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Strategies for Vaccine Design. Jay A. Berzofsky, M.D., Ph.D. Chief, Vaccine Branch, CCR, NCI. Preparing for Biothreats: Emerging and Re-emerging Infectious Diseases Boston University, Boston, MA, December 14, 2005. Rationale.

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strategies for vaccine design

Strategies for Vaccine Design

Jay A. Berzofsky, M.D., Ph.D.

Chief, Vaccine Branch, CCR, NCI

Preparing for Biothreats: Emerging and Re-emerging Infectious Diseases

Boston University, Boston, MA, December 14, 2005

slide2

Rationale

  • For viruses causing acute, self-limited infections, the most widely used strategy is to mimic the natural infection with an attenuated, inactivated, or subunit vaccine.
  • However, for viruses causing chronic infection, such as HIV or hepatitis C virus, or for cancer, the natural disease does not induce sufficient immunity to eradicate the infection or tumor.
  • A vaccine must elicit better immunity than the virus or cancer itself.
vaccine strategies to elicit cytotoxic t lymphocytes ctl need to focus on several properties
Vaccine strategies to elicit cytotoxic T lymphocytes (CTL) need to focus on several properties:
  • Quantity of CTL.
  • Avidity of CTL ==> Greater efficacy at clearing virus or killing tumor
  • Longevity or memory of CTL.

Strategies based on use of:

Cytokines

Costimulatory molecules

Inhibitors of negative regulation

Enhanced epitopes--sequences modified to increase binding to MHC molecules

Targeting of vaccines to mucosal sites

slide5

Peptide Fragments of Viral Proteins Bind Specifically in the Grooveof Major Histocompatibility Molecules such as HLA-A, B, C

Sendai Virus Peptide Bound to H-2Kb

From DH Fremont, M. Matsumura, EA Stura, PA Peterson,

& IA Wilson. Science 257: 919-926, 1992

Strategy: Epitope Enhancement by Sequence Modification to Increase Peptide Affinity for the MHC Molecule

slide6

IL-2 & IL-15: SHARED FUNCTIONS IN IMMUNE SYSTEM

(ADOPTIVE IMMUNITY)

Macrophage

DC

Epithelium

BM Stroma

Activated

CD4

IL-2

IL-15

B

CTL

CD4

CD8

Proliferation

Effector

Function

Proliferation

IgA

slide7

IL-2 & IL-15: DISTINCT FUNCTIONS

IL-15

IL-2

Activated

T cells

Memory

T cells

Mast cell

proliferation

Antigen-

Induced

Cell Death

NK cell

development

Maintenance

slide8

Boosted

Unimmunized

5

vPE16

vPE16/VV-IL-15

vPE16/VV-IL-2

4

% of IFN-gamma producing

CD8+ T cells

3

2

1

0

6 months

8 months

3 wks

2 months

14 months

4 months

Time after Booster Immunization

IL-15 expression by a vaccine vector induced longer-lived

memory CD8+ CTL: IFN-gamma-producing cells

Explained by 1. Higher IL-15Ra expression

2. Greater homeostatic proliferation

Oh et al., PNAS 2003

slide9

Immunization with antigen + IL-15 induces higher avidity memory CD8+ CTL

vPE16

120

vPE16/IL-15

100

80

% of maximum lysis

60

40

20

0

1

10

0.1

0.01

0.001

1E-05

0.0001

Control

Target cells pulsed with [P18-I10], mM

2 months after immunization

Oh et al., PNAS 2004

slide10

High Avidity CTL Clear Virus Infection in SCID Mice

More Effectively Than Low Avidity CTL

Alexander-Miller et al., PNAS 1996

improved viral clearance by high avidity ctl

Improved viral clearance by high avidity CTL

Low

avidity

CTL

High

avidity

CTL

Derby et al., J. Immunol. 2001

slide12

Role of IL-15 and costimulation in CTL Avidity Maturation

APC

IL-15 in vaccine

Signal 1

Signal 2

CD8 T cells

Strong

Signal 2

Selection

Induction

Increased survival

and

Homeostatic proliferation

Increased

CD8 ab

Higher

functional avidity

Induction at

individual cell level

Selection at

population level

High

Avidity

CTL

Increased

IL-15Ra

IL-15

Oh et al. J. Immunol. , 2003; and Oh et al. PNAS, 2004

slide13

IL-15 with vaccine

CD4+ Helper T cell

CD40L

IL-15

IL-12

TCR

B7 costimulator

CD4+ T-cell Help for CD8+ CTL Mediated Through Activation of Dendritic Cell

+

CD8 Cytotoxic T cell

TCR

CD28

MHC

Class I

CD40

MHC

Class

II

Dendritic Cell

slide14

Immunotherapy of cancer or HIV is still not an established modality of treatment.

WHY?

Immune suppression by tumor or HIV

Immune evasion

Immune suppression

by immune cells

M2 macrophages

or tumor associated macrophages (TAM)

Myeloid suppressor cells (MSC)

CD4+CD25+ T regulatory cells (Treg)

Natural Killer (NK) T cells

regulatory suppressor t cells

Ts

Th3

Tr1

NKT

TReg

Regulatory/Suppressor T cells

CD4

Contact inhibition MHC class II-restricted

CD25 (IL-2Ra)

TGF-bMHC class II-restricted

abTCR

IL-10 (& TGF-b) MHC class II-restricted

CD4

IFN-g, IL-4, IL-13CD1d-restricted

NK1.1

CD8

? Qa-1-restricted

abTCR

slide16

TGF-

IL-13

NKT cells and IL-13 suppress CTL tumor immune surveillance though the IL-4R-STAT6 pathway

to induce TGF-b production by CD11b+Gr-1+ cells

CTL

Tumor cells

tumor lysis

suppression of CTL activation

APC

glycolipid

CD1d

CD1d-restricted

CD4+NKT

IL-4Ra

IL-13Ra1

STAT6

CD11b+ Gr1+

Terabe et al., Nat Immunol, 2000., Terabe et al., J Exp Med, 2003.

slide17

CD1- KO

Wild-type BALB/c

anti-CD8

anti-CD4

anti-CD4,CD8

Absence of CD1d-restricted NKT cells unmasks CD8+ Cell-

dependent immunosurveillance and not improved

by deletion of CD4+ Cells

>250

200

150

Number of Nodules

100

Lungs stained with India ink

for contrast

50

0

Untreated

RatIgG

BALB/c

CD1-KO

Park et al., Internat. J. Cancer, 2005.

slide18

Prevention of lung tumor metastases of CT26 by anti-TGF-b antibody

Number of nodules/lung

control

mAb(13C4)

control

anti-TGF-b

(1D11)

Terabe et al., J Exp Med , 2003

slide19

Conclusions: CT26 model

CTL

Tumor cells

tumor lysis

suppression of CTL activation

APC

TGF-

IL-13

CD1d

glycolipid

CD1d-restricted

CD4+NKT

IL-4Ra

IL-13Ra1

STAT6

CD11b+ Gr1+

  • Even in a non-regressor tumor model, this new immunoregulatory circuit plays a role in suppressing CD8+ CTL-mediated immunosurveillance.
  • Abrogation of this pathway unmasks otherwise inapparent spontaneous natural tumor immunosurveillance and reduces tumor growth even in the absence of any vaccine or other immunotherapy.
slide20

Enhancement of Vaccine Elicited CD8+ CTL response by in vivo treatment with an IL-13 inhibitor

Immunization: PCLUS6.1-P18 +GM-CSF+CD40L

% specific lysis

E:T ratio

Ahlers et al.

PNAS, Oct. 2002

slide21

INTRARECTAL IMMUNIZATION WITH SYNTHETIC PEPTIDE

HIV VACCINE INDUCES BOTH SYSTEMIC AND MUCOSAL CTL

TARGET CELLS

+ peptide

- peptide

Intrarectal

Subcutaneous

Immunization

Immunization

SPLEEN

PEYER'S PATCH

LAMINA

PROPRIA

0

10

20

30

40

50

0

10

20

30

40

50

% SPECIFIC LYSIS AT 50:1

Belyakov et al. PNAS 1998

slide24

Berzofsky et al., Nature Reviews Immunology 2001;

Belyakov et al., Nature Medicine, 2001.

slide26
Comparison of Mucosal Peptide or Poxviral Vaccine with Peptide-Prime, Poxviral Boost in Rhesus Macaques

Prime

Boost

All animals received GM-CSF, IL-12, CpG, and LT(R192G)

In DOTAP with or without peptide at the times of peptide priming.

slide27

Peptide-Prime/NYVAC Boost Mucosal Vaccine Delays Acute

Peak Viremia, Suggesting Delayed Dissemination from

Mucosal Site of Transmission

Belyakov et al., Blood, in press 2006

slide28

7

6

5

4

3

2

1

0

0

1

2

3

4

Strong inverse correlation between vaccine-induced Tetramer+CD8+ T cells in colon before challenge and viral load in blood after challenge

r = -0.84; p<0.00001

Viral Load (log10)

% CL10-Tetramer+CD8+

Belyakov et al., Blood, in press 2006

slide29

No correlation between vaccine-induced Tetramer-binding T cells in blood before challenge and viral load in blood after challenge

r = 0.007, p > 0.7

7-

6-

5-

4-

Viral Load (log10)

3-

2-

1-

0-

% CL10-Tetramer+CD8+

Belyakov et al., Blood, in press 2006

slide30

Inverse Relationship with Viral Load is greater for high avidity CTL

Day 17 after Challenge

Low avidity

Viral load (log10)

High avidity

Belyakov et al., Blood, in press 2006

conclusions
Conclusions
  • Natural transmission of many viruses is through mucosal surfaces. High avidity mucosal CTL may prevent or reduce dissemination from this site and abort the infection.
  • Mucosal immunization is most effective at inducing mucosal CTL.
  • CTL avidity is critical in clearing virus infections.
  • CTL avidity & longevity can be increased by immunization in the presence of IL-15 or costimulatory molecules.
  • Immunogenicity can be increased by
    • Use of appropriate cytokines
    • Epitope enhancement by sequence modification to increase binding to MHC molecules
    • Blockade of negative regulatory pathways, including NKT cells and T reg cells, IL-13 and TGF-beta