Chapter 24 : New Pneumococcal Vaccines: Basic Science Developments

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

New Pneumococcal Vaccines: Basic Science Developments, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816537/9781555812973_Chap24-1.gif /docserver/preview/fulltext/10.1128/9781555816537/9781555812973_Chap24-2.gif


The first experimental vaccines, comprising killed whole cells, were tested in the early 1900s, albeit with inconclusive results. Polyvalent capsular polysaccharide (PS)-protein conjugates vaccines are aimed at preventing invasive diseases such as pneumonia, meningitis, and bacteremia, as well as less serious but highly prevalent infections such as otitis media. They are being targeted principally at specific groups at high risk of pneumococcal disease, particularly children under 2 years and adults over 65 years of age. The increasing prevalence of penicillin-resistant and multiply resistant pneumococci is complicating management of patients with suspected pneumococcal disease, particularly those with meningitis. Polyvalent PS-protein conjugate vaccines are very expensive to produce, and addition of further PS types or periodic reformulation to take account of altered serotype prevalence will add further to this cost. This may place the vaccine even further out of the reach of many developing countries, whose need for effective pneumococcal vaccines is greatest. Studies on the vaccine potential of pneumococcal surface protein A (PspA) have extended to human trials, and immune sera from volunteers immunized with a family 1 PspA fragment reacted with 37 different strains belonging to diverse capsular and PspA types. A further strategy under consideration for prevention of pneumococcal disease is the use of DNA vaccines. The ongoing high global morbidity and mortality associated with pneumococcal disease, and the complications caused by increasing rates of resistance to antimicrobials, have underpinned extensive efforts in recent years to develop more effective vaccination strategies against .

Citation: Paton J. 2004. New Pneumococcal Vaccines: Basic Science Developments, p 382-402. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch24
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Protection against pulmonary infection with elicited by immunization with PspA, PdB (genetically toxoided pneumolysin), PsaA, or combinations thereof. CBA/N mice were immunized with the indicated proteins on alum or with alum alone, challenged with 10 CFU of strain EF3030 (capsular group 19), and sacrificed 7 days later to determine numbers of CFU in their lungs. Significance of difference relative to control mice (alum only): ?, < 0.04; ??, < 0.001. (Reproduced with permission from the Journal of Infectious Diseases [ ].)

Citation: Paton J. 2004. New Pneumococcal Vaccines: Basic Science Developments, p 382-402. In Tuomanen E, Mitchell T, Morrison D, Spratt B (ed), The Pneumococcus. ASM Press, Washington, DC. doi: 10.1128/9781555816537.ch24
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Adamou, J. E.,, J. H. Heinrichs,, A. L. Erwin,, W. Walsh,, T. Gayle,, M. Dormitzer,, R. Dagan,, Y. A. Brewah,, P. Barren,, R. Lathigra,, S. Langermann,, S. Koenig,, and S. Johnson. 2001. Identification and characterization of a novel family of pneumococcal proteins that are protective against sepsis. Infect. Immun. 69:949958.
2. 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. 62:56835688.
3. Arulanandam, B. P.,, J. M. Lynch,, D. E. Briles,, S. Hollingshead,, and D. W. Metzger. 2001. Intranasal vaccination with pneumococcal surface protein A and interleukin-12 augments antibody-mediated opsonization and protective immunity against Streptococcus pneumoniae infection. Infect. Immun. 69:67186724.
4. Austrian, R. 1981. Some observations on the pneumococcus and on the current status of pneumococcal disease and its prevention. Rev. Infect. Dis. 3(Suppl.):S1S17.
5. Austrian, R. 2001. Pneumococcal otitis media and pneumococcal vaccines, a historical perspective. Vaccine 19:S71S77.
6. Avery, O. T.,, and W. F. Goebel. 1931. Chemo-immunological studies on conjugated carbohydrate-proteins. V. The immunological specificity of an antigen prepared by combining the capsular polysaccharide of type III pneumococcus with foreign protein. J. Exp. Med. 54:437447.
7. Balachandran, P.,, A. Brooks-Walter,, A. Virolainen- Julkunen,, S. K. Hollingshead,, and D. E. Briles. 2002. Role of pneumococcal surface protein C in nasopharyngeal carriage and pneumonia and its ability to elicit protection against carriage of Streptococcus pneumoniae. Infect. Immun. 70:25262534.
8. Balachandran, P.,, S. K. Hollingshead,, J. C. Paton,, and D. E. Briles. 2001. The autolytic enzyme LytA of Streptococcus pneumoniae is not responsible for releasing pneumolysin. J. Bacteriol. 183:31083116.
9. Berry, A. M.,, J. E. Alexander,, T. J. Mitchell,, P. W. Andrew,, D. Hansman,, and J. C. Paton. 1995. Effect of defined point mutations in the pneumolysin gene on the virulence of Streptococcus pneumoniae. Infect. Immun. 63:19691974.
10. Berry, A. M.,, R. A. Lock,, D. Hansman,, and J. C. Paton. 1989. Contribution of autolysin to the virulence of Streptococcus pneumoniae. Infect. Immun. 57:23242330.
11. 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. 64:52555262.
12. Berry, A. M.,, and J. C. Paton. 2000. Additive attenuation of virulence of Streptococcus pneumoniae by mutation of the genes encoding pneumolysin and other putative pneumococcal virulence proteins. Infect. Immun. 68:133140.
13. 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. 57:20372042.
14. 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,, K. Edwards, and Northern California Kaiser Permanente Vaccine Study Center Group. 2000. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr. Infect. Dis. J. 19:187195.
15. Bosarge, J. R.,, J. M. Watt,, D. O. McDaniel,, E. Swiatlo,, and L. S. McDaniel. 2001. Genetic immunization with the region encoding the alpha-helical domain of PspA elicits protective immunity against Streptococcus pneumoniae. Infect. Immun. 69:54565463.
16. 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. 68:796800.
17. 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 recombinant pneumococcal surface protein A (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA. J. Infect. Dis. 182:16941701.
18. Briles, D. E.,, S. K. Hollingshead,, J. C. Paton,, E. W. Ades,, L. Novak,, F. W. van Ginkel,, and W. H. Benjamin, Jr. 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. 188:339348.
19. Briles, D. E.,, J. C. Paton,, M. H. Nahm,, and E. Swiatlo,. 1999. Immunity to Streptococcus pneumoniae, p. 263280. In M. W. Cunningham, and R. S. Fujinami (ed.), Effects of Microbes on the Immune System. Lippincott, Williams and Wilkins, Philadelphia, Pa.
20. 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. 67:65336542.
21. Broome, C. 1996. Meningococcal and pneumococcal disease vaccines, p. 2832. In Progress of Vaccine Research and Development—1996. Document WHO/VRD/GEN/96.02. World Health Organization, Geneva, Switzerland.
22. Brown, J. S.,, S. M. Gilliland,, and D. W. Holden. 2001. A Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence. Mol. Microbiol. 40:572585.
23. Brown, J. S.,, A. D. Ogunniyi,, M. C. Woodrow,, D. W. Holden,, and J. C. Paton. 2001. Immunization with components of two iron-uptake ABC transporters protects mice against systemic Streptococcus pneumoniae infection. Infect. Immun. 69:67026706.
24.Centers for Disease Control and Prevention. 1997. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). Morb. Mortal. Wkly. Rep. 46(RR-8):124.
25. Cheng, Q.,, D. Finkel,, and M. K. Hostetter. 2000. Novel purification scheme and functions for a C3-binding protein from Streptococcus pneumoniae. Biochemistry 39:54505457.
26. Coffey, T. J.,, M. C. Enright,, M. Daniels,, J. K. Morona,, R. Morona,, W. Hryniewicz,, J. C. Paton,, and B. G. Spratt. 1998. Recombinational exchanges at the capsular polysaccharide biosynthetic locus lead to frequent serotype changes among natural isolates of Streptococcus pneumoniae. Mol. Microbiol. 27:7384.
27. Crain, M. J.,, W. D. Waltman II,, J. S. Turner,, J. Yother,, D. F. Talkington,, L. S. 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. 58:32933299.
28. Dagan, R.,, N. Givon-Lavi,, O. Zamir,, and D. Fraser. 2003. Effect of a nonavalent conjugate vaccine on carriage of antibiotic-resistant Streptococcus pneumoniae in day-care centers. Pediatr. Infect. Dis. J. 22:532540.
29. Dave, S.,, A. Brooks-Walter,, M. K. Pangburn,, and L. S. McDaniel. 2001. PspC, a pneumococcal surface protein, binds human factor H. Infect. Immun. 69:34353437.
30.. De, B. K.,, J. S. Sampson,, E. W. Ades,, R. C. Huebner,, D. L. Jue,, S. E. Johnson,, M. Espina,, A. R. Stinson,, D. E. Briles,, and G. M. Carlone. 2000. Purification and characterization of Streptococcus pneumoniae palmitoylated pneumococcal surface adhesin A expressed in Escherichia coli. Vaccine 18:18111821.
31. Dintilhac, A.,, G. Alloing,, C. Granadel,, and J. P. Claverys. 1997. Competence and virulence of S. pneumoniae: Adc and PsaA mutants exhibit a requirement for Zn and Mn resulting from inactivation of metal permeases. Mol. Microbiol. 25:727739.
32. Douglas, R. M.,, J. C. Paton,, S. J. Duncan,, and D. Hansman. 1983. Antibody response to pneumococcal vaccination in children younger than five years of age. J. Infect. Dis. 148:131137.
33. Duthy, T. G.,, R. J. Ormsby,, E. Giannakis,, A. D. Ogunniyi,, U. H. Stroeher,, J. C. Paton,, and D. L. Gordon. 2002. The human complement regulator factor H binds pneumococcal surface protein PspC via short consensus repeat domains 13 to 15. Infect. Immun. 70:56045611.
34. Eskola, J. 2001. Polysaccharide-based pneumococcal vaccines in the prevention of acute otitis media. Vaccine 19:S78S82.
35. Eskola, J.,, T. Kilpi,, A. Palmu,, J. Jokinen,, J. Haapakoski,, E. Herva,, A. Takala,, H. Kayhty,, P. Karma,, R. Kohberger,, G. Siber,, P. H. Makela, and the Finnish Otitis Media Study Group. 2001. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N. Engl. J. Med. 344:403409.
36. Feldman, C.,, N. C. Munro,, P. K. Jeffery,, T. J. Mitchell,, P. W. Andrew,, G. J. Boulnois,, D. Guerreiro,, J. A. Rohde,, H. C. Todd,, P. J. Cole,, and R. Wilson. 1991. Pneumolysin induces the salient histological features of pneumococcal infection in the rat lung in vivo. Am. J. Respir. Cell Mol. Biol. 5:416423.
37. Fraser, D.,, N. Givon-Lavi,, N. Bilenko,, and R. Dagan. 2001. A decade (1989-1998) of pediatric invasive pneumococcal disease in 2 populations residing in 1 geographical location: implications for vaccine choice. Clin. Infect. Dis. 33:421427.
38. Gilbert, C.,, K. Robinson,, R. W. Le Page,, and J. M. Wells. 2000. Heterologous expression of an immunogenic pneumococcal type 3 capsular polysaccharide in Lactococcus lactis. Infect. Immun. 68:32513260.
39. Gor, D. O.,, X. Ding,, Q. Li,, J. R. Schreiber,, M. Dubinsky,, and N. S. Greenspan. 2002. Enhanced immunogenicity of pneumococcal surface adhesin A by genetic fusion to cytokines and evaluation of protective immunity in mice. Infect. Immun. 70:55895595.
40. Gosink, K. K.,, E. R. Mann,, C. Guglielmo,, E. I. Tuomanen,, and H. R. Masure. 2000. Role of novel choline binding proteins in virulence of Streptococcus pneumoniae. Infect. Immun. 68:56905695.
41. Hakansson, A.,, H. Roche,, S. Mirza,, L. S. McDaniel,, A. Brooks-Walter,, and D. E. Briles. 2001. Characterization of the binding of human lactoferrin to pneumococcal surface protein A (PspA). Infect. Immun. 69:33723381.
42. Hammerschmidt, S.,, G. Bethe,, P. Remanen,, and G. S. Chhatwal. 1999. Identification of pneumococcal surface protein A as a lactoferrin-binding protein of Streptococcus pneumoniae. Infect. Immun. 67:16831687.
43. Hammerschmidt, S.,, S. 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. 25:11131124.
44. Hammerschmidt, S.,, M. P. Tillig,, S. Wolff,, J. P. Vaerman,, and G. S. Chhatwal. 2000. Species-specific binding of human secretory component to SpsA protein of Streptococcus pneumoniae via a hexapeptide motif. Mol. Microbiol. 36:726736.
45. 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. 68:58895900.
46. Houldsworth, S.,, P. W. Andrew,, and T. J. Mitchell. 1994. Pneumolysin stimulates production of tumor necrosis factor α and interleukin-1β by human mononuclear phagocytes. Infect. Immun. 62:15011503.
47. Hvalbye, B. K.,, I. S. Aaberge,, M. Lovik,, and B. Haneberg. 1999. Intranasal immunization with heat-inactivated Streptococcus pneumoniae protects mice against systemic pneumococcal infection. Infect. Immun. 67:43204325.
48. Iannelli, F.,, M. R. Oggioni,, and G. Pozzi. 2002. Allelic variation in the highly polymorphic locus pspC of Streptococcus pneumoniae. Gene 284:6371.
49. Jakobsen, H.,, D. Schulz,, M. Pizza,, R. Rappuoli,, and I. Jonsdottir. 1999. Intranasal immunization with pneumococcal polysaccharide conjugate vaccines with non-toxic mutants of Escherichia coli heat-labile enterotoxins as adjuvants protects mice against invasive pneumococcal infections. Infect. Immun. 67:58925897.
50. 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. 275:3725737263.
51. Jarva, H.,, R. Janulczyk,, J. Hellwage,, P. F. Zipfel,, L. Bjorck,, and S. Meri. 2002. Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locusencoded Hic protein that binds to short consensus repeats 8-11 of factor H. J. Immunol. 168:18861894.
52. Jedrzejas, M. J.,, S. K. Hollingshead,, J. Lebowitz,, L. Chantalat,, D. E. Briles,, and E. J. Lamani. 2000. Production and characterization of the functional fragment of pneumococcal surface protein A. Arch. Biochem. Biophys. 373:116125.
53. Johnson, S. E.,, J. K. Dykes,, D. L. Jue,, J. S. Sampson,, G. M. Carlone,, and E. W. Ades. 2002. Inhibition of pneumococcal carriage in mice by subcutaneous immunization with peptides from the common surface protein pneumococcal surface adhesin A. J. Infect. Dis. 185:489496.
54. Kang, H. Y.,, J. Srinivasan,, and R. Curtiss III. 2002. Immune responses to recombinant pneumococcal PspA antigen delivered by live attenuated Salmonella enterica serovar Typhimurium vaccine. Infect. Immun. 70:17391749.
55. Klein, D. L., 2000. Pneumococcal disease and the role of conjugate vaccines, p. 467477. In A. Tomasz (ed.), Streptococcus pneumoniae. Molecular Biology and Mechanisms of Disease. Mary Ann Liebert, Inc., Larchmont, N.Y.
56. Klein, J. O. 2001. The burden of otitis media. Vaccine 19:S2S8.
57. Klugman, K. P. 1990. Pneumococcal resistance to antibiotics. Clin. Microbiol. Rev. 3:171196.
58. Klugman, K. P. 1996. Epidemiology, control and treatment of multiresistant pneumococci. Drugs 52(Suppl. 2):4246.
59. Lawrence, M. C.,, P. A. Pilling,, A. D. Ogunniyi,, A. M. Berry,, and J. C. Paton. 1998. The crystal structure of pneumococcal surface antigen PsaA reveals a metal-binding site and a novel structure for a putative ABC-type binding protein. Structure 6:15531561.
60. Lee, C. J.,, S. D. Banks,, and J. P. Li. 1991. Virulence, immunity and vaccine related to S. pneumoniae. Crit. Rev. Microbiol. 18:89114.
61. Lee, C.-J.,, R. A. Lock,, T. J. Mitchell,, P. W. Andrew,, G. J. Boulnois,, and J. C. Paton. 1994. Protection of infant mice from challenge with Streptococcus pneumoniae type 19F by immunization with a type 19F polysaccharidepneumolysoid conjugate. Vaccine 12:875878.
62. Lesinski, G. B.,, S. L. Smithson,, N. Srivastava,, D. Chen,, G. Widera,, and M. A. Westerink. 2001. A DNA vaccine encoding a peptide mimic of Streptococcus pneumoniae serotype 4 capsular polysaccharide induces specific anti-carbohydrate antibodies in Balb/c mice. Vaccine 19:17171726.
63. Lipsitch, M.,, J. K. Dykes,, S. E. Johnson,, E. W. Ades,, J. King,, D. E. Briles,, and G. M. Carlone. 2000. Competition among Streptococcus pneumoniae for intranasal colonization in a mouse model. Vaccine 18:28952901.
64. Lopez, R.,, M. P. Gonzalez,, E. Garcia,, J. L. Garcia,, and P. Garcia. 2000. Biological roles of two new murein hydrolases of Streptococcus pneumoniae representing examples of module shuffling. Res. Microbiol. 151:437443.
65. MacLeod, C. M.,, R. G. Hodges,, M. Heidelberger,, and W. G. Bernhard. 1945. Prevention of pneumococcal pneumonia by vaccination. J. Exp. Med. 82:445465.
66. Malley, R.,, M. Lipsitch,, A. Stack,, R. Saladino,, G. Fleisher,, S. Pelton,, C. Thompson,, D. Briles,, and P. Anderson. 2001. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect. Immun. 69:48704873.
67. 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. 180:11711176.
68. McCool, T. L.,, T. R. Cate,, G. Moy,, and J. N. Weiser. 2002. The immune response to pneumococcal proteins during experimental human carriage. J. Exp. Med. 195:359365.
69. McDaniel, L. S.,, B. A. Ralph,, D. O. Mc- Daniel,, and D. E. Briles. 1994. Localization of protection-eliciting epitopes on PspA of Streptococcus pneumoniae between amino acid residues 192 and 260. Microb. Pathog. 17:323337.
70. 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. 165:381394.
71. McGee, L.,, K. P. Klugman,, and A. Tomasz. 2000. Serotypes and clones of antibiotic-resistant pneumococci, p. 375-379. In A. Tomasz (ed.), Streptococcus pneumoniae. Molecular Biology and Mechanisms of Disease. Mary Ann Liebert, Inc., Larchmont, N.Y.
72. Michon, F.,, P. C. Fusco,, C. A. Minetti,, M. Laude-Sharp,, C. Uitz,, C. H. Huang,, A. J. D’Ambra,, 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 16:17321741.
73. Miyaji, E. N.,, W. O. Dias,, M. Gamberini,, V. C. Gebara,, R. P. Schenkman,, J. Wild,, P. Riedl,, J. Reimann,, R. Schirmbeck,, and L. C. Leite. 2001. PsaA (pneumococcal surface adhesin A) and PspA (pneumococcal surface protein A) DNA vaccines induce humoral and cellular immune responses against Streptococcus pneumoniae. Vaccine 20:805812.
74. Miyaji, E. N.,, W. O. Dias,, M. M. Tanizaki,, and L. C. Leite. 2003. Protective efficacy of PspA (pneumococcal surface protein A)-based DNA vaccines: contribution of both humoral and cellular immune responses. FEMS Immunol. Med. Microbiol. 37:5357.
75. Miyaji, E. N.,, D. M. Ferreira,, A. P. Lopes,, M. C. Brandileone,, W. O. Dias,, and L. C. Leite. 2002. Analysis of serum cross-reactivity and cross-protection elicited by immunization with DNA vaccines against Streptococcus pneumoniae expressing PspA fragments from different clades. Infect. Immun. 70:50865090.
76. Musher, D. M.,, H. M. Phan,, and R. E. Baughn. 2001. Protection against bacteremic pneumococcal infection by antibody to pneumolysin. J. Infect. Dis. 183:827830.
77. Musher, D. M.,, D. A. Watson,, and R. E. Baughn. 2001. Genetic control of the immunological response to pneumococcal capsular polysaccharides. Vaccine 19:623627.
78. 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 crossreactive antibodies. Vaccine 18:17431754.
79. Nayak, A. R.,, S. A. Tinge,, R. C. Tart,, L. S. McDaniel,, D. E. Briles,, and R. Curtiss III. 1998. A live recombinant oral Salmonella vaccine expressing pneumococcal surface protein A induces protective responses against Streptococcus pneumoniae. Infect. Immun. 66:37443751.
80. Obaro, S. K.,, R. A. Adegbola,, W. A. Banya,, and B. M. Greenwood. 1996. Carriage of pneumococci after pneumococcal vaccination. Lancet 348:271272.
81. Ogunniyi, A. D.,, R. L. Folland,, S. Hollingshead,, D. E. Briles,, and J. C. Paton. 2000. Immunization of mice with combinations of pneumococcal virulence proteins elicits enhanced protection against challenge with Streptococcus pneumoniae. Infect. Immun. 68:30283033.
82. Ogunniyi, A. D.,, P. Giammarinaro,, and J. C. Paton. 2002. The genes encoding virulenceassociated proteins and the capsule of Streptococcus pneumoniae are upregulated and differentially expressed in vivo. Microbiology 148:20452053.
83. Ogunniyi, A. D.,, M. C. Woodrow,, J. T. Poolman,, and J. C. Paton. 2001. Protection against Streptococcus pneumoniae elicited by immunization with pneumolysin and CbpA. Infect. Immun. 69:59976003.
84. Ortqvist, A.,, J. Hedlund,, L. A. Burman,, E. Elbel,, M. Hofer,, M. Leinonen,, I. Lindblad,, B. Sundelof,, M. Kalin, and Swedish Pneumococcal Vaccine Study Group. 1998. Randomised trial of 23-valent pneumococcal capsular polysaccharide vaccine in prevention of pneumonia in middle-aged and elderly people. Lancet 351:399403.
85. 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. 68:41804188.
86. Paton, J. C. 1996. The contribution of pneumolysin to the pathogenicity of Streptococcus pneumoniae. Trends Microbiol. 4:103106.
87. Paton, J. C.,, A. M. Berry,, and R. A. Lock. 1997. Molecular analysis of putative pneumococcal virulence proteins. Microb. Drug Resist. 3:110.
88. Paton, J. C.,, and P. Giammarinaro. 2001. Genome-based analysis of pneumococcal virulence factors: the quest for novel vaccine antigens and drug targets. Trends Microbiol. 9:515518.
89. Paton, J. C.,, R. A. Lock,, and D. J. Hansman. 1983. Effect of immunization with pnuemolysin on survival time of mice challenged with Streptococcus pneumoniae. Infect. Immun. 40:548552.
90. 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. Boulnois. 1991. Purification and immunogenicity of genetically obtained pneumolysin toxoids and their conjugation to Streptococcus pneumoniae type 19F polysaccharide. Infect. Immun. 59:22972304.
91. Paton, J. C.,, and J. K. Morona,. 2000. Streptococcus pneumoniae capsular polysaccharide, p. 201213. In V. Fischetti,, R. Novick,, J. Ferretti,, D. Portnoy,, and J. Rood (ed.), Gram-Positive Pathogens. ASM Press, Washington, D.C.
92. Paton, J. C.,, J. K. Morona,, S. Harrer,, D. Hansman,, and R. Morona. 1993. Immunization of mice with Salmonella typhimurium C5 aroA expressing a genetically toxoided derivative of the pneumococcal toxin pneumolysin. Microb. Pathog. 14:95102.
93. Paton, J. C.,, I. R. Toogood,, R. Cockington,, and D. Hansman. 1986. Antibody response to pneumococcal vaccine in children aged 5 to 15 years. Am. J. Dis. Child. 140:135138.
94. Ren, B.,, A. J. Szalai,, O. Thomas,, S. K. Hollingshead,, and D. E. Briles. 2003. Both family 1 and family 2 PspA proteins can inhibit complement deposition and confer virulence to a capsular serotype 3 strain of Streptococcus pneumoniae. Infect. Immun. 71:7585.
95. Rijkers, G. T.,, E. A. Sanders,, M. A. Breukels,, and B. J. Zegers. 1998. Infant B cell responses to polysaccharide determinants. Vaccine 16:13961400.
96. 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. 148:11361159.
97. Robbins, J. B.,, R. Schneerson,, P. Anderson,, and D. H. Smith. 1996. Prevention of systemic infections, especially meningitis, caused by Haemophilus influenzae type b. Impact on public health and implications for other polysaccharide- based vaccines. JAMA 276:11811185.
98. Rosenow, C.,, P. Ryan,, J. N. Weiser,, S. Johnson,, P. Fontan,, A. Ortqvist,, and H. R. Masure. 1997. Contribution of novel cholinebinding proteins to adherence, colonization and immunogenicity of Streptococcus pneumoniae. Mol. Microbiol. 25:819829.
99. Rubins, J. B.,, D. Charboneau,, C. Fasching,, 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 the pathogenesis of pneumococcal pneumonia. Am. J. Respir. Crit. Care Med. 153:13391346.
100. Sampson, J. S.,, Z. Furlow,, A. M. Whitney,, D. Williams,, R. Facklam,, and G. M. Carlone. 1997. Limited diversity of Streptococcus pneumoniae psaA among pneumococcal vaccine serotypes. Infect. Immun. 65:19671971.
101. Seo, J. Y.,, S. Y. Seong,, B. Y. Ahn,, I. C. Kwon,, H. Chung,, and S. Y. Jeong. 2002. Cross-protective immunity of mice induced by oral immunization with pneumococcal surface adhesin a encapsulated in microspheres. Infect. Immun. 70:11431149.
102. Seong, S. Y.,, N. H. Cho,, I. C. Kwon,, and S. Y. Jeong. 1999. Protective immunity of microsphere- based mucosal vaccines against lethal intranasal challenge with Streptococcus pneumoniae. Infect. Immun. 67:35873592.
103. Simberkoff, M. S.,, A. P. Cross,, M. Al- Ibrahim,, A. L. Baltch,, P. J. Geiseler,, J. Nadler,, A. S. Richmond,, R. P. Smith,, G. Schiffman,, D. S. Shepard, et al. 1986. Efficacy of pneumococcal vaccine in high-risk patients: results of a Veterans Administration Cooperative Study. N. Engl. J. Med. 315:13181327.
104. Spratt, B. G.,, and B. M. Greenwood. 2000. Prevention of pneumococcal disease by vaccination: does serotype replacement matter? Lancet 356:12101211.
105. Tai, S. S.,, C. Yu,, and J. K. Lee. 2003. A solute binding protein of Streptococcus pneumoniae iron transport. FEMS Microbiol. Lett. 220:303308.
106. Talkington, D. F.,, B. G. Brown,, J. A, Tharpe, A. Koenig, and H. Russell. 1996. Protection of mice against fatal pneumococcal challenge by immunization with pneumococcal surface adhesin A (PsaA). Microb. Pathog. 21:1722.
107. Talkington, D. F.,, D. L. Crimmins,, D. C. Voellinger,, J. Yother,, and D. E. Briles. 1991. A 43-kilodalton pneumococcal surface protein, PspA: isolation, protective abilities, and structural analysis of the amino-terminal sequence. Infect. Immun. 59:12851289.
108. Tseng, H. J.,, A. G. McEwan,, J. C. Paton,, and M. P. Jennings. 2002. Virulence of Streptococcus pneumoniae: PsaA mutants are hypersensitive to oxidative stress. Infect. Immun. 70:16351639.
109. Tu, A.-H. T.,, R. L. Fulgham,, M. A. Mc- Cory,, D. E. Briles,, and A. J. Szalai. 1999. Pneumococcal surface protein A (PspA) inhibits complement activation by Streptococcus pneumoniae. Infect. Immun. 67:47204724.
110. Vakevainen, M.,, C. Eklund,, J. Eskola,, and H. Kayhty. 2001. Cross-reactivity of antibodies to type 6B and 6A polysaccharides of Streptococcus pneumoniae evoked by pneumococcal conjugate vaccine in infants. J. Infect. Dis. 184:789793.
111. Vela Coral, M. C.,, 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. 7:832836.
112. Wizemann, T. M.,, J. H. Heinrichs,, J. E. Adamou,, A. L. Erwin,, C. Kunsch,, G. H. Choi,, S. C. Barash,, C. A. Rosen,, H. R. Masure,, E. Tuomanen,, A. Gayle,, Y. A. Brewah,, W. Walsh,, P. Barren,, R. Lathigra,, M. Hanson,, S. Langermann,, S. Johnson,, and S. Koenig. 2001. Use of a whole genome approach to identify vaccine molecules affording protection against Streptococcus pneumoniae infection. Infect. Immun. 69:15931598.
113. Wortham, C.,, L. Grinberg,, D. C. Kaslow,, D. E. Briles,, L. S. McDaniel,, A. Lees,, M. Flora,, C. M. Snapper,, and J. J. Mond. 1998. Enhanced protective antibody responses to PspA after intranasal or subcutaneous injections of PspA genetically fused to granulocytemacrophage colony-stimulating factor or interleukin- 2. Infect. Immun. 66:15131520.
114. Wu, H. Y.,, M. H. Nahm,, Y. Guo,, M. W. Russell,, and D. E. Briles. 1997. Intranasal immunization of mice with PspA (pneumococcal surface protein A) can prevent intranasal carriage and infection with Streptococcus pneumoniae. J. Infect. Dis. 175:839846.
115. Wuorimaa, T.,, and H. Kayhty. 2002. Current state of pneumococcal vaccines. Scand. J. Immunol. 56:111129.
116. Yamamoto, M.,, L. S. McDaniel,, K. Kawabata,, D. E. Briles,, R. J. Jackson,, J. R. McGhee,, and H. Kiyono. 1997. Oral immunization with PspA elicits protective humoral immunity against Streptococcus pneumoniae infection. Infect. Immun. 65:640644.
117. 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. 174:601609.
118. Yother, J.,, and J. M. White. 1994. Novel surface attachment mechanism for the Streptococcus pneumoniae protein PspA. J. Bacteriol. 176: 29762985.
119. Zhang, J. R.,, K. E. Mostov,, M. E. Lamm,, M. Nanno,, S. Shimida,, M. Ohwaki,, and E. Tuomanen. 2000. The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells. Cell 102:827837.

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error