basic and clinical immunology of pneumococcal vaccines
TRANSCRIPT
Basic and Clinical Immunology of Pneumococcal
Vaccines
Richard Insel
Juvenile Diabetes Research Foundation
9/9/2003
Licensed Pneumococcal VaccinesPolysaccharideSaccharide-protein conjugates
Other Pneumococcal VaccinesProtein vaccines
T BAPC
Adaptive ImmunityInnate Immunity
Immunologic Responses to Vaccines
Activation of Antibody Responses by Vaccines
Antibody Secreting
Plasma Cell
Peptide-specific T Cell
Dendritic Cell
ActivatedT Cell
B Cell
Vaccine Antigens +/-
Adjuvant
Memory B Cell
2º Immunization
Activation of Antibody Responses by Vaccines
Antibody Secreting
Plasma Cell
Peptide-specific T Cell
Dendritic Cell
ActivatedT Cell
B Cell
Vaccine Antigens +/-
Adjuvant
Memory B Cell
2º Immunization
Germinal Center
Lightzone
Darkzone
BCR
Plasma Cell (short lived)
CD 40LCD 40
CD 28
CD 86
Extrafollicular (PALS)
T lymphocyte
B lymphocyte
B Cell Activation in Secondary Lymphoid Tissues
DC
Memory B Cell
Centroblasts
Centrocytes
Cell ProliferationTelomere MaintenanceV Gene Hypermutation
Isotype Switching
FDC
DarkZone
LightZone
Affinity MaturationSelection/Apoptosis
B Cell Development in Germinal Centers
Plasma Cell (long lived)
TT
T
B Cell Activation by Conjugate Vaccines
• Proliferation- clonal expansion
• Differentiation to antibody-secreting plasma cell
• Differentiation to memory B cell
• Maturation of naïve, “immature” B cell of infant to a polysaccharide-responsive B cell, conjugate priming
Memory B CellGC B cell
Naïve B cell
CD27/CD70OX40L/OX40
GC Precursor
Short Lived Plasma Cell
EXTRAFOLLICULAR GERMINAL CENTER (GC)
Dark Zone Light Zone
Isotype SwitchingAffinity Maturation Selection
Memory GenerationSecondary Antibody Responses
Primary Antibody Responses
Clonal ExpansionSomatic Hypermutation
CD40/CD40LCD40/CD40L
Development of Plasma Cells and Memory B Cells: Receptor-Ligand Interactions
Long Lived Plasma Cell
Long Lived Plasma Cell
Contribution to and Maintenance of Serum Antibody
• Short-lived plasma cells- days-wks
• Long-lived plasma cells- months
• Reactivation of memory B cells- years– Persistent antigen (PS)– Cross-reactive antigen (microbial flora)– Polyclonal activation by T cell cytokines
(e.g. IL-15), CpG stimulation
PS Activation of Antibody Responses
Antibody Secreting
Plasma Cell
Dendritic Cell B Cell
TACIBLyS, APRIL
PSCD21
Ab C3d
B Cell Activation by Conjugate Vaccines
• Proliferation- clonal expansion• Differentiation to antibody-secreting plasma
cell• Differentiation to memory B cell
• Maturation of naïve, “immature” B cell of infant to a polysaccharide-responsive B cell, conjugate priming
PS Activation of Antibody Responses
Antibody Secreting
Plasma Cell
Dendritic Cell B Cell
TACIBLyS, APRIL
PSCD21
Ab C3d
“Maturation”
Immat B Cell
Conjugates, Environmental Antigens (via BCR,TLR,etc)
PS Activation of Antibody Responses
Antibody Secreting
Plasma Cell
Dendritic Cell B Cell
? Memory B Cell
? GC Independent
TACIBLyS, APRIL
PSCD21
Ab C3d
? Persistent Ag, cross-reactive Ags,
cytokines
? “Matured”
Human Antibody to Polysaccharides
• Restricted V gene repertoire (Vh3), limited heterogeneity, oligoclonal, “set-point”
• Wide individual variation in responses- genetic control of post-imm IgG, IgG2 Ab titer, avidity, ability to respond, overcome with conjugates
• Functional Ab important- Avidity, OPA
Adult Ab Responses to Pneumococcal Conjugates
• IgG2 predominates in “natural” and vacc-induced Ab in adult
• Conjugates induce IgG, some IgG1 and prominent IgG2 with IgG2 predominance post-imm (difference vs. infants), some IgM and IgA Ab
• PS vaccines induce IgG1 and prominent IgG2 with IgG2 predominance post-imm, IgM, IgA Ab
(Soininen, A, et al. Vaccine 17:1889, 1999; Wuorimaa, T et al. Vaccine 19:1863, 2001)
Adult Ab Responses to Pneumococcal Conjugates
• In general, conjugates may induce total Ab, IgG1 and IgG2 Ab, % with 2-fold IgG1 increases, and IgG1 Ab/IgG2 Ab, AbSC sltly > PS induced Ab – but-
• Individual host, conjugate vaccine, serotype variation
• Limited increase in post-immunization Ab avidity
(Soininen, A, et al. Vaccine 17:1889, 1999; Wuorimaa, T et al. Vaccine 19:1863, 2001)
Outstanding Questions
• ? Superiority of conjugates vs PS in healthy and elderly adults– Titers-magnitude and persistence– Avidity– Functional Ab (OPA)– Memory
• Role of conjugates alone or with PS• Issues in elderly adults
Immune Responses in Aged Adults
• Poor primary antibody responses• Poor generation and maintenance of memory• Low avidity antibody with poor function • Decreased helper T cell activity• Decrease in frequency of B-cell precursors,
B cell responses, Ab secretion/B cell• Accessory cell defect• Wide individual variation
Outstanding Questions
• Role of memory vs circulating antibody in protection
• Bacteremic vs non-bacteremic pneumonia
• Prevention of carriage
• Individual serotype and population host variation
• Limited vaccine serotypes
• ? Serotype replacement
• ? Decreased immunogenicity with increased vaccine serotypes
• Cost and complexity of manufacturing
Pneumococcal Conjugate Vaccines: Limitations
Pneumococcal Protein Vaccine Candidates
Pneumococcal Protein Vaccine Candidates
VaccineCandidate
BacteremiaProtection
PneumoniaProtection
CarriageProtect
Cross-SerotypeProtection
HumanTrials
PspA ++ ++ + +/- Phase 1
PspC + ++ +/-
PsaA - - ++ +
Pneumolysoid + ++ - +
I.N. Bacteria - + ++ +
PspA + PsaA +,Pneumolysoid
+++ +++ ++ +
Issues with Protein Vaccine Candidates
• What are immune correlates of protection?
• Pneumococcus- variability, recombinogenicity, replacement
• How predictive are the animal models?
• Role of prevention of carriage