Pneumococcal immunization through a novel mechanism

Summary

Principal Investigator: Richard Malley
Abstract: The capsular polysaccharide-protein conjugate vaccine is effective in prevention of invasive disease by Streptococcus pneumoniae (pneumococci) of the serotypes included but is costly to make and administer, minimally effective against otitis media, and subject to serotype replacement (in which non-included serotypes become more prevalent). Therefore, novel approaches to immunization are needed. We found unexpectedly that mice immunized intranasally with the pneumococcal cell wall polysaccharide (CWPS, an antigen commonto all serotypes) develop long-lasting resistance to nasopharyngeal colonization and middle ear infection with pneumococci of different serotypes. Strikingly, protection by the vaccine(i.e. CWPS + mucosal adjuvant) is independent of antibody and dependent on the presence of CD4+ T cells. This polysaccharide-induced, cell-mediated mucosal immunity against colonization by an "extracellular" encapsulated bacterium has not, to our knowledge, been previously demonstrated and therefore represents a novel approachto vaccination. We hypothesize that the zwitterionic property of CWPS is critical in eliciting this T-cell-dependent response. Our first goal is to determine the structural basis of protection by CWPS by further purification, polymer synthesis, chemical modifications to alter the zwitterionic motif, auto-coupling, or coupling to a protein carrier. Thus either the zwitterion hypothesis will be confirmed and/or the minimal protective structure will be defined. Secondly, we will examine in more detail the mechanisms whereby CD4+ T cells confer protection against pneumococcal colonization. Adoptive transfer experiments will characterize the nature of the protective T cell responses. Further approaches will include polarization of T cell responses by use of knockout mice or administration of cytokines, neutrophil depletion experiments, and histopathology with confocal microscopy. In a third aim, we will evaluate the role of innate immune responses in modulating acquired immunity to colonization, by use of Toll-like receptor (TLR) knockout mice and co-administration of TLR ligands as adjuvants at the time of immunization. Our studies will increase basic understanding of immunity to pneumococcal colonization and could lead to a simple, defined, and possibly synthetic vaccine that would complement or replace the multivalent capsular conjugates in vaccination against this, highly prevalent pathogen of children.
Funding Period: ----------------2005 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide
    Richard Malley
    Division of Infectious Diseases, Children s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
    Infect Immun 74:2187-95. 2006
  2. pmc Identification of protective pneumococcal T(H)17 antigens from the soluble fraction of a killed whole cell vaccine
    Kristin L Moffitt
    Division of Infectious Diseases, Boston Children s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 7:e43445. 2012
  3. pmc Interleukin-17A mediates acquired immunity to pneumococcal colonization
    Ying Jie Lu
    Department of Medicine, Division of Infectious Diseases, Children s Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS Pathog 4:e1000159. 2008
  4. pmc Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells
    Krzysztof Trzcinski
    Harvard School of Public Health, Department of Epidemiology, 665 Huntington Avenue, Building 1, Room 903, Boston, MA 02115, USA
    Infect Immun 76:2678-84. 2008
  5. ncbi Serum antipneumococcal antibodies and pneumococcal colonization in adults with chronic obstructive pulmonary disease
    Richard Malley
    Division of Infectious Diseases, Department of Medicine, Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Infect Dis 196:928-35. 2007
  6. pmc Antibody-independent, CD4+ T-cell-dependent protection against pneumococcal colonization elicited by intranasal immunization with purified pneumococcal proteins
    Alan Basset
    Division of Infectious Diseases, Children s Hospital Boston, Enders 861 3, 300 Longwood Avenue, Boston, MA 02115, USA
    Infect Immun 75:5460-4. 2007
  7. pmc SpxB is a suicide gene of Streptococcus pneumoniae and confers a selective advantage in an in vivo competitive colonization model
    Gili Regev-Yochay
    Department of Epidemiology and Department of Immunology and Infectious Diseases, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, USA
    J Bacteriol 189:6532-9. 2007
  8. pmc Interference between Streptococcus pneumoniae and Staphylococcus aureus: In vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae
    Gili Regev-Yochay
    Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, USA
    J Bacteriol 188:4996-5001. 2006
  9. pmc Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity
    Fan Zhang
    Division of Infectious Diseases, Department of Medicine, Boston Children s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:13564-9. 2013
  10. pmc Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease
    Amit Srivastava
    Division of Infectious Diseases, Department of Medicine, Children s Hospital, Boston, MA 02115, USA
    Infect Immun 75:342-9. 2007

Scientific Experts

  • Richard Malley
  • Ying Jie Lu
  • Claudette M Thompson
  • Marc Lipsitch
  • Porter W Anderson
  • Amit Srivastava
  • Krzysztof Trzcinski
  • Kristin L Moffitt
  • Alan Basset
  • Fan Zhang
  • Gili Regev-Yochay
  • Sophie Forte
  • Daniel M Weinberger
  • Debby Bogaert
  • Unhwan Ha
  • Sabina Sayeed
  • Shousun Szu
  • Mark Alderson
  • George Robertson
  • Jee Look
  • Puja Yadav
  • John D Clements
  • Andrea Tate
  • Jean Francois Maisonneuve
  • Robert Seid
  • James Galagan
  • Aaron Brandes
  • Ian Chr Skovsted
  • Kathleen F Harney
  • Jane Gross
  • Linda Bagrade
  • Jay K Kolls
  • Anna Lundgren
  • Adam Finn
  • Qibo Zhang
  • Mathuram Santosham
  • Edwin W Ades
  • Jian dong Li
  • Susan K Hollingshead
  • Jacques Pouyssegur
  • Alexander J McAdam
  • Ofer Levy
  • David E Briles
  • Christina Hermos
  • Hirofumi Jono
  • Gilles Pages
  • Nathaniel Johnson
  • Tomoaki Koga
  • Raymond Reid
  • Heather Casey
  • Jae Hyang Lim

Detail Information

Publications19

  1. pmc Antibody-independent, interleukin-17A-mediated, cross-serotype immunity to pneumococci in mice immunized intranasally with the cell wall polysaccharide
    Richard Malley
    Division of Infectious Diseases, Children s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
    Infect Immun 74:2187-95. 2006
    ..C-Ps also protected in a model of fatal aspiration pneumonia by heavily capsulated serotype 3. These findings suggest a novel immunization strategy against S. pneumoniae...
  2. pmc Identification of protective pneumococcal T(H)17 antigens from the soluble fraction of a killed whole cell vaccine
    Kristin L Moffitt
    Division of Infectious Diseases, Boston Children s Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 7:e43445. 2012
    ..We propose that, by providing protection against pneumococcal colonization, one or more of these proteins may serve as components of a multivalent pneumococcal vaccine...
  3. pmc Interleukin-17A mediates acquired immunity to pneumococcal colonization
    Ying Jie Lu
    Department of Medicine, Division of Infectious Diseases, Children s Hospital, and Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS Pathog 4:e1000159. 2008
    ..We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines...
  4. pmc Protection against nasopharyngeal colonization by Streptococcus pneumoniae is mediated by antigen-specific CD4+ T cells
    Krzysztof Trzcinski
    Harvard School of Public Health, Department of Epidemiology, 665 Huntington Avenue, Building 1, Room 903, Boston, MA 02115, USA
    Infect Immun 76:2678-84. 2008
    ..These results are consistent with the recruitment and/or activation of phagocytic or other nonspecific effectors by antigen-specific CD4(+) T cells...
  5. ncbi Serum antipneumococcal antibodies and pneumococcal colonization in adults with chronic obstructive pulmonary disease
    Richard Malley
    Division of Infectious Diseases, Department of Medicine, Children s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Infect Dis 196:928-35. 2007
    ..We thus conclude that, in adult patients with COPD, resistance to pneumococcal colonization is unlikely to be determined by higher serum antibody concentrations to pneumococcal antigens...
  6. pmc Antibody-independent, CD4+ T-cell-dependent protection against pneumococcal colonization elicited by intranasal immunization with purified pneumococcal proteins
    Alan Basset
    Division of Infectious Diseases, Children s Hospital Boston, Enders 861 3, 300 Longwood Avenue, Boston, MA 02115, USA
    Infect Immun 75:5460-4. 2007
    ..Overall, our results show that intranasal immunization with a mixture of pneumococcal proteins protects against colonization in an antibody-independent, CD4+ T-cell-dependent manner...
  7. pmc SpxB is a suicide gene of Streptococcus pneumoniae and confers a selective advantage in an in vivo competitive colonization model
    Gili Regev-Yochay
    Department of Epidemiology and Department of Immunology and Infectious Diseases, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, USA
    J Bacteriol 189:6532-9. 2007
    ..We conclude that a suicide gene of pneumococcus is spxB, which induces an apoptosis-like death in pneumococci and confers a selective advantage in nasopharyngeal cocolonization...
  8. pmc Interference between Streptococcus pneumoniae and Staphylococcus aureus: In vitro hydrogen peroxide-mediated killing by Streptococcus pneumoniae
    Gili Regev-Yochay
    Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave, Boston, MA 02115, USA
    J Bacteriol 188:4996-5001. 2006
    ..These results provide a possible mechanistic explanation for the interspecies interference observed in epidemiologic studies...
  9. pmc Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity
    Fan Zhang
    Division of Infectious Diseases, Department of Medicine, Boston Children s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 110:13564-9. 2013
    ..Moreover, MAPS can serve as a tool for structure-activity analysis of cellular immunogens. ..
  10. pmc Recombinant bactericidal/permeability-increasing protein rBPI21 protects against pneumococcal disease
    Amit Srivastava
    Division of Infectious Diseases, Department of Medicine, Children s Hospital, Boston, MA 02115, USA
    Infect Immun 75:342-9. 2007
    ..We have thus discovered a novel interaction between pneumococcus and rBPI21, a potent antimicrobial peptide previously considered to target only gram-negative bacteria...
  11. ncbi A novel role for IkappaB kinase (IKK) alpha and IKKbeta in ERK-dependent up-regulation of MUC5AC mucin transcription by Streptococcus pneumoniae
    Unhwan Ha
    Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
    J Immunol 178:1736-47. 2007
    ..pneumoniae...
  12. pmc Association of the pneumococcal pilus with certain capsular serotypes but not with increased virulence
    Alan Basset
    Division of Infectious Diseases, Department of Medicine, Children s Hospital Boston, Enders 861 3, Boston, MA 02115, USA
    J Clin Microbiol 45:1684-9. 2007
    ..3% after 2000; P = 0.019). Therefore, our data show that the pilus is present in a minority of strains and is associated with certain serotypes and that its frequency has been reduced by the conjugate pneumococcal vaccine...
  13. pmc Protection against Pneumococcal colonization and fatal pneumonia by a trivalent conjugate of a fusion protein with the cell wall polysaccharide
    Ying Jie Lu
    Division of Infectious Diseases, Children s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
    Infect Immun 77:2076-83. 2009
    ..Thus, a covalent construct of three antigens common to all serotypes exhibits protection with both mucosal and systemic administration...
  14. pmc Pneumococcal capsular polysaccharide structure predicts serotype prevalence
    Daniel M Weinberger
    Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
    PLoS Pathog 5:e1000476. 2009
    ....
  15. ncbi Antibody and cell-mediated immunity to Streptococcus pneumoniae: implications for vaccine development
    Richard Malley
    Division of Infectious Diseases, Department of Medicine, Children s Hospital Boston, Harvard Medical School, Boston, MA, USA
    J Mol Med (Berl) 88:135-42. 2010
    ..This review focuses on the experimental and clinical evidence in support of this hypothesis. The implications for future vaccine development against Streptococcus pneumoniae are also discussed...
  16. pmc Options for inactivation, adjuvant, and route of topical administration of a killed, unencapsulated pneumococcal whole-cell vaccine
    Ying Jie Lu
    Division of Infectious Diseases, Children s Hospital, and Harvard Medical School, Boston, MA 02115, USA
    Clin Vaccine Immunol 17:1005-12. 2010
    ....
  17. pmc Next generation pneumococcal vaccines
    Kristin L Moffitt
    Division of Infectious Diseases, Children s Hospital, Harvard Medical School, Boston, MA, United States
    Curr Opin Immunol 23:407-13. 2011
    ..The immunological basis for these different approaches is discussed as well...
  18. pmc A bivalent vaccine to protect against Streptococcus pneumoniae and Salmonella typhi
    Ying Jie Lu
    Division of Infectious Diseases, Children s Hospital Boston, and Harvard Medical School, Boston, MA 02115, United States
    Vaccine 30:3405-12. 2012
    ..Our results support further evaluation of this bivalent immunogen for the prevention of pneumococcal colonization and disease, and of typhoid fever...
  19. pmc Mechanisms in the serotype-independent pneumococcal immunity induced in mice by intranasal vaccination with the cell wall polysaccharide
    Ying Jie Lu
    Children s Hospital and Harvard Medical School, Boston, MA 02115, United States
    Microb Pathog 47:177-82. 2009
    ..We suggest that mucosal immunization with CWPS primes T(H)17 cells, which - upon contact with the phosphocholine of colonizing pneumococci - elaborate IL-17A, enhancing phagocytosis...