. 1987;6:622-629.

2. Novak R, Henriques B, Charpentier E, Normark S, Tuomanen E. Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature. 1999;399:590-593.

3. Henrichsen J. Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol. 1995;33:2759-2762.

4. Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy. JAMA. 1993;270:1826-1831.

5. Overturf GD, the Committee on Infectious Diseases. Technical report: prevention of pneumococcal infections, including the use of pneumococcal conjugate and polysaccharide vaccines and antibiotic prophylaxis. Pediatrics. 2000;106:367-376.

6. Committee on Infectious Diseases. Policy statement: recommendations for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (Prevnar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis. Pediatrics. 2000;106:362-366.

7. Koskela M, Leinonen M, Häivä V, Timonen M, Mäkelä PH. First and second dose antibody responses to pneumococcal polysaccharide vaccine in infants. Pediatr Infect Dis /. 1986;5:45-50.

8. O'Brien KL, Steinhoff MC, Edwards K, Keyserling H, Thorns ML, Madore D. Immunologic priming of young children by pneumococcal glycoprotein conjugate, but not polysaccharide vaccines. Pediatr Infect Dis }. 1996; 15:425-430.

9. Stein KE. Thymus-independent and thymus^dependent responses to polysaccharide antigens. / Infect Dis. 1992; 165(suppl 1):S49-S52.

10. Siber GR. Pneumococcal disease: prospects for a new generation of vaccines. Science. 1994;265:1385-1387.

11. Santosham M, Wolff M, Reid R, et al. The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influenzae type B polysaccharide and Neisseria meningitidis outer-membrane protein complex. N Engl ] Med. 1991;324:1767-1772.

12. Booy R, Moxon ER, MacFarlane JA, Mayon-White RT, Slack MPE. Efficacy of Haemophilus influenzae type B conjugate vaccine in Oxford region. Lancet. 1992;340:847. Letter.

13. Granoff DM, Holmes SJ, Osterholm MT, et al. Induction of immunologic memory in infants primed with Haemophilus influenzae type B conjugate vaccines. / Infect Dis. 1993;168:663-671.

14. Schuchat A, Robinson K, Wenger JD, et al. Bacterial meningitis in the United States in 1995. N Engl ) Med. 1997;337:970-976.

15. Anderson EL, Decker MD, Englund JA, et al. Interchangeability of conjugated Haemophilus influenzae type B vaccine in infants. JAMA. 1995;273:849-853.

16. Centers for Disease Control and Prevention. Achievements in public health, 1900-1999: impact of vaccines universally recommended for children- United States, 19901999. MMWR. 1999;48:243-248.

17. Butler JC, Breiman RF, Lipman HB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978-1994: implications for development of a conjugate vaccine. / Infect Dis. 1995;171:885-889.

18. Yu X, Gray B, Chang S, Ward JI, Edwards KM, Nahm MH. Immunity to cross-reactive serotypes induced by pneumococcal conjugate vaccines in infants. / Infect Dis. 1999;180:1569-1576.

19. Sniadack DH, Schwartz B, Lipman H, et al. Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children: implications for vaccine strategies. Pediatr Infect Dis J. 1995;14:503-510.

20. Steinhoff MC, Edwards K, Keyserling H, et al. A randomized comparison of three bivalent Streptococcus pneumoniae glycoprotein conjugate vaccines in young children: effect of polysaccharide size and linkage characteristics. Pediatr Infect Dis /. 1994;13:368-372.

21. Leach A, Ceesay SJ, Banya WAS, Greenwood BM. Pilot trial of a pentavalent pneumococcal polysaccharide /protein conjugate vaccine in Gambian infants. Pediatr Infect Dis J. 1996;15:333-339.

22. Käyhty H, Âhman H, Rönnberg P-R, Tillikainen R, Eskola J. Pneumococcal polysaccharide: meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children. / Infect Dis. 1995;172:1273-1278.

23. Anderson EL, Kennedy DJ, Geldmacher KM, Donnelly J, Mendelman PM. Immunogenicity of heptavalent pneumococcal conjugate vaccine in infants. J Pediatr. 1996;128:649-653.

24. Dagan R, Muallem M, Melamed R, Leroy O, Yagupsky P. Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Dis J. 1997;16:1060-1064.

25. Âhman H, Käyhty H, Lehtonen H, Leroy O, Froeschle J, Eskola J. Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory. Pediatr Infect Dis }. 1998;17:211-216.

26. Renneis MB, Edwards KM, Keyserling HL, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United States infants. Pediatrics. 1998;101:604-611.

27. Shinefield HR, Black S, Ray P, et al. Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers. Pediatr Infect Dis J. 1999; 18:757-763.

28. Eskola J, Anttila M. Pneumococcal conjugate vaccines. Pediatr Infect Dis }. 1999;18:543-551.

29. Yu X, Gray B, Chang S, Ward JI, Edwards KM, Nahm MH. Immunity to cross-reactive serotypes induced by pneumococcal conjugate vaccines in infants. J Infect Dis. 1999; 180:1569-1576.

30. Miernyk KM, Parkinson AJ, Rudolph KM, et al. Immunogenicity of a heptavalent pneumococcal conjugate vaccine in Apache and Navajo Indian, Alaska Native, and non-Native American children aged < 2 years. Clin Infect Dis. 2000;31:34-41.

31. Neiminen T, Käyhty H, Virolainen A, Eskola J. Circulating antibody secreting cell response to parenteral pneumococcal vaccines as an indicator of salivary IgA antibody response. Vaccine. 1998;16:313-319.

32. Choo S, Zhang Q, Seymour L, Akhtar S, Finn A. Primary and booster salivary antibody responses to a 7-valent pneumococcal conjugate vaccine in infants. / Infect Dis. 2000;182:1260-1263.

33. Dagan R, Melamed R, Muallem M, et al. Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. / Infect Dis. 1996;174:1271-1278.

34. Mbelle N, Huebner RE, Wasas AD, Kimura A, Chang I, Klugman KP. Immunogenicity and impact on nasopharyngeal carriage of a nonvalent pneumococcal conjugate vaccine. / Infect Dis. 1999;180:1171-1176.

35. Nowak-Wegrzyn A, Winkelstein JA, Swift AJ, Lederman HM, The Pneumococcal Conjugate Vaccine Study Group. Serum opsonic activity in infants with sickle-cell disease immunized with pneumococcal polysaccharide protein conjugate vaccine. Clin Diagn Lab Immunol. 2000;7:788793.

36. Davis CW, Mclntyre PB. Invasive pneumococcal infection in children, 1981-92: a hospital-based study. / Paediatr Child Health. 1995;31:317-322.

37. Stanek RJ, Mufson MA. A 20-year epidemiological study of pneumococcal meningitis. Clin Infect Dis. 1999;28:12651272.

38. Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187-195.

39. Shinefield H, Black S, Elvin L, Ray P, Lewis E, Fireman B. Impact of the introduction of pneumococcal conjugate vaccine on the epidemiology of invasive disease in children less than five years of age within Northern California Kaiser Permanente. Presented at the Annual Meeting of the Infectious Diseases Society of America; October 25-28, 2001; San Francisco, CA. Abstract 28.

40. Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1997;46(RR-08):l-24.

41. Dagan R, Sikuler-Cohen M, Zamir O, Janeo J, Givon-Lavi N, Fraser D. Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees. Pediatr Infect Dis ]. 2001;20:951-958.

42. Shappert SM. Office visits for otitis media: United States, 1975-90. Vital and Health Statistics of the Centers for Disease Control/National Center for Health Statistics. 1992;214:1-18.

43. Gates GA. Cost-effectiveness considerations in otitis media treatment. Otolaryngol Head Neck Surg. 1996; 114:525-530.

44. Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403-409.

45. Centers for Disease Control and Prevention. Preventing pneumococcal disease among infants and young children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2000;49(RR09):l-35.

46. O'Brien KL, Moulton L, Reid RR, et al. Invasive disease efficacy of a 7-valent pneumococcal conjugate vaccine among Navajo and White Mountain Apache children. Presented at the Pediatric Academic Societies Annual Meeting; April 28-May 1, 2001; Baltimore, MD. Abstract 1371.

47. Shinefield HR, Black SB, Lewis E, Hackell J, Malinoski F. Efficacy of seven valent pneumococcal conjugate vaccine in premature and low birth weight infants. Presented at the Pediatric Academic Societies Annual Meeting; April 28-May 1, 2001; Baltimore, MD. Abstract 1465.

48. Coffey TJ/ Enright MC, Daniels M, et al. Recombinational exchanges at the capsular polysaccharide biosynthetic locus lead to frequent serotype changes among natural isolates of Streptococcus pneumoniae. MoI Microbiol. 1998;27:73-83.

49. Wu H-Y, Nahm MH, Guo Y, Russell MW, Briles DE. Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage, pulmonary infection, and sepsis with Streptococcus pneumoniae. J Infect Dis. 1997;175:839-846.

50. McDaniel LS, Loechel F, Benedict C, et al. Immunization with a plasmid expressing pneumococcal surface protein A (PspA) can elicit protection against fatal infection with Streptococcus pneumoniae. Gene Ther. 1997;4:375-377.

51. Nabors GS, Braun PA, Herrmann DJ, et al. Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules. Vaccine. 2000;18:1743-1754.

TABLE

Pneumococcal Conjugate Vaccines That Have Entered Clinical Trials*

10.3928/0090-4481-20020401-10

Sign up to receive

Journal E-contents