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T-cell HIV Vaccines. Giuseppe Pantaleo, M.D. Professor of Medicine Director, Swiss Vaccine Research Institute Lausanne, Switzerland. Challenges In The Development Of An HIV Vaccine. Identification of immune correlates of protection Induction of a broad neutralizing antibody response

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t cell hiv vaccines

T-cell HIV Vaccines

Giuseppe Pantaleo, M.D.

Professor of Medicine

Director, Swiss Vaccine Research Institute

Lausanne, Switzerland

slide2

Challenges In The DevelopmentOf 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
Vaccine Concepts and Designs
  • Live Vectors
  • DNA
  • Combination of Elements
  • Peptide Epitopes (limitedimmunogenicity)
  • Pseudovirions (pre-clinical)
  • Live-Attenuated (Not Under Study in Humans)
  • Whole-Killed (Not Under Study in Humans)
  • Recombinant Viral Proteins
slide4

Due to the Lack of Protein-BasedEnv Vaccines Able To InduceNeutralizingAntibodies, Candidate HIV Vaccines Have Been DesignedPrimarily to Induce T-Cell Immune Responses

slide5

T-cell HIV Vaccines Concept

T-cell Vaccines Do Not Prevent Infection But They Will Be EventuallyAssociatedwith Control of Virus Replication and Prevention of HIV-AssociatedDisease

slide6

Vaccine

 

T-Cell HIV Vaccine Concept

Virus

exposure

Placebo

Help CTL

Virus

----

slide7

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-cellresponses 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
effective immunity induced by rad5 hiv siv vaccine in a siv challenge model
Effective immunity induced by rAd5 HIV (SIV) vaccine in a SIV challenge model

Low responder

High responder

slide9

Interpretation This cell-mediated immunity vaccine did not prevent HIV-1 infection orreduce 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.

slide12

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
Messages from the StepStudy
  • The Stepstudy marks the end of the HIV T-cell vaccine concept (at least of the Ad5 vectorusedalone)
  • It draws the attention on the potential danger of pre-existingimmunity
  • It shows a potentialsinergybetween Ad5 pre-existingimmunity and circumcisionwith regard to the observedincreased in HIV acquisition
  • It indicatesthat the magnitude and the quality (breadth) of the vaccine-induced T-cellresponses (particularly CD8 T-cellresponses) are not optimal
slide14

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
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
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 issues1
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

improvement of the current vaccine combination
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)

what is next1
What Is Next?

Vaccine candidates

Poxvirus-based vectors

- NYVAC

- MVA

- ALVAC

Adenovirus

- Ad26

- Ad35

DNA vectors

Protein

- gp140 monomer or trimer

dna c nyvac c platform harari et al jem 2008 bart et al vaccine 2008 mccormack vaccine 2008

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

clinical trial design
Clinical Trial Design

0

4

8

20

24

28

48

72

Weeks

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

  • 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
proportion of responders at primary endpoints week 26 28
Proportion of Responders at Primary Endpoints (Week 26/28)

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%)

magnitude of ifn g elispot responses at week 26 28 overall sfus 10 6 cells
Magnitude of IFN-g ELISpot Responses at Week 26/28 Overall (SFUs/106 cells)

Note: Sum of SFU/Mio cells from all peptide pools with a positive response per participant

magnitude of ifn g elispot responses at week 26 28 itt
Magnitude of IFN-g ELISpot Responses at Week 26/28 (ITT)

Note: Magnitude statistically different between groups for Env at both weeks but not for Gag/Pol/Nef (Other)

SFUs/Mio cells

2200

3 x DNA

2 x DNA

2000

1800

1600

1400

1200

1000

800

600

400

200

0

ENV

Other

ENV

Other

ENV

Other

ENV

Other

Week 26

Week 28

Week 26

Week 28

30

functional profile of hiv specific t cell responses

2.39e-3

2.99e-3

0.013

0.033

5

5

10

10

4

4

10

10

3

3

10

10

2

10

2

10

0

0

100

100

1.79e-3

1.2e-3

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

<APC-A>

<APC-A>

0.013

0.036

0

8.5e-3

5

5

10

10

4

4

10

10

3

3

10

10

2

2

10

10

0.04

0.11

0.069

0.13

0

5

5

10

10

0.067

0.027

0.016

2.66e-3

0

5

5

10

10

100

0

100

8.5e-3

4

4

10

10

2

3

4

5

4

2

3

4

5

0

10

10

10

10

4

10

10

0

10

10

10

10

3

3

10

10

3

3

10

10

2

10

2

10

0.031

0.017

0.05

0.019

2

2

5

5

10

10

10

10

0

0

0

99.8

0.032

99.8

7.13e-3

0

4

4

99.9

3.54e-3

10

100

0.017

10

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

3

3

10

10

2

10

2

10

0

0

99.9

3.71e-3

99.9

1.65e-3

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

0.22

0.093

0.077

0.019

5

5

10

10

4

4

10

10

3

3

10

10

2

2

10

10

0

0

99.7

4.18e-3

99.8

0.12

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

Functional Profile of HIV-Specific T-Cell Responses

CD4 T-cell responses

CD8 T-cell responses

Subject#1042

Gr#1

TNF-α

TNF-α

IL-2

IL-2

Neg

Env 1

Env 2

IFN-

IFN-

functional profile of hiv specific t cell responses1

0.4

0.3

0.2

0.1

0

IFNg

+

+

+

+

-

-

-

IL-2

+

+

-

-

+

+

-

TNFa

+

-

+

-

+

-

+

Functional Profile of HIV-Specific T-Cell Responses

CD4 T-cell responses

CD8 T-cell responses

Gr#1

Gr#2

Gr#1

Gr#2

Gr#1

Gr#1

0.4

Gr#2

Gr#2

0.3

0.2

Frequency of CD4 T-cells

Frequency of CD8 T-cells

0.1

0

IFNg

+

+

+

+

-

-

-

IL-2

+

+

-

-

+

+

-

TNFa

+

-

+

-

+

-

+

number of pools recognized

8

6

Number of responses per subject

4

2

0

Number of Pools Recognized

P=0.02

Median

CD4 T cells

CD8 T cells

CD4 T cells

CD8 T cells

Gr1

N=14

Gr2

N=11

distribution of hiv regions targeted by cd4 t cell responses

GAG

POL

NEF

ENV

Distribution of HIV Regions Targeted By CD4 T-Cell Responses

P=0.06

Gr#1

N=44 responses

Gr#2

N=28 responses

Number of responses

Gr#1

Gr#2

Gag, Pol or Nef

ENV

distribution of hiv regions targeted by cd8 t cell responses

GAG

POL

NEF

ENV

Distribution of HIV Regions Targeted By CD8 T-Cell Responses

P=0.01

Gr#1

N=22 responses

Gr#2

N=8 responses

Number of responses

Gr#1

Gr#2

ENV

Gag, Pol or Nef

total magnitude of t cell responses sum of responding pools

2.0

1.5

Percentage of T-cells

1.0

0.5

0.0

CD4 T cells

CD8 T cells

CD4 T cells

CD8 T cells

Total Magnitude of T-Cell Responses (Sum of Responding Pools)

Gr1

N=14

Gr2

N=11

ev03 anrs vac20 nyvac and hiv specific cd4 and cd8 t cell responses in the gut

5

5

5

10

10

10

4

4

4

10

10

10

0.52

1.13

10.1

3

3

3

10

10

10

0

0

0

2

3

4

5

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

0

10

10

10

10

5

5

5

10

10

10

4

4

4

10

10

10

11.9

0.87

6.42

3

3

3

10

10

10

0

0

0

2

3

4

5

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

0

10

10

10

10

5

5

5

10

10

10

4

0.57

4

4

10

10

10

0.5

4.85

3

3

3

10

10

10

0

0

0

2

3

4

5

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

0

10

10

10

10

5

5

5

10

10

10

4

4

4

10

10

10

0.34

10.6

24

3

3

3

10

10

10

0

0

0

2

3

4

5

2

3

4

5

2

3

4

5

0

10

10

10

10

0

10

10

10

10

0

10

10

10

10

EV03/ANRS VAC20: NYVAC- and HIV-Specific CD4 and CD8 T-Cell Responses in the Gut

Gated on CD3+CD4+

Gated on CD3+CD8+

unstimulated

NYVAC

HIV

unstimulated

NYVAC

HIV

Blood

Blood

Gut

Gut

CD4

CD8

CFSE

CFSE

what is next2
What Is Next?

Potential vaccine commbinations (withnovelenvprotein 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)

current and future poxvirus vectors portfolio
Current and Future Poxvirus Vectors Portfolio

Vaccinia Virus

Ankara (MVA)

Canarypox

virus

Vaccinia Virus

Copenhagen

NYVAC

200 passages

in CEF cells

Deletion of 18

ORFs

Reinsertion of

K1L & C7L

Gene deletion

571 passages

In CEF cells

MVA

ALVAC

NYVAC

Attenuated

Rc NYVAC KC

Gene deletion

mutants

Combined NYVAC

Rc Plus

Gene deletion

conclusions
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

acknowledgements
Acknowledgements

Vaccine Immunotherapy Centre

Div. 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

FalitsaMandraka

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 AIDS

Vaccine Discovery

(CAVD)

Nina Russell

Jose Esparza

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

European Commission

EuroVacc Foundation

ANRS

CAVD

&

All Study Volunteers

primary immunogenicity endpoints
Primary Immunogenicity Endpoints

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)

magnitude of ifn g elispot responses at week 26 28 by peptide group median iqr sfus 10 6 cells
Magnitude of IFN-g ELISpot Responses at Week 26/28 by Peptide Group (median (IQR) SFUs/106 cells)
challenges in hiv vaccine development
Challenges in HIV Vaccine Development
  • 30 commerciallyavailable effective vaccines
  • 16 vaccine derivedfrom live replcationcompetentattenuatedpathogens
  • 12 vaccine derivedfrompathogen modifications
  • Only 2 vaccines, HPV and HBV derivedfromsyntheticproducts