Chapter 24 : Pneumococcal Vaccines

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This chapter provides a summary of issues critical to the development and application of pneumococcal vaccines. In the preantibiotic era, vaccination attempts utilized whole killed pneumococci injected parenterally. Although such vaccines were sometimes protective in humans, they were also highly reactogenic. These killed vaccines were mainly used to elicit antibody in animals for passive treatment of infected humans. In 1933 it was clearly demonstrated that antibody to type-specific capsular polysaccharides (PS) could be highly protective. However, it soon became apparent that different strains of each expressed one of many different PS. Most subsequent vaccine attempts focused on the use of mixtures of the isolated PSs to elicit protection. However, the inability of young children to make adequate responses to most soluble PS led to the development and licensing of an immunogenic PS-protein conjugate vaccine for children. The problem of poor vaccine immunogenicity in children is being addressed by conjugation of the PS to protein carriers, thereby converting the PS from T-cell-independent to T-cell-dependent antigens. These antigens include the pneumococcal surface protein PspA; autolysin (lytA), an enzyme on the pneumococcal cell wall; and pneumolysin, a cytoplasmic protein that is released when pneumococci are autolyzed.

Citation: Briles D, Paton J, Swiatlo E, Crain M. 2006. Pneumococcal Vaccines, p 289-298. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch24
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1. Ahman, H.,, H. Kayhty,, H. Lehtonen,, O. Leroy,, J. Froeschle,, and J. Eskola. 1998. Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory. Pediatr. Infect. Dis. J. 17: 211 216.
2. Alexander, J. E.,, A. M. Berry,, J. C. Paton,, J. B. Rubins,, P. W. Andrew,, and T. J. Mitchell. 1998. Amino acid changes affecting the activity of pneumolysin alter the behavior of pneumococci in pneumonia. Microb. Pathog. 24: 167 174.
3. Alexander, J. E.,, R. A. Lock,, C. C. A. M. Peeters,, J. T. Poolman,, P. W. Andrew,, T. J. Mitchell,, D. Hansman,, and J. C. Paton. 1994. Immunization of mice with pneumolysin toxoid confers a significant degree of protection against at least nine serotypes of Streptococcus pneumoniae. Infect. Immun. 62: 5683 5688.
4.Anonymous. 1999. Pneumococcal vaccines. WHO position paper. Wkly. Epidemiol. Rec. 74: 177183.
5. Austrian, R.,, and J. Gold. 1964. Pneumococcal bacteremia with special reference to bacteremic pneumococcal pneumonia. Ann. Intern. Med. 60: 759 776.
6. Avery, O. T.,, and W. F. Goebel. 1933. Chemoimmunological studies of the soluble specific substance of pneumococcus. I. The isolation and properties of the acetyl polysaccharide of pneumococcus type I. J. Exp. Med. 58: 731 755.
7. Balachandran, P.,, A. Brooks-Walter,, A. Virolainen-Julkunen,, S. K. Hollingshead,, and D. E. Briles. 2002. The role of pneumococcal surface protein C (PspC) in nasopharyngeal carriage and pneumonia and its ability to elicit protection against carriage of Streptococcus pneumoniae. Infect. Immun. 70: 2526 2534.
8. Barbour, M. L.,, R. T. Mayon-White,, C. Coles,, D. W. Crook,, and E. R. Moxon. 1995. The impact of conjugate vaccine on carriage of Haemophilus influenzae type b. J. Infect. Dis. 171: 93 98.
9. Benton, K.,, and D. E. Briles. 1994. Pneumolysin facilitates pneumococcal sepsis by interfering with an antipneumococcal inflammatory response, p. 104. Abstr. 94th Annu. Meet. Am. Soc. Microbiol. 1994. American Society for Microbiology, Washington, D.C.
10. Benton, K. A.,, J. C. Paton,, and D. E. Briles. 1997. The hemolytic and complement-activating properties of pneumolysin do not contribute individually to virulence in a pneumococcal bacteremia model. Microb. Pathog. 23: 201 209.
11. Berry, A. M.,, and J. Paton,, C. 2000. Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins. Infect. Immun. 68: 133 140.
12. Berry, A. M.,, and J. C. Paton. 1996. Sequence heterogeneity of PsaA, a 37-kilodalton putative adhesin essential for virulence of Streptococcus pneumoniae. Infect. Immun. 64: 5255 5262.
13. Berry, A. M.,, J. C. Paton,, and D. Hansman. 1992. Effect of insertional inactivation of the genes encoding pneumolysin and autolysin on the virulence of Streptococcus pneumoniae type 3. Microb. Pathog. 12: 87 93.
14. Berry, A. M.,, J. Yother,, D. E. Briles,, D. Hansman,, and J. C. Paton. 1989. Reduced virulence of a defined pneumolysin-negative mutant of Streptococcus pneumoniae. Infect. Immun. 57: 2037 2042.
15. Binder, C. J.,, S. Horkko,, A. Dewan,, M. K. Chang,, E. P. Kieu,, C. S. Goodyear,, P. X. Shaw,, W. Palinski,, J. L. Witztum,, and G. J. Silverman. 2003. Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat. Med. 9: 736 743.
16. Black, S.,, H. Shinefield,, R. Cohen,, D. Floret,, J. Gaudelus,, C. Olivier,, and P. Reinert. 2004. Clinical effectiveness of seven-valent pneumococcal conjugate vaccine (Prevenar) against invasive pneumococcal diseases: prospects for children in France. Arch. Pediatr. 11: 843 853.
17. Black, S.,, H. Shinefield,, B. Fireman,, E. Lewis,, P. Ray,, J. R. Hansen,, L. Elvin,, K. M. Ensor,, J. Hackell,, G. Siber,, F. Malinoski,, D. Madore,, I. Chang,, R. Kohberger,, W. Watson,, R. Austrian,, and K. Edwards. 2000. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Northern California Kaiser Permanente Vaccine Study Center Group. Pediatr. Infect. Dis. J. 19: 187 195.
18. Black, S. B.,, H. R. Shinefield,, S. Ling,, J. Hansen,, B. Fireman,, D. Spring,, J. Noyes,, E. Lewis,, P. Ray,, J. Lee,, and J. Hackell. 2002. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia. Pediatr. Infect. Dis. J. 21: 810 815.
19. Block, S. L.,, J. Hedrick,, C. J. Harrison,, R. Tyler,, A. Smith,, R. Findlay,, and E. Keegan. 2004. Communitywide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr. Infect. Dis. J. 23: 829 833.
20. Bogaert, D.,, R. De Groot,, and P. W. Hermans. 2004. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect. Dis. 4: 144 154.
21. Bogaert, D.,, A. van Belkum,, M. Sluijter,, A. Luijendijk,, R. de Groot,, H. C. Rumke,, H. A. Verbrugh,, and P. W. Hermans. 2004. Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet 363: 1871 1872.
22. Boulnois, G. J.,, J. C. Paton,, T. J. Mitchell,, and P. W. Andrew. 1991. Structure and function of pneumolysin, the multifunctional, thiol-activated toxin of Streptococcus pneumoniae. Mol. Microbiol. 5: 2611 2616.
23. Brandileone, M. C.,, A. L. Andrade,, E. M. Teles,, R. C. Zanella,, T. I. Yara,, J. L. Di Fabio,, and S. K. Hollingshead. 2004. Typing of pneumococcal surface protein A (PspA) in Streptococcus pneumoniae isolated during epidemiological surveillance in Brazil: towards novel pneumococcal protein vaccines. Vaccine 22: 3890 3896.
24. Briese, T.,, and R. Hakenbeck. 1985. Interaction of the pneumococcal amidase with lipoteichoic acid and choline. Eur. J. Biochem. 146: 417 427.
25. Briles, D. E.,, E. Ades,, J. C. Paton,, J. S. Sampson,, G. M. Carlone,, R. C. Huebner,, A. Virolainen,, E. Swiatlo,, and S. K. Hollingshead. 2000. Intranasal immunization of mice with a mixture of the pneumococcal proteins PsaA and PspA is highly protective against nasopharyngeal carriage of Streptococcus pneumoniae. Infect. Immun. 68: 796 800.
26. Briles, D. E.,, C. Forman,, J. C. Horowitz,, J. E. Volanakis,, W. H. Benjamin, Jr.,, L. S. McDaniel,, J. Eldridge,, and J. Brooks. 1989. Antipneumococcal effects of C-reactive protein and monoclonal antibodies to pneumococcal cell wall and capsular antigens. Infect. Immun. 57: 1457 1464.
27. Briles, D. E.,, S. K. Hollingshead,, J. King,, A. Swift,, P. A. Braun,, M. K. Park,, L. M. Ferguson,, M. H. Nahm,, and G. S. Nabors. 2000. Immunization of humans with rPspA elicits antibodies, which passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA. J. Infect. Dis. 182: 1694 1701.
28. Briles, D. E.,, S. K. Hollingshead,, J. C. Paton,, E. W. Ades,, L. Novak,, F. W. van Ginkel,, and W. H. J. Benjamin. 2003. Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae. J. Infect. Dis. 188: 339 348.
29. Briles, D. E.,, S. K. Hollingshead,, E. Swiatlo,, A. Brooks-Walter,, A. Szalai,, A. Virolainen,, L. S. McDaniel,, K. A. Benton,, P. White,, K. Prellner,, A. Hermansson,, P. C. Aerts,, H. Van Dijk,, and M. J. Crain. 1997. PspA and PspC: their potential for use as pneumococcal vaccines. Microb. Drug Resist. 3: 401 408.
30. Briles, D. E.,, G. S. Nabors,, A. Brooks-Walter,, J. Paton,, C., and S. Hollingshead. 2001. The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumoniae. Vaccine 19: S87 S95.
31. Briles, D. E.,, M. Nahm,, K. Schroer,, J. Davie,, P. Baker,, J. Kearney,, and R. Barletta. 1981. Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 Streptococcus pneumoniae. J. Exp. Med. 153: 694 705.
32. Briles, D. E.,, J. C. Paton,, and S. K. Hollingshead,. 2004. Pneumococcal common proteins and other vaccine strategies, p. 459 469. In M. M. Levine,, J. B. Kaper,, R. Rappuoli,, M. Liu,, and M. F. Good (ed.), New Generation Vaccines, 3rd ed. Marcel Dekker, Inc., New York, N.Y.
33. Briles, D. E.,, J. C. Paton,, M. H. Nahm,, and E. Swiatlo,. 2000. Immunity to Streptococcus pneumoniae, p. 263 280. In M. Cunningham, and R. S. Fujinami (ed.), Effect of Microbes on the Immune System. Lippincott-Raven, Philadelphia, Pa.
34. Brooks-Walter, A.,, D. E. Briles,, and S. K. Hollingshead. 1999. The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia. Infect. Immun. 67: 6533 6542.
35. Buchanan, R. M.,, D. E. Briles,, B. P. Arulanandam,, M. A. Westerink,, R. H. Raeder,, and D. W. Metzger. 2001. IL-12-mediated increases in protection elicited by pneumococcal and meningococcal conjugate vaccines. Vaccine 19: 2020 2028.
36. Butler, J. C., 2004. Epidemiology of pneumococcal disease, p. 148 168. In E. I. Tuomanen (ed.), The Pneumococcus. ASM Press, Washington, D.C.
37. Butler, J. C.,, R. F. Breiman,, J. F. Campbell,, H. B. Lipman,, C. V. Broome,, and R. R. Facklam. 1993. Pneumococcal polysaccharide vaccine efficacy. An evaluation of current recommendations. JAMA 270: 1826 1831.
38. Canvin, J. R.,, A. P. Marvin,, M. Sivakumaran,, J. C. Paton,, G. J. Boulonois,, P. W. Andrew,, and T. J. Mitchell. 1995. The role of pneumolysin and autolysin in the pathology of pneumoniae and septicemia in mice infected with a type 2 pneumococcus. J. Infect. Dis. 172: 119 123.
39. Chiavolini, D.,, G. Memmi,, T. Maggi,, F. Iannelli,, G. Pozzi,, and M. R. Oggioni. 2003. The three extra-cellular zinc metalloproteinases of Streptococcus pneumoniae have a different impact on virulence in mice. BMC Microbiol. 3: 14.
40. Coral, M. C. V.,, N. Fonseca,, E. Castaneda,, J. L. Di Fabio,, S. K. Hollingshead,, and D. E. Briles. 2001. Families of pneumococcal surface protein A (PspA) of Streptococcus pneumoniae invasive isolates recovered from Colombian children. Emerg. Infect. Dis. 7: 832 836.
41. Cornu, C.,, D. Yzebe,, P. Leophonte,, J. Gaillat,, J. P. Boissel,, and M. Cucherat. 2001. Efficacy of pneumococcal polysaccharide vaccine in immunocompetent adults: a meta-analysis of randomized trials. Vaccine 19: 4780 4790.
42. Crain, M. J.,, W. D. Waltman,, J. S. Turner,, J. Yother,, D. E. Talkington,, L. M. McDaniel,, B. M. Gray,, and D. E. Briles. 1990. Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae. Infect. Immun. 58: 3293 3299.
43. Dagan, R.,, R. Melamed,, M. Muallem,, L. Piglansky,, D. Greenburg,, O. Abramson,, P. M. Mendalman,, N. Bohidar,, and P. Yagupsky. 1996. Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine. J. Infect. Dis. 174: 1271 1278.
44. Dullforce, P.,, D. C. Sutton,, and A. W. Heath. 1998. Enhancement of T cell-independent immune responses in vivo by CD40 antibodies. Nat. Med. 4: 88 91.
45. Eskola, J.,, S. Black,, and H. Shinefield,. 2004. Pneumococcal conjugate vaccines, p. 589. In S. A. Plotkin, and W. A. Orenstein (ed.), Vaccines. W. B. Saunders, Philadelphia, Pa.
46. Eskola, J.,, T. Kilpi,, A. Palmu,, J. Jokinen,, J. Haapakoski,, E. Herva,, A. Takala,, H. Kayhty,, P. Karma,, R. Kohberger,, G. Siber,, and P. H. Makela. 2001. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N. Engl. J. Med. 344: 403 409.
47. Eskola, J.,, A. K. Takala,, and H. Kayhty. 1993. Haemophilus influenzae type b polysaccharide-protein conjugate vaccines in children. Curr. Opin. Pediatr. 5: 55 59.
48. Esposito, S.,, R. Droghetti,, N. Faelli,, A. Lastrico,, C. Tagliabue,, L. Cesati,, C. Bianchi,, and N. Principi. 2003. Serum concentrations of pneumococcal anticapsular antibodies in children with pneumonia associated with Streptococcus pneumonia infection. Clin. Infect. Dis. 37: 1261 1264.
49. Fedson, D. S.,, J. Anthony,, and G. Scott. 1999. The burden of pneumococcal disease among adults in developed and developing countries: what is and is not known. Vaccine 17(Suppl.)1: S11 S18.
50. Fedson, D. S.,, and D. M. Musher,. 2004. Pneumococcal polysaccharide vaccine, p. 529 588. In S. A. Plotkin, and W. A. Orenstein (ed.), Vaccines. W. B. Saunders, Philadelphia, Pa.
51. Fedson, D. S.,, E. D. Shapiro,, F. M. LaForce,, M. A. Mufson,, D. M. Musher,, J. S. Spika,, R. F. Breiman,, and C. V. Broome. 1994. Pneumococcal vaccine after 15 years of use. Another view. Arch. Intern. Med. 154: 2531 2535.
52. Garcia-Suarez Mdel, M.,, M. D. Cima-Cabal,, N. Florez,, P. Garcia,, R. Cernuda-Cernuda,, A. Astudillo,, F. Vazquez,, J. R. De los Toyos,, and F. J. Mendez. 2004. Protection against pneumococcal pneumonia in mice by monoclonal antibodies to pneumolysin. Infect. Immun. 72: 4534 4540.
53. Ghaffar, F.,, T. Barton,, J. Lozano,, L. S. Muniz,, P. Hicks,, V. Gan,, N. Ahmad,, and G. H. McCracken, Jr. 2004. Effect of the 7-valent pneumococcal conjugate vaccine on nasopharyngeal colonization by Streptococcus pneumoniae in the first 2 years of life. Clin. Infect. Dis. 39: 930 938.
54. Goldenberg, H. B.,, T. L. McCool,, and J. N. Weiser. 2004. Cross-reactivity of human immunoglobulin G2 recognizing phosphorylcholine and evidence for protection against major bacterial pathogens of the human respiratory tract. J. Infect. Dis. 190: 1254 1263.
55. Gor, D. O.,, D. Xuedong,, D. E. Briles,, M. R. Jacobs,, and N. S. Greenspan. Relationship between surface accessibility for PpmA, PsaA, PspA and antibody mediated immunity to systemic infection by Streptococcus pneumoniae. Infect. Immun., in press.
56. Gray, B. M.,, G. M. Converse III,, and H. C. Dillon. 1979. Serotypes of Streptococcus pneumoniae causing disease. J. Infect. Dis. 140: 979 983.
57. Hamel, J.,, N. Charland,, I. Pineau,, C. Ouellet,, S. Rioux,, D. Martin,, and B. R. Brodeur. 2004. Prevention of pneumococcal disease in mice immunized with conserved surface-accessible proteins. Infect. Immun. 72: 2659 2670.
58. Hammerschmidt, S.,, S. R. Talay,, P. Brandtzaeg,, and G. S. Chhatwal. 1997. SpsA, a novel pneumococcal surface protein with specific binding to secretory immunoglobulin A and secretory component. Mol. Microbiol. 25: 1113 1124.
59. Hava, D. L.,, and A. Camilli. 2002. Large-scale identification of serotype 4 Streptococcus pneumoniae virulence factors. Mol. Microbiol. 45: 1389 1406.
60. Heffron, R. 1939. Pneumonia. The Commonwealth Fund, New York, N.Y.
61. Henrichsen, J. 1995. Six newly recognized types of Streptococcus pneumoniae. J. Clin. Microbiol. 33: 2759 2762.
62. Hollingshead, S. K.,, R. S. Becker,, and D. E. Briles. 2000. Diversity of PspA: mosaic genes and evidence for past recombination in Streptococcus pneumoniae. Infect. Immun. 68: 5889 5900.
63. Huo, Z.,, O. Spencer,, J. Miles,, J. Johnson,, R. Holliman,, J. Sheldon,, and P. Riches. 2004. Antibody response to pneumolysin and to pneumococcal capsular polysaccharide in healthy individuals and Streptococcus pneumoniae infected patients. Vaccine 22: 1157 1161.
64. Iannelli, F.,, D. Chiavolini,, S. Ricci,, M. R. Oggioni,, and G. Pozzi. 2004. Pneumococcal surface protein C contributes to sepsis caused by Streptococcus pneumoniae in mice. Infect. Immun. 72: 3077 3080.
65. Iannelli, F.,, M. R. Oggioni,, and G. Pozzi. 2002. Allelic variation in the highly polymorphic locus pspC of Streptococcus pneumoniae. Gene 284: 63 71.
66. Janulczyk, R.,, F. Iannelli,, A. G. Sjoholm,, G. Pozzi,, and L. Bjorck. 2000. Hic, a novel surface protein of Streptococcus pneumoniae that interferes with complement function. J. Biol. Chem. 275: 37257 37263.
67. Johnston, J. W.,, L. E. Myers,, M. M. Ochs,, W. H. Benjamin, Jr.,, D. E. Briles,, and S. K. Hollingshead. 2004. Lipoprotein PsaA in virulence of Streptococcus pneumoniae: surface accessibility and role in protection from superoxide. Infect. Immun. 72: 5858 5867.
68. Kadioglu, A.,, W. Coward,, M. J. Colston,, C. R. Hewitt,, and P. W. Andrew. 2004. CD4-T-lymphocyte interactions with pneumolysin and pneumococci suggest a crucial protective role in the host response to pneumococcal infection. Infect. Immun. 72: 2689 2697.
69. Kaplan, S. L.,, and E. O. Mason, Jr. 2002. Mechanisms of pneumococcal antibiotic resistance and treatment of pneumococcal infections in 2002. Pediatr. Ann. 31: 250 260.
70. Kenny, J. J.,, G. Guelde,, R. T. Fisher,, and D. L. Longo. 1994. Induction of phosphocholine-specific antibodies in X-linked immune deficient mice: in vivo protection against a Streptococcus pneumoniae challenge. Int. Immunol. 6: 561 568.
71. Kuo, J.,, M. Douglas,, H. K. Ree,, and A. A. Lindberg. 1995. Characterization of a recombinant pneumolysin and its use as a protein carrier for pneumococcal type 18C conjugate vaccine. Infect. Immun. 63: 2706 2713.
72. Lee, C.-J.,, R. A. Lock,, P. W. Andrew,, T. J. Mitchell,, D. Hansman,, and J. C. Paton. 1994. Protection in infant mice from challenge with Streptococcus pneumoniae type 19F by immunization with a type 19F polysaccharidepneumolysoid conjugate. Vaccine 12: 875 877.
73. Lock, R. A.,, D. Hansman,, and J. C. Paton. 1992. Comparative efficacy of autolysin and pneumolysin as immunogens protecting mice against infection by Streptococcus pneumoniae. Microb. Pathog. 12: 137 143.
74. Lock, R. A.,, Q. Q. Zhang,, A. M. Berry,, and J. C. Paton. 1996. Sequence variation in the Streptococcus pneumoniae pneumolysin gene affecting haemolytic activity and electrophoretic mobility of the toxin. Microb. Pathog. 21: 71 83.
75. Long, J. P.,, H. H. Tong,, and T. F. DeMaria. 2004. Immunization with native or recombinant Streptococcus pneumoniae neuraminidase affords protection in the chinchilla otitis media model. Infect. Immun. 72: 4309 4313.
76. Lopez, R.,, and E. Garcia. 2004. Recent trends on the molecular biology of pneumococcal capsules, lytic enzymes, and bacteriophage. FEMS Microbiol. Rev. 28: 553 580.
77. Malley, R.,, P. Henneke,, S. C. Morse,, M. J. Cieslewicz,, M. Lipsitch,, C. M. Thompson,, E. Kurt-Jones,, J. C. Paton,, M. R. Wessels,, and D. T. Golenbock. 2003. Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc. Natl. Acad. Sci. USA 100: 1966 1971.
78. Mbelle, N.,, R. E. Huebner,, A. D. Wasas,, A. Kimura,, I. Chang,, and K. P. Klugman. 1999. Immunogenicity and impact on nasopharyngeal carriage of a nonavalent pneumococcal conjugate vaccine. J. Infect. Dis. 180: 1171 1176.
79. McCormick, A. W.,, C. G. Whitney,, M. M. Farley,, R. Lynfield,, L. H. Harrison,, N. M. Bennett,, W. Schaffner,, A. Reingold,, J. Hadler,, P. Cieslak,, M. H. Samore,, and M. Lipsitch. 2003. Geographic diversity and temporal trends of antimicrobial resistance in Streptococcus pneumoniae in the United States. Nat. Med. 9: 424 430.
80. McDaniel, L. S.,, W. H. Benjamin, Jr.,, C. Forman,, and D. E. Briles. 1984. Blood clearance by anti-phosphocholine antibodies as a mechanism of protection in experimental pneumococcal bacteremia. J. Immunol. 133: 3308 3312.
81. McDaniel, L. S.,, D. O. McDaniel,, S. K. Hollingshead,, and D. E. Briles. 1998. Comparison of the PspA sequence from Streptococcus pneumoniae EF5668 to the previously identified PspA sequence from strain Rx1 and ability of PspA from EF5668 to elicit protection against pneumococci of different capsular types. Infect. Immun. 66: 4748 4754.
82. McDaniel, L. S.,, B. A. Ralph,, D. O. McDaniel,, and D. E. Briles. 1994. Localization of protection-eliciting epitopes on PspA of Streptococcus pneumoniae between amino acid residues 192 and 260. Microb. Pathog. 17: 323 337.
83. McDaniel, L. S.,, J. S. Sheffield,, E. Swiatlo,, J. Yother,, M. J. Crain,, and D. E. Briles. 1992. Molecular localization of variable and conserved regions of pspA, and identification of additional pspA homologous sequences in Streptococcus pneumoniae. Microb. Pathog. 13: 261 269.
84. McDaniel, L. S.,, J. Yother,, M. Vijayakumar,, L. McGarry,, W. R. Guild,, and D. E. Briles. 1987. Use of insertional inactivation to facilitate studies of biological properties of pneumococcal surface protein A (PspA). J. Exp. Med. 165: 381 394.
85. Michon, F.,, P. C. Fusco,, C. A. S. A. Minetti,, M. Laude-Sharp,, S. Moore,, D. P. Remeta,, I. Heron,, and M. S. Blake. 1998. Multivalent pneumococcal capsular polysaccharide conjugate vaccines employing genetically detoxified pneumolysin as a carrier protein. Vaccine 16: 1732 1741.
86. Mirza, S.,, S. K. Hollingshead,, J. H. Williams, Jr.,, and D. E. Briles. 2004. PspA protects Streptococcus pneumoniae from killing by apolactoferrin and antibody to PspA enhances killing of pneumococci by apolactoferrin. Infect. Immun. 72: 5031 5040.
87. Mitchell, T. J.,, P. W. Andrew,, F. K. Saunders,, A. N. Smith,, and G. J. Boulnois. 1991. Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute-phase protein. Mol. Microbiol. 5: 1883 1888.
88. Mitchell, T. J.,, F. Mendez,, J. C. Paton,, P. W. Andrew,, and G. J. Boulnois. 1990. Comparison of pneumolysin genes and proteins from Streptococcus pneumoniae types 1 and 2. Nucleic Acids Res. 18: 4010.
89. Musher, D. M.,, H. M. Phan,, and R. E. Baughn. 2001. Protection against bacteremic pneumococcal infection by antibody to pneumolysin. J. Infect. Dis. 183: 827 830.
90. Nabors, G. S.,, P. A. Braun,, D. J. Herrmann,, M. L. Heise,, D. J. Pyle,, S. Gravenstein,, M. Schilling,, L. M. Ferguson,, S. K. Hollingshead,, D. E. Briles,, and R. S. Becker. 2000. Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies. Vaccine 18: 1743 1754.
91. Nieminen, T.,, J. Eskola,, and H. Kayhty. 1998. Pneumococcal conjugate vaccination in adults: circulating antibody secreting cell response and humoral antibody responses in saliva and in serum. Vaccine 16: 630 636.
92. Oggioni, M. R.,, G. Memmi,, T. Maggi,, D. Chiavolini,, F. Iannelli,, and G. Pozzi. 2003. Pneumococcal zinc metalloproteinase ZmpC cleaves human matrix metalloproteinase 9 and is a virulence factor in experimental pneumonia. Mol. Microbiol. 49: 795 805.
93. Ogunniyi, A. D.,, R. L. Folland,, D. B. Briles,, S. K. Hollingshead,, and J. C. Paton. 2000. Immunization of mice with combinations of pneumococcal virulence proteins elicits enhanced protection against challenge with Streptococcus pneumoniae. Infect. Immun. 68: 3028 3033.
94. Overturf, G. D. 2002. Pneumococcal vaccination of children. Semin. Pediatr. Infect. Dis. 13: 155 164.
95. Overweg, K.,, A. Kerr,, M. Sluijter,, M. H. Jackson,, T. J. Mitchell,, A. P. de Jong,, R. de Groot,, and P. W. Hermans. 2000. The putative proteinase maturation protein A of Streptococcus pneumoniae is a conserved surface protein with potential to elicit protective immune responses. Infect. Immun. 68: 4180 4188.
96. Overweg, K.,, C. D. Pericone,, G. G. C. Verhoef,, G. N. Weiser,, H. D. Meiring,, A. P. J. M. De Jong,, R. De Groot,, and P. W. M. Hermans. 2000. Differential protein expression in phenotypic variants of Streptococcus penumoniae. Infect. Immun. 68: 4604 4610.
97. Paton, J. C. 1996. The contribution of pneumolysin to the pathogenicity of Streptococcus pneumoniae. Trends Microbiol. 4: 103 106.
98. Paton, J. C.,, P. W. Andrew,, G. J. Boulnois,, and T. J. Mitchell. 1993. Molecular analysis of the pathogenicity of Streptococcus pneumoniae: the role of pneumococcal proteins. Annu. Rev. Microbiol. 47: 89 115.
99. Paton, J. C.,, A. M. Berry,, and R. A. Lock. 1997. Molecular analysis of putative pneumococcal virulence proteins. Microb. Drug. Resist. 3: 3 10.
100. Paton, J. C.,, R. A. Lock,, and D. C. Hansman. 1983. Effect of immunization with pneumolysin on survival time of mice challenged with Streptococcus pneumoniae. Infect. Immun. 40: 548 552.
101. Paton, J. C.,, R. A. Lock,, C.-J. Lee,, J. P. Li,, A. M. Berry,, T. J. Mitchell,, P. W. Andrew,, D. Hansman,, and G. J. Bulnois. 1991. Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide. Infect. Immun. 59: 2297 2304.
102. Paton, J. C.,, B. Rowan-Kelly,, and A. Ferrante. 1984. Activation of human complement by the pneumococcal toxin pneumolysin. Infect. Immun. 43: 1085 1087.
103. Powers, D. C.,, E. L. Anderson,, K. Lottenbach,, and C. M. Mink. 1996. Reactogenicity and immunogenicity of a protein-conjugated pneumococcal oligosaccharide vaccine in older adults. J. Infect. Dis. 173: 1014 1018.
104. Rapola, S.,, V. Jantti,, R. Haikala,, R. Syrjanen,, G. M. Carlone,, J. S. Sampson,, D. E. Briles,, J. C. Paton,, A. K. Takala,, T. M. Kilpi,, and H. Kayhty. 2000. Natural development of antibodies to pneumococcal surface protein A, pneumococcal surface adhesin A, and pneumolysin in relation to pneumococcal carriage and acute otitis media. J. Infect. Dis. 182: 1146 1152.
105. Regev-Yochay, G.,, R. Dagan,, M. Raz,, Y. Carmeli,, B. Shainberg,, E. Derazne,, G. Rahav,, and E. Rubinstein. 2004. Association between carriage of Streptococcus pneumoniae and Staphylococcus aureus in children. JAMA 292: 716 720.
106. Ren, B.,, A. J. Szalai,, S. K. Hollingshead,, and D. E. Briles. 2004. Effects of PspA and antibodies to PspA on activation and deposition of complement on the pneumococcal surface. Infect. Immun. 72: 114 122.
107. Ren, B.,, A. J. Szalai,, O. Thomas,, S. K. Hollingshead,, and D. E. Briles. 2003. Both family 1 and family 2 PspAs can inhibit complement deposition and confer virulence to a capsular 3 serotype Streptococcus pneumoniae. Infect. Immun. 71: 75 85.
108. Rijkers, G. T.,, E. A. Sanders,, M. A. Breukels,, and B. J. Zegers. 1998. Infant B cell responses to polysaccharide determinants. Vaccine 16: 1396 1400.
109. Rijkers, G. T.,, E. A. M. Sanders,, M. A. Breukels,, and B. J. M. Zegers. 1996. Responsiveness of infants to capsular polysaccharides: implications for vaccine development. Rev. Med. Microbiol. 7: 3 12.
110. Robbins, J. B.,, R. Austrian,, C.-J. Lee,, S. C. Rastogi,, G. Schiffman,, J. Henrichsen,, P. H. Makela,, C. V. Broome,, R. R. Facklam,, R. H. Tiesjema,, and J. C. Parke, Jr. 1983. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J. Infect. Dis. 148: 1136 1159.
111. Roche, H.,, A. Hakansson,, S. K. Hollingshead,, and D. E. Briles. 2003. Regions of PspA/EF3296 best able to elicit protection against Streptococcus pneumoniae in a murine infection model. Infect. Immun. 71: 1033 1041.
112. Roche, H.,, B. Ren,, L. S. McDaniel,, A. Hakansson,, and D. E. Briles. 2003. Relative roles of genetic background and variation in PspA in the ability of antibodies to PspA to protect against capsular type 3 and 4 strains of Streptococcus pneumoniae. Infect. Immun. 71: 4498 4505.
113. Rosenow, C.,, P. Ryan,, J. N. Weiser,, S. Johnson,, P. Fontan,, A. Ortqvist,, and H. R. Masure. 1997. Contribution of novel choline-binding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae. Mol. Microbiol. 25: 819 829.
114. Rubins, J. B.,, D. Charboneau,, C. Fashing,, A. M. Berry,, J. C. Paton,, J. E. Alexander,, P. W. Andrew,, T. J. Mitchell,, and E. N. Janoff. 1996. Distinct roles for pneumolysin’s cytotoxic and complement activities in pathogenesis of pneumococcal pneumonia. Am. J. Respir. Crit. Care Med. 153: 1339 1346.
115. Rubins, J. B.,, D. Charboneau,, J. C. Paton,, T. J. Mitchell,, and P. W. Andrew. 1995. Dual function of pneumolysin in the early pathogenesis of murine pneumococcal pneumonia. J. Clin. Investig. 95: 142 150.
116. Rubins, J. B.,, A. K. G. Puri,, D. Carboneau,, R. Mac-Donald,, N. Opstad,, and E. N. Janoff. 1998. Magnitude, duration, quality, and function of pneumococcal vaccine responses in elderly adults. J. Infect. Dis. 178: 431 440.
117. Sankilampi, U.,, P. O. Honkanen,, A. Bloigu,, and M. Leinonen. 1997. Persistence of antibodies to pneumococcal capsular polysaccharide vaccine in the elderly. J. Infect. Dis. 176: 1100 1104.
118. Shapiro, E. D.,, A. T. Berg,, R. Austrian,, D. Schroeder,, V. Parcells,, A. Margolis,, R. K. Adair,, and J. D. Clemmens. 1991. Protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N. Engl. J. Med. 325: 1453 1460.
119. Shaw, P. X.,, S. Horkko,, M. K. Chang,, L. K. Curtiss,, W. Palinski,, G. J. Silverman,, and J. L. Witztum. 2000. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J. Clin. Investig. 105: 1731 1740.
120. Shelly, M. A.,, H. Jacoby,, G. J. Riley,, B. T. Graves,, M. Pichichero,, and J. J. Treanor. 1997. Comparison of pneumococcal polysaccharide and CRM 197 conjugated pneumococcal oligosaccharide vaccines in young and elderly adults. Infect. Immun. 65: 242 247.
121. Siber, G. R. 1994. Pneumococcal disease: prospects for a new generation of vaccines. Science 265: 1385 1387.
122. Tong, H. H.,, L. E. Blue,, M. A. James,, and T. F. De-Maria. 2000. Evaluation of the virulence of a Streptococcus pneumoniae neuraminidase-deficient mutant in nasopharyngeal colonization and development of otitis media in the chinchilla model. Infect. Immun. 68: 921 924.
123. Virolainen, A.,, W. Russell,, M. J. Crain,, S. Rapola,, H. Kaythy,, and D. E. Briles. 2000. Human antibodies to pneumococcal surface protein A, PspA. Pediatr. Infect. Dis. J. 19: 134 138.
124. White, B. 1938. The Biology of Pneumococcus. The Commonwealth Fund, New York, N.Y.
125. Whitney, C. G.,, M. M. Farley,, J. Hadler,, L. H. Harrison,, N. M. Bennett,, R. Lynfield,, A. Reingold,, P. R. Cieslak,, T. Pilishvili,, D. Jackson,, R. R. Facklam,, J. H. Jorgensen,, and A. Schuchat. 2003. Decline in invasive pneumococcal disease after the introduction of proteinpolysaccharide conjugate vaccine. N. Engl. J. Med. 348: 1737 1746.
126. Wu, H.-Y.,, M. Nahm,, Y. Guo,, M. Russell,, and D. E. Briles. 1997. Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage, pulmonary infection, and sepsis with Streptococcus pneumoniae. J. Infect. Dis. 175: 839 846.
127. Yother, J.,, and D. E. Briles. 1992. Structural properties and evolutionary relationships of PspA, a surface protein of Streptococcus pneumoniae, as revealed by sequence analysis. J. Bacteriol. 174: 601 609.
128. Yother, J.,, and J. M. White. 1994. Novel surface attachment mechanism for the Streptococcus pneumoniae protein PspA. J. Bacteriol. 176: 2976 2985.
129. Zysk, G.,, G. Bethe,, R. Nau,, D. Koch,, V. C. Grafin Von Bassewitz,, H. P. Heinz,, and R. R. Reinert. 2003. Immune response to capsular polysaccharide and surface proteins of Streptococcus pneumoniae in patients with invasive pneumococcal disease. J. Infect. Dis. 187: 330 333.

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