# Presentation: 612043

## Basic and Clinical Immunology of Pneumococcal Vaccines

- <date/time>

- Basic and Clinical Immunology of Pneumococcal Vaccines

- Richard Insel
- Juvenile Diabetes Research Foundation
- _[rinsel@jdrf.org](mailto:rinsel@jdrf.org)_
- 9/9/2003

## Licensed Pneumococcal Vaccines

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- 	Polysaccharide
- 	Saccharide-protein conjugates

- Other Pneumococcal Vaccines
- 	Protein vaccines

## Immunologic Responses to Vaccines

- <date/time>

- T

- B

- APC

- Adaptive Immunity

- Innate Immunity

## Activation of Antibody Responses by Vaccines 

- <date/time>

- Activation of Antibody Responses by Vaccines

**Antibody **
**Secreting**
**Plasma Cell**** **

**Peptide-specific **
**T Cell**

**Dendritic Cell**

**Activated**
**T Cell**

**B Cell**

- Vaccine Antigens +/- Adjuvant

- Memory
- B Cell

- 2o Immunization

## Activation of Antibody Responses by Vaccines 

- <date/time>

- Activation of Antibody Responses by Vaccines

**Antibody **
**Secreting**
**Plasma Cell**** **

**Peptide-specific **
**T Cell**

**Dendritic Cell**

**Activated**
**T Cell**

**B Cell**

- Vaccine Antigens +/- Adjuvant

- Memory
- B Cell

- 2o Immunization

## B Cell Activation

- <date/time>

- Germinal Center

- Light
- zone

- Dark
- zone

- BCR

- Plasma Cell (short lived)

-  CD 40L

- CD 40

- CD 28

- CD 86

- Extrafollicular
-  (PALS)

- T lymphocyte

- B lymphocyte

-  in Secondary Lymphoid Tissues

- DC

## B Cell Development in Germinal Centers

- <date/time>

- Memory B Cell

- Centroblasts

- Centrocytes

- Cell Proliferation
- Telomere Maintenance
- V Gene Hypermutation

- Isotype Switching

- FDC

- Dark
- Zone

- Light
- Zone

- Affinity Maturation
- Selection/Apoptosis

- Plasma Cell    (long lived)

- T

- T

- T

## B Cell Activation by Conjugate Vaccines

- <date/time>

- 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

## Development of  Plasma Cells and Memory B Cells: 

- <date/time>

**Memory B Cell**

**GC B cell**

**Naïve B cell**

**CD27/CD70**
**OX40L/OX40**

**GC Precursor **

**Short Lived Plasma Cell**

**EXTRAFOLLICULAR**

**GERMINAL CENTER (GC)**

**Dark Zone**

**Light Zone**

**Isotype Switching**
**Affinity Maturation Selection**
**Memory Generation**
**Secondary Antibody Responses**

**Primary Antibody Responses**

**Clonal Expansion**
**Somatic Hypermutation**

- 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

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- 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

- <date/time>

**Antibody **
**Secreting**
**Plasma Cell**** **

**Dendritic Cell**

**B Cell**

- TACI

- BLyS, APRIL

- PS

- CD21

- Ab

- C3d

## B Cell Activation by Conjugate Vaccines

- <date/time>

- 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

- <date/time>

**Antibody **
**Secreting**
**Plasma Cell**** **

**Dendritic Cell**

**B Cell**

- TACI

- BLyS, APRIL

- PS

- CD21

- Ab

- C3d

-  “Maturation”

**Immat B Cell**

- Conjugates,  Environmental Antigens (via BCR,TLR,etc)

## PS Activation of Antibody Responses

- <date/time>

**Antibody **
**Secreting**
**Plasma Cell**** **

**Dendritic Cell**

**B Cell**

**? Memory **
**B Cell**

- ? GC Independent

- TACI

- BLyS, APRIL

- PS

- CD21

- Ab

- C3d

- ? Persistent Ag, cross-reactive Ags, cytokines

- ? “Matured”

## Human Antibody to Polysaccharides

- <date/time>

- 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

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- 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

- <date/time>

- 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

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- ? 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

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- 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

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- 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

- <date/time>

- Limited vaccine serotypes
- ? Serotype replacement
- ? Decreased immunogenicity with increased vaccine serotypes
- Cost and complexity of manufacturing

- Pneumococcal Conjugate Vaccines: Limitations

## Pneumococcal Protein Vaccine Candidates

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**Pneumococcal Protein Vaccine**** ****Candidates**

## Pneumococcal Protein Vaccine Candidates

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## Issues with Protein Vaccine Candidates

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- What are immune correlates of protection?
- Pneumococcus- variability, recombinogenicity, replacement
- How predictive are the animal models?
- Role of prevention of carriage