Prime-Boost Immunization with Adenoviral · PDF filePrime-Boost Immunization with Adenoviral...
Transcript of Prime-Boost Immunization with Adenoviral · PDF filePrime-Boost Immunization with Adenoviral...
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Prime-Boost Immunization with Adenoviral Vaccines
Robert A. Seder, M.D. April 18th, 2012
Dale and Betty Bumpers
Vaccine Research Center National Institute of Allergy and Infectious Diseases National Institutes of Health
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Immune Requirements for Vaccines: HIV, Malaria and Tuberculosis
• HIV, Malaria and TB vaccination will require generation of antibody and/or T cell responses: • Phase III efficacy trials for HIV and Malaria have shown ~30%
protection correlating with antibody • CD8+ T cells will improve HIV viral control or malaria in the liver
• CD8+ T cells can be induced by:
• Protein/DC Targeted Vaccines: • Requires cross-presentation-low magnitude
• DNA Vaccines: Require multiple immunizations • Viral Vaccine Vectors:
• Most efficient method of inducing robust T cell immunity
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Priming: How do novel chAds compare to human rAds for
induction of protective CD8 T cell responses?
Question
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Experimental Outline
Day 0 Vaccinate
Group: Vaccine:
1 rAd5:SIV-Gag
2 rAd28:SIV-Gag
3 rAd35:SIV-Gag
6 chAd3:SIV-Gag
7 chAd63:SIV-Gag
8 PBS
Days 14, 21, 28, 35 and 70 Peripheral blood- CD8+ SIV Gag Tetramer time course
• Administered each vector : •1 x 109 PU
•1 x 108 PU
•1 x 107 PU
• Vaccinated SQ in footpad
Day 90-100 Infectious challenge
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Dose Titration of Vectors Correlates With Hierarchy Observed in Clinical Studies
SIV-Gag specific CD8+
T cells (%)
Days after vaccination
rAd5 rAd28 rAd35
chAd63 chAd3
1 x 109 PU 1 x 108 PU 1 x 107 PU PBS
Key to dose:
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0 25 50 750
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A Predictive Hierarchy for CD8+ T Cell Immunity Is Observed at 1 x 107 PU Dose
SIV-Gag specific CD8+ T cells (%)
0 25 50 750
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rAd5 rAd28 rAd35 PBS
Key to vectors: rAd5 chAd3 chAd63 PBS
Key to vectors:
0 25 50 750
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SIV Gag specific CD4+ T cell responses were low and comparable for all Ads
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TNF+ IL-2+ TNF+ IL-2+
IFN-g+ TNF+ IL-2+
IFN-g+
Differentiation Terminal effector
Naïve cell
IFN-g+ TNF+
IFN-g+ IL-2+
CD8
IFN-g
TNF
CD4
T Cell Quality
Darrah et al, Nat Med, 2007: Using Leishmania major infection model: • Protective vaccines induced CD4 Th1 cells
that co-expressed IFN-g, IL-2 and TNF • CD4 Th1 cells that co-expressed 3
cytokines had higher MFI
3 cytokines 2 cytokines 1 cytokine Key to IFN-g, IL-2 and TNF co-expression:
Betts et al, Blood, 2006: Using HIV long-term non-progressors: • Lower long-term viral load has more multi-
functional cells • Includes MIP1b, CD107a (degranulation)
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In spleen at day 70 post-vaccination:
G+ 2+ T+ G+ 2+ T- G+ 2- T+ G+ 2- T- G- 2+ T+ G- 2+ T- G- 2- T+ Key:
rAd5:
1 x 109 PU 1 x 108 PU 1 x 107 PU
Quality of Ad5 CD8+ T Cells
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CFUs in spleen (log10)
1 x 10e9 PU 1 x 10e8 PU Key: 1 x 10e7 PU
rAd5 rAd28 rAd35 PBS chAd63 chAd3 PBS rAd5
Protection Against Listeria-SIV Correlates With CD8 Response Magnitude
0 5 10 153
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5
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7
hAd5 Control
aCD4 aCD8
+ - - - - - - -
+ + - -
+ - + -
+ - - +
+ - + +
% SIV Gag CD8 T cells
CFUs in spleen (log10)
0 5 10 153
4
5
6
7 y = -0.1647x + 5.4151 R² = 0.27259 P < 0.0001
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• Chimp-derived Ad vectors potently induce Gag- specific CD8+ T cell responses • Have a broad range of effective dose compared to low
sero-prevalent human-derived vectors • chAd3 protects against Listeria challenge at all doses
and against Ebola in NHP
•Dose titration highlights hierarchy in magnitude and protective capacity responses between the vectors at the lowest dose:
Summary
rAd5 rAd35 ≈ chAd3 > chAd63 = rAd28 > >>
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• What is the mechanistic basis for the hierarchy in CD8 immunity? • How do these vectors differ in:
• Amount or duration of antigen expression? • Innate immunity?
Question
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Prime-Boost Immunization for HIV Vaccines
• HIV Phase III Trials
– ALVAC (Env/Gag)-Env Protein/Alum (RV-144)-~30% Protection
– DNA (Env/Gag)-Ad5 (Env/Gag) (HVTN 505)-Ongoing
Ongoing and Future Clinical Studies
– DNA-Pox (MVA, NYVAC)
– Ad26-MVA
Question: What is optimal Prime-Boost Regimen for inducing robust HIV Env and Gag immunity
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Prime-Boost Immunization for HIV Vaccines
• Prime
– Compare DNA vs rAd priming- Does the magnitude of the primed CD8+ T cell response correlate with improved immunity after boosting?
• Boost
– Compare potency of Pox versus Ad viral boost for CD4 and CD8+ T cell responses
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0 10 20 30 40 50 60 700
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rAd28 / -
- / rAd5
- / chAd3
- / -0 10 20 30 40 50 60 70
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rAd28 / rAd5
rAd28 / chAd3
rAd28 / -
- / rAd5
- / chAd3
- / -0 10 20 30 40 50 60 70
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rAd28 / -
- / -0 10 20 30 40 50 60 70
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DNA / -
- / rAd5
- / chAd3
- / -0 10 20 30 40 50 60 70
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DNA / rAd5
DNA / chAd3
DNA / -
- / rAd5
- / chAd3
- / -
rAd5 and chAd3 Strongly Boost DNA or Ad28 Primed CD8+ T Cell Responses
0 10 20 30 40 50 60 700
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DNA / -
- / -
Key to Prime / Boost:
Key to Prime / Boost:
Days after boost
% of CD3+CD8+ T cells that are
Tetramer+
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NYVAC Boosts Ad-Primed CD8 T cell Responses More Robustly than Heterologous chAd3
Days after boost
Key to Prime / Boost:
Key to Prime / Boost:
% of CD3+CD8+ T cells that are
Tetramer+
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chAd3 boosted
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NYVAC boosted
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PBS
0 10 20 30 40 50 60 700
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chAd3
PBS
0 10 20 30 40 50 60 700
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rAd5
rAd28
rAd35
chAd3
PBS
0 10 20 30 40 50 60 700
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rAd5
rAd28
rAd35
chAd3
PBS
0 10 20 30 40 50 60 700
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rAd5
rAd28
rAd35
chAd3
PBS
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rAd35
PBS
0 10 20 30 40 50 60 700
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PBS
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Prime-Boost Immunization with Ad and Pox Induce Potent HIV Env Specific CD4+ T Cell Responses
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
MVA Boost
chAd 63
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
Priming
chAd 63
HIV Env CD4+/IFN-g
Responses (%)
Time of Boost Peak Post Boost
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Quality of a Primed-Boosted CD4+ T Cell Response
rAd5 rAd28 rAd35 MVA
Time of MVA boost
Peak post MVA boost
rAd5 rAd28 rAd35 MVA
Ad prime at 1 x 108 PU:
G+ 2+ T+ G+ 2+ T- G+ 2- T+ G+ 2- T- G- 2+ T+ G- 2+ T- G- 2- T+
Key to pies:
Key to arc: IFNγ production
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Prime-Boost Immunization with Ad and Pox Induce Potent HIV Env Specific CD8+ T Cell Responses
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
MVA Boost
chAd 63
rAd 5
rAd 28
rAd 35
chAd 3
MVA chAd 3 Ctl
Priming
chAd 63
HIV Env CD8+/IFN-g
Responses (%)
Time of Boost Peak Post Boost
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Quality of a Primed-Boosted CD8+ T Cell Response
rAd5 rAd28 rAd35 MVA
Time of MVA boost
Peak post MVA boost
rAd5 rAd28 rAd35 MVA
Ad prime at 1 x 108 PU:
G+ 2+ T+ G+ 2+ T- G+ 2- T+ G+ 2- T- G- 2+ T+ G- 2+ T- G- 2- T+
Key to pies:
Key to arc: IFNγ production
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• Priming:
•Ad 28, ChAd 3, ChAd 63 efficiently prime T cells •Ad35 is limited for priming CD4 and CD8 T cell immunity •Pox viral vectors are limited for priming CD8+ T cells
• Boosting:
• Pox viral vectors potently boost CD4, CD8 and Ab responses and are true heterologous boost following Ad priming • Multiple Ad vectors boost T cell responses
•Maintenance:
•For CD4+ T cells and antibody- pox or protein/adjuvant vaccines can be used •For CD8+ T cells will need Ad or Pox
Summary: Lessons Learned