Research ArticleDISEASE PREVENTION

Comprehensive vaccine design for commensal disease progression

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Science Advances  18 Oct 2017:
Vol. 3, no. 10, e1701797
DOI: 10.1126/sciadv.1701797
  • Fig. 1 LEPS vaccine effectiveness compared to commercial standards.

    Mice were vaccinated at 0 and 14 days with (i) LEPS containing CPS from the S. pneumoniae serotype 19F, (ii) Prevnar 13 (PCV13), (iii) Pneumovax 23 (PPSV23), (iv) PBS (sham), and (v) various controls [CPS alone, CPS + CRM197, and empty LEPS (EL) + CRM197]. Serum was collected at 14 and 28 days. (A and B) Antibody class shifting of LEPS, PCV13, and PPSV23 (A) and total IgG titers (B). a.u., arbitrary units. (C) Protection against lethal challenge of serotype 19F in a murine sepsis model. (D) Functional antibody activity assessment of select vaccination strategies using the OPA assay. (E) Nasopharynx bacterial burden assessed in unimmunized or immunized mice measured at 5 days after colonization. CFU, colony-forming units. (F) 19F CPS antibody titers measured at 28 days (post 2) in mice serum without (white) or with (black) CD4+ T cell depletion. NS, not significant.

  • Fig. 2 Immune response assessment of the PncO and GlpO protein antigens.

    (A) Anti-PncO and anti-GlpO antibody titers in mice serum after initial (post 1) and booster (post 2) vaccination with either alum adjuvant or empty LEPS. (B) IgG1 (TH1 corresponding) and IgG2a (TH1 corresponding) titers in mice serum after a booster vaccination. IgG1/IgG2a ratio is shown above the bars. (C) Anti-PncO and anti-GlpO antibody titers in mice serum with or without CD4+ T cell depletion. (D) Murine challenge protection sepsis model after vaccination with either PspA (a commonly used pneumococcal protein antigen) (26) or PncO + GlpO with or without CD4+ cell depletion; S. pneumoniae serotype 19F was the challenge strain, and four mice were used per formulation. (E) Titers of interferon-γ (IFN-γ) (TH1 corresponding) and interleukin-17A (IL-17A) (TH17 corresponding) in mice serum after PncO + GlpO vaccination. (F) Anti-PncO and anti-GlpO antibody titers in rabbit serum after initial and booster vaccination.

  • Fig. 3 Assessment of the full LEPS platform featuring CPS encapsulation across 20 serotypes and surface localization of GlpO and PncO.

    (A) IgG titers against PncO, GlpO, and encapsulated CPS from indicated S. pneumoniae serotypes in mice serum after vaccination. (B) Mouse challenge protection data comparison between PCV13, PPSV23, and the complete LEPS system (LEPS20/PncO + GlpO) using a colonization model and in vivo perturbation with influenza A administration to prompt pneumonia development. Survival is indicated across vaccination options when challenged with the indicated serotypes, which are, in part, covered by PCV13 (19F) and PPSV23 (19F and 11A) and fully covered by LEPS20/PncO + GlpO. (C) Bacterial counts from the nasopharynx surface (NP), nasopharynx wash (lavage), lungs, and blood 1 and 5 days after IAV administration when challenged with 11A (left) and 35C (right) serotypes.

  • Fig. 4

    IPD incidence rates in children (age, <5) (A) and the elderly (age, ≥65) (B) from 1998 to 2040. The total incidence rate of IPD was segmented into disease caused by Prevnar 7 (PCV7), PCV13, PPSV23, and nonvaccine-type (NVT) serotypes. Nonvaccine-type serotypes are defined as those not contained in PCV13 (A) or PPSV23 (B) vaccines. Incidence rates for PCV7 serotypes from 1998 to 2007 were obtained from Pilishvili et al. (30). Total incidence rates and incidence rates for PCV13 serotypes were obtained from the Centers for Disease Control and Prevention’s Active Bacterial Core surveillance program for S. pneumoniae (www.cdc.gov/abcs/reports-findings/survreports/spneu-types.html). Incidence rates beyond 2007 (PCV7 serotypes) and 2015 (PCV13 serotypes) were predicted from trends observed in previous years. Reduction in the total IPD after Prevnar 15 (PCV15) introduction was projected on the basis of the serotype invasiveness (31, 32) and previous trends for PCV7 and PCV13 with the rates stabilizing for 4 years after the introduction of the vaccine. Projections for IPD with (dotted lines) or without (solid lines) LEPS introduction were made beyond 2030. A reduction of IPD by 80% over 4 years (A) or 90% over 10 years (B) after the introduction of LEPS was based on the 98% sequence coverage of the GlpO and PncO protein antigens (25) and activity demonstrated against 70 S. pneumoniae serotypes (fig. S2).

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/10/e1701797/DC1

    fig. S1. Commensal disease progression model featuring pneumococcal disease.

    fig. S2. The LEPS platform.

    fig. S3. LEPS characterization.

    fig. S4. Protective capabilities of LEPS immunizations when challenged with serotypes that span the current Prevnar 7 and Prevnar 13 treatment options.

    fig. S5. LEPS vaccine strategy in rabbits.

    fig. S6. OPA assay for GlpO and PncO directed against specific S. pneumoniae cell types.

    fig. S7. Evaluation of immunogenicity of GlpO and PncO administered either jointly (coadministration) or as a booster (add-on) with Prevnar 7.

    fig. S8. Additional assessment of LEPS20/PncO and GlpO when using a murine IAV-induced pneumonia model with serotype 19F.

    fig. S9. Additional murine disease model assessment of LEPS20/PncO and GlpO.

    fig. S10. Alternative LEPS formulation procedures and comparison in murine challenge protection assays.

    table S1. OPA comparison between Prevnar 13, Pneumovax 23, and a LEPS formulation containing 20 polysaccharides (that is, 20 valent).

    table S2. OPA comparison between Prevnar 13, Pneumovax 23, and the PncO + GlpO protein antigens (administered with alum adjuvant).

    table S3. GlpO and PncO summary.

  • Supplementary Materials

    This PDF file includes:

    • fig. S1. Commensal disease progression model featuring pneumococcal disease.
    • fig. S2. The LEPS platform.
    • fig. S3. LEPS characterization.
    • fig. S4. Protective capabilities of LEPS immunizations when challenged with serotypes that span the current Prevnar 7 and Prevnar 13 treatment options.
    • fig. S5. LEPS vaccine strategy in rabbits.
    • fig. S6. OPA assay for GlpO and PncO directed against specific S. pneumoniae cell types.
    • fig. S7. Evaluation of immunogenicity of GlpO and PncO administered either jointly (coadministration) or as a booster (add-on) with Prevnar 7.
    • fig. S8. Additional assessment of LEPS20/PncO and GlpO when using a murine IAV-induced pneumonia model with serotype 19F.
    • fig. S9. Additional murine disease model assessment of LEPS20/PncO and GlpO.
    • fig. S10. Alternative LEPS formulation procedures and comparison in murine challenge protection assays.
    • table S1. OPA comparison between Prevnar 13, Pneumovax 23, and a LEPS formulation containing 20 polysaccharides (that is, 20 valent).
    • table S2. OPA comparison between Prevnar 13, Pneumovax 23, and the PncO + GlpO protein antigens (administered with alum adjuvant).
    • table S3. GlpO and PncO summary.

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