T-cell HIV Vaccines Giuseppe Pantaleo, M.D. Professor of Medicine Director, Swiss Vaccine Research...
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Transcript of T-cell HIV Vaccines Giuseppe Pantaleo, M.D. Professor of Medicine Director, Swiss Vaccine Research...
T-cell HIV Vaccines
Giuseppe Pantaleo, M.D.Professor of MedicineDirector, Swiss Vaccine Research InstituteLausanne, Switzerland
Challenges In The Development Of An HIV Vaccine
Identification of immune correlates of protection
Induction of a broad neutralizing antibody response
Induction of effective T cell responses
Viral diversity
Viral escape
Super-infection
Influence of genetic background
Induction of mucosal and systemic immunity
Complexity of immunization regimens
Vaccine Concepts and Designs
Live Vectors DNA Combination of Elements Peptide Epitopes (limited immunogenicity) Pseudovirions (pre-clinical) Live-Attenuated (Not Under Study in
Humans) Whole-Killed (Not Under Study in Humans) Recombinant Viral Proteins
Due to the Lack of Protein-Based Env
Vaccines Able To Induce Neutralizing
Antibodies, Candidate HIV Vaccines Have
Been Designed Primarily to Induce T-Cell
Immune Responses
T-cell Vaccines Do Not Prevent Infection
But They Will Be Eventually Associated
with Control of Virus Replication and
Prevention of HIV-Associated Disease
T-cell HIV Vaccines Concept
T-Cell HIV Vaccine Concept
Help CTL
Vaccine
----Virus
Placebo
Virus
exposure
Rationale for the Effectiveness of HIV
T-Cell Vaccines
- Certain experimental vaccines confer protection in monkeys infected
with SIV
- There is evidence that HIV-1-specific T-cell responses may confer
protection (e.g. exposed non-infected subjects)
- A small percentage (<5%) of HIV-1-infected subjects show no signs of
disease progression (e.g. long-term nonprogressors)
- A decrease in viral load is associated with clinical benefit
Low responder High responder
Effective immunity induced by rAd5 HIV (SIV) vaccine in a SIV challenge model
Interpretation This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level.
Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine
recipients are being explored.
Vol. 307 November 29, 2008
Vol. 307 November 29, 2008
Vol. 307 November 29, 2008
Interpretation Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nefvaccine was highly immunogenic for inducing HIV-
specific CD8+ T cells. Our findings suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or
differ in breadth or function from those recorded in this trial.
Messages from the Step Study
The Step study marks the end of the HIV T-cell vaccine concept (at least of the Ad5 vector used alone)
It draws the attention on the potential danger of pre-existing immunity
It shows a potential sinergy between Ad5 pre-existing immunity and circumcision with regard to the observed increased in HIV acquisition
It indicates that the magnitude and the quality (breadth) of the vaccine-induced T-cell responses (particularly CD8 T-cell responses) are not optimal
CONCLUSIONS
This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a
community-based population with largely heterosexual risk. Vaccination did not affect the viral load or
CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer
insight for future research. (ClinicalTrials.gov number, NCT00223080.)
Major Messages from the RV-144 Study
The vaccine combination is potentially more effective (61% reduction of HIV acquisition at 1 year post vaccination)
The vaccine protective effect is waning over time (31.2% at 3 years post-vaccination)
The delta in the reduction of the number of infections is 18 (30 in the placebo vs. 12 in the vaccine group) at 1 year and 23 (74 in the placebo vs. 51 in the vaccine group) at 3 years
Therefore, most of the protective effect is gained during the 1st year post-vaccination
RV-144 Results and Immunological Issues
The limited set of immunological results of the RV-144 trial do not allow to rule out or to favor any specific cellular or humoral mechanism of protection.
In this regard:• The same protein component of the vaccine combination was not
associated to protection when used alone in the Vaxgen phase III trial. However, due to differences in the target population, i.e. high risk IVDU population in the Vaxgen trial versus low risk in the RV-144 trial, the two studies cannot be compared.
• The poxvirus component of the vaccine, i.e. ALVAC, was never previously tested in phase III trial.
RV-144 Results and Immunological Issues
The results of the RV-144 trial re-underscore a number of immunological issues that have been repetitively raised in the recent past but have never been concretely addressed. These include:• the need of developing an integrated vaccine-induced immune
response (innate plus humoral plus adaptive)• the exploration of additional mechanisms of protection beyond
the conventional CD4 and cytotoxic CD8 T-cell and neutralizing antibody responses
What Is Next?
Improvement of the Current Vaccine Combination
Augment (above the 61% efficacy observed at 1 year post-infection) the overall protection from infection
Induce durable protection Improve both components of the vaccine, i.e. the
priming component (ALVAC) and the boosting component (the Env protein)
20
What Is Next?
Vaccine candidates Poxvirus-based vectors
- NYVAC- MVA- ALVAC
Adenovirus- Ad26- Ad35
DNA vectors Protein
- gp140 monomer or trimer
November 15, 2008, Vol. 198
November 15, 2008, Vol. 198
DNA-C + NYVAC-C PlatformHarari et al. JEM, 2008; Bart et al., Vaccine, 2008; McCormack, Vaccine, 2008
Supported by the European Union, EuroVacc, ANRS and CAVD
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Clinical Trial Design
Randomized trial with a parallel group design
Open to the participants and investigators but blind to laboratory personnel
Attendance to clinics at least 14 occasions over 72 weeks
0 4 8 20 24 28 48 72Weeks
Group 1 (n=74)
Group 2 (n=73)
DNA-C (4 mg) priming at week 0, 4 and 8 for group 1 at week 0 and 4 for group 2
NYVAC-C (107.5
PFUs) boosting at week 24 for group 1 and at week 20 and 24 for group 2
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Proportion of Responders at Primary Endpoints (Week 26/28)
ITT Analysis 3 x DNAn = 70
2 x DNAn = 70
Total n = 140
Response 64 (91%) 56 (80%) 120 (86%)
PP Analysis 3 x DNAn = 67
2 x DNAn = 68
Total n = 135
Response 63 (94%) 55 (81%) 118 (87%)
Chi2 Test: p = 0.053; Risk difference: 11.4% (95% CI 0.0 – 22.9%)
Chi2 Test: p = 0.021; Risk difference: 13.1% (95% CI 2.2 – 24.1%)
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Proportion of Responders Over Time
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Magnitude of IFN-g ELISpot Responses at Week 26/28 Overall (SFUs/106 cells)
Week 26 Week 28
ITT Analysis3 x DNA
n=582 x DNA
n=503 x DNA
n=612 x DNA
n=54
Mean (SD)Median
(IQR;range)
774 (622) 545
(340-1101;75-3454)
398 (318) 328
(178-488;63-1514)
597 (519) 445
(170-855; 88-2773)
357 (319) 235
(123-505;60-1326)
Mann-Whitney test
p<0.001 p<0.001
Note: Sum of SFU/Mio cells from all peptide pools with a positive response per participant
TVDCPoxvirus T Cell Vaccine Discovery
Consortium30
Magnitude of IFN-g ELISpot Responses at Week 26/28 (ITT)
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
ENV Other ENV Other ENV Other ENV Other
3 x DNA 2 x DNA
SFUs/Mio cells
Week 28Week 26Week 28Week 26
Note: Magnitude statistically different between groups for Env at both weeks but not for
Gag/Pol/Nef (Other)
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Functional Profile of HIV-Specific T-Cell Responses
Neg
Env 1
Env 2
Subject#1042
Gr#1
0 10
2
10
3
10
4
10
5
<APC-A>
0
10
2
10
3
10
4
10
5
0.033 2.99e-3
1.2e-31000 10
2
10
3
10
4
10
5
<APC-A>
0
10
2
10
3
10
4
10
5
0.013 2.39e-3
1.79e-3100
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.05 0.019
1.65e-399.90 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.031 0.017
3.71e-399.9
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.069 0.13
7.13e-399.8
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.04 0.11
0.03299.8
IL-2
IFN-
TN
F-α
CD4 T-cell responses
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.036 0.013
0100
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
8.5e-3 0
8.5e-3100
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.093 0.22
4.18e-399.7
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.019 0.077
0.1299.8
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.067 0.027
3.54e-399.9
0 10
2
10
3
10
4
10
5
0
10
2
10
3
10
4
10
5
0.016 2.66e-3
0.017100IL
-2 TN
F-α
IFN-
CD8 T-cell responses
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Group = Gr1 Group = Gr2
0
0.1
0.2
0.3
0.4
IFNgIL-2
TNFa(Pies)(Bar#)
+++
++-
+-+
+--
-++
5
-+-
--+
---
Excluded values: stimulation = SEB; stimulation = NEGAveraged over: patients ID; stimulationThreshold = 0
Group = Gr1Group = Gr2
Group = Gr1 Group = Gr2
0
0.1
0.2
0.3
0.4
IFNgIL-2
TNFa(Pies)(Bar#)
+++
++-
+-+
+--
-++
5
-+-
--+
---
Excluded values: stimulation = SEB; stimulation = NEGAveraged over: patients ID; stimulationThreshold = 0
Group = Gr1Group = Gr2
0
0.1
0.2
0.3
0.4
IFNg
IL-2
TNFa
+
+
+
+
+
-
+
-
+
+
-
-
-
+
+
-
+
-
-
-
+
Group = Gr1 Group = Gr2
0
0.1
0.2
0.3
0.4
IFNgIL-2
TNFa(Pies)(Bar#)
+++
++-
+-+
+--
-++
5
-+-
--+
---
Excluded values: stimulation = SEB; stimulation = NEGAveraged over: patients ID; stimulationThreshold = 0
Group = Gr1Group = Gr2
Group = Gr1 Group = Gr2
0
0.1
0.2
0.3
0.4
IFNgIL-2
TNFa(Pies)(Bar#)
+++
++-
+-+
+--
-++
5
-+-
--+
---
Excluded values: stimulation = SEB; stimulation = NEGAveraged over: patients ID; stimulationThreshold = 0
Group = Gr1Group = Gr2
0
0.1
0.2
0.3
0.4
IFNg
IL-2
TNFa
+
+
+
+
+
-
+
-
+
+
-
-
-
+
+
-
+
-
-
-
+
Gr#1
Gr#2
Gr#1
Gr#2
Gr#1 Gr#2 Gr#1 Gr#2
Fre
qu
en
cy o
f C
D4
T-ce
lls
Fre
qu
en
cy o
f C
D8
T-ce
lls
CD4 T-cell responses CD8 T-cell responses
Functional Profile of HIV-Specific T-Cell Responses
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Number of Pools Recognized
P=0.02
0
2
4
6
8
Nu
mb
er
of
resp
on
ses
pe
r su
bje
ct
CD4 T c
ells
CD8 T c
ells
CD4 T c
ells
CD8 T c
ells
Gr1
N=14
Gr2
N=11
Median
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Distribution of HIV Regions Targeted By CD4 T-Cell Responses
ENV n o n -EN V
0
5
10
15
20
25
30
Gr#1
N=44 responses
Gr#2
N=28 responses
GAG
POL
NEF
ENV
Nu
mb
er
of
res
po
ns
es
ENV Gag, Pol or Nef
P=0.06
Gr#1
Gr#2
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Distribution of HIV Regions Targeted By CD8 T-Cell Responses
ENV n o n -EN V
0
2
4
6
8
10
12
14
Gr#1
N=22 responses
Gr#2
N=8 responses
Nu
mb
er
of
res
po
ns
es
ENV Gag, Pol or Nef
P=0.01
GAG
POL
NEF
ENV
Gr#1
Gr#2
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Total Magnitude of T-Cell Responses (Sum of Responding Pools)
CD4 T c
ells
CD8 T c
ells
CD4 T c
ells
CD8 T c
ells
0.0
0.5
1.0
1.5
2.0
Per
cen
tag
e o
f T-
cells
Gr1
N=14
Gr2
N=11
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
EV03/ANRS VAC20: NYVAC- and HIV-Specific CD4 and CD8 T-Cell Responses in the Gut
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
0.87
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
11.9
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
6.42
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
0.52
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
10.1
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
1.13
unstimulated NYVAC HIV
Blood
Gut
Gated on CD3+CD4+
CFSE
CD
4
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
0.34
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
24
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
10.6
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
0.5
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
4.85
0 10 2 10 3 10 4 10 5
0
10 3
10 4
10 5
0.57
Gated on CD3+CD8+
unstimulated NYVAC HIV
Blood
Gut
CFSE
CD
8
38
What Is Next?
Potential vaccine commbinations (with novel env protein
candidates) Poxvirus-based vaccine combinations
- NYVAC (2X or 4X) plus gp120/140 (2X or multiple)- DNA (3X) plus NYVAC (1X) plus gp120/140 (2X or multiple)- ALVAC (4X) plus gp120/140 (2X or multiple)
Adenovirus-based vaccine combinations- Ad26 (1X) plus Ad35 (1X) plus gp120/140 (2X or multiple)- Ad26 (2X) plus MVA (1X) plus gp120/140 (2X or multiple)
TVDC
Current and Future Poxvirus Vectors Portfolio
571 passages
In CEF cells
Deletion of 18
ORFs
200 passages
in CEF cells
Vaccinia Virus
Ankara (MVA)
Vaccinia Virus
Copenhagen
Canarypox
virus
MVA NYVACALVAC
Gene deletion
Combined NYVAC
Rc Plus
Gene deletion
NYVAC
Attenuated
Rc NYVAC KC
Reinsertion of
K1L & C7L
Gene deletion
mutants
40
Conclusions
T-cell vaccines remain an important component of the overall HIV vaccine strategy
They serve as the priming component in combination regimens with env proteins
It is conceivable that improved T-cell vaccines may substantially impact the magnitude, quality and durability of the antibody response induced by env protein vaccines
The Step and RV-144 efficacy trials have indicated that the current NHPs challenge model is not suitable for the prediction of the clinical efficacy of vaccine candidates in humans
The evaluation of improved vaccine combinations in efficacy clinical trials is the only strategy for the correct evaluation of the vaccine effectiveness
AcknowledgementsVaccine Immunotherapy CentreDiv. of Immunology and Allergy CHUV – Lausanne, Switzerland Pierre-Alexandre Bart Erika Castro David Bonnet
Kim Ellefsen-Lavoie Alexandre Harari
St. Mary Hospital,Imperial College London, UK Jonathan Weber Rebecca Chandler Lucy Garvey Ken Legg Ngaire Latch
University of Regensburg, Germany Bernd Salzberger Ralf Wagner Hans Wolf Birgit Fritsch Falitsa Mandraka Gabriele Birkenfeld Caspar Franzen Josef Köstler
ANRS Jean-Francois
Delfraissy Yves Levy Anne de Saunière Véronique Rieux
EuroVacc Foundation Song Ding
Sanofi Pasteur, France Jim Tartaglia Claude Meric
Collaboration for AIDSVaccine Discovery (CAVD) Nina Russell Jose Esparza
European Commission
EuroVacc Foundation
ANRS
CAVD
&
All Study Volunteers
Cochin, Paris, France
Odile Launay
Pierre Loulergue
Yvette Henin
Henri Mondor, Paris,
France
Yves Lévy
Jean-Daniel Lelièvre
Christine Lacabaratz
Tenon, France
Gilles Pialoux
Marseille, France
Isabelle Poizot-Martin
Catherine Farnarier
Toulouse, France
Lise Cuzin
Florence Nicot
INSERM CTU U897, France
Genevieve Chene
Philippe Reboud
Inga Tschöpe
Carine Grondin
Valérie Boilet
MRC CTU, London, UK
Sheena McCormack
Abdel Babiker
Wolfgang Stöhr
Liz Brodnicki
Patrick Kelleher
Mary Rauchenberger
Shabana Khan
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Proportion of Responders at Week 26/28 per Peptide Group
ITT Analysis 3 x DNAn = 70
2 x DNAn = 70
Total n = 140
Env 63/70 (90%) 54/69 (78%) 117/139 (84%)
Gag/Pol/Nef 27/70 (39%) 17/70 (24%) 44/140 (31%)
PP Analysis 3 x DNAn = 67
2 x DNAn = 68
Total n = 135
Env 62/67 (93%) 53/67 (79%) 115/134 (86%)
Gag/Pol/Nef 26/67 (39%) 17/68 (25%) 43/135 (32%)
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Primary Immunogenicity Endpoints ITT Analysis 3 x DNA
n = 702 x DNAn = 69
Total n = 139
Response 26 (37%) 15 (22%) 41 (30%)
PP Analysis 3 x DNAn = 67
2 x DNAn = 67
Total n = 134
Response 25 (37%) 15 (22%) 40 (30%)
Chi2 Test: p = 0.047; Risk difference: 15.4% (95% CI 0.5 – 30.3%)
Risk atio: 1.7 (95% CI 1.0 – 2.9)
Chi2 Test: p = 0.059; Risk difference: 14.9% (95% CI -0.3 – 30.2%)
Risk ratio: 1.7 (95% CI 1.0 – 2.9)
TVDCPoxvirus T Cell Vaccine Discovery
Consortium
Magnitude of IFN-g ELISpot Responses at Week 26/28 by Peptide Group (median (IQR) SFUs/106 cells)
Week 26 Week 28
ITT analysis3 x DNA
n=212 x DNA
n=133 x DNA
n=212 x DNA
n=13
Gag/Pol/Nef180 (120-331) 109 (85-174) 145 (83-229) 113 (83-218)
p=0.12 P=0.82
Week 26 Week 28
ITT analysis3 x DNA
n=582 x DNA
n=483 x DNA
n=592 x DNA
n=54
Env 539 (315-1013) 294 (182-496) 442 (170-833) 217 (123-488)
p<0.001 p=0.003
Challenges in HIV Vaccine Development
30 commercially available effective vaccines 16 vaccine derived from live replcation
competent attenuated pathogens 12 vaccine derived from pathogen
modifications Only 2 vaccines, HPV and HBV derived from
synthetic products